US20230030119A1 - Rna interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (ctnnb1) gene expression using short interfering nucleic acid (sina) - Google Patents

Rna interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (ctnnb1) gene expression using short interfering nucleic acid (sina) Download PDF

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US20230030119A1
US20230030119A1 US17/219,974 US202117219974A US2023030119A1 US 20230030119 A1 US20230030119 A1 US 20230030119A1 US 202117219974 A US202117219974 A US 202117219974A US 2023030119 A1 US2023030119 A1 US 2023030119A1
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sina
nucleic acid
nucleotides
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Duncan Brown
James J. Cunningham
Marian Gindy
Victoria Pickering
Matthew G. Stanton
Steven M. Stirdivant
Walter R. Strapps
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Sirna Therapeutics Inc
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Definitions

  • sequence listing submitted via EFS in compliance with 37 CFR ⁇ 1.52(e)(5), is incorporated herein by reference.
  • the sequence listing text file submitted via EFS contains the File “SequenceListingSIRONC2”, created on Jul. 25, 2011 which is 2,173,912 bytes in size.
  • Beta catenin (also known as cadherin-associated protein and ⁇ -catenin), is a member of the catenin family of cytosolic proteins. ⁇ -catenin is encoded by the CTNNB1 gene.
  • ⁇ -catenin is a pivotal player in the Wnt/Wg signaling pathway, mediators of several developmental processes.
  • GSK-3 ⁇ glycogen synthase kinase 3
  • Dsh an intracellular signaling protein known as dishevelled (Dsh)
  • GSK-3 ⁇ is inhibited by the activation of Dsh.
  • ⁇ -catenin levels increase in the cytosol and are translocated into the nucleus to perform a variety of functions.
  • ⁇ -catenin acts together with the transcription factors TCF and LEF to activate specific target genes involved in different processes.
  • ⁇ -catenin undergoes phosphorylation upon growth factor stimulation resulting in reduced cell adhesion, thereby functioning as a component of adherin junctions which are multiprotein complexes that mediate cell adhesion, cell-cell communication and cytoskeletal anchoring.
  • liver development both embryonic and postnatal
  • liver regeneration following partial hepatectomy
  • HGF hepatocyte growth factor
  • ⁇ -catenin The role of ⁇ -catenin in the development of colorectal cancer has been shown to be regulated by the expression product of the APC (adenomatous polyposis of the colon) gene, a tumor suppressor.
  • APC adenomatous polyposis of the colon
  • the APC protein normally binds ⁇ -catenin in conjunction with TCF/LEF forming a transcription factor complex.
  • Morin el al. (Morin et al., Science, 1997, 275:1787-1790) report that APC protein down-regulates the transcriptional activation mediated by ⁇ -catenin and Tcf-4 in colon cancer.
  • Mutations in the ⁇ -catenin gene are either truncations that lead to deletion of part of the N-terminus of ⁇ -catenin, or point mutations that affect the serine and threonine residues that are targeted by GSK3 ⁇ / ⁇ or CKI ⁇ , These mutant ⁇ -catenin proteins are refractory to phosphorylation and thus escape proteasomal degradations. Consequently, ⁇ -catenin accumulates within affected cells. Stabilized and nuclear-localized ⁇ -catenin is a hallmark of nearly all cases of colon cancer. (Clevers, H., 2006 , Cell 127:469-480). Morin et al.
  • HCC hepatocellular carcinoma
  • Wnt/beta-catenin pathway a complex and heterogeneous disease accounting for more than 660,000 new cases per year worldwide.
  • Multiple reports have shown that Wnt signaling components are activated in human HCC patients.
  • Ativated Wnt signaling and nuclear beta-catenin correlate with recurrence of disease and poor prognosis (Takigawa et al. 2008 , Curr Drug Targets November; 901):1013-24). Elevated nuclear beta-catenin staining has been documented in 17-66% of HCC patients (Zulehner et al. 2010 , Am J Pathol .
  • Beta-catenin siRNAs inhibit proliferation and viability of human HCC cell lines (Zeng et al. 2007).
  • treatment of human HCC cell lines with an anti-Wnt-1 antibody or TCF4/beta-catenin antagonists induce apoptosis, reduction of c-Myc, cyclin D1 and survivin expression as well as suppress tumor growth in vivo (Wei et al. 2009 , Mol Cancer September 24; 8:76; Wei el al. 2010 , Int J Cancer . May 15; 126(10):2426-36.2010).
  • Hepatocellular carcinoma is a common and aggressive cancer for which effective therapies are lacking.
  • the Wnt/beta-catenin pathway is activated in a high proportion of HCC cases ( ⁇ 50%), frequently owing to mutations in beta-catenin (i.e. CTNNB1) or in the beta-catenin destruction complex (e.g. Axin1).
  • CTNNB1 beta-catenin
  • Axin1 beta-catenin destruction complex
  • the Writ pathway as a target has proven to be challenging and is currently undruggable by small molecule inhibitors, making beta-catenin an attractive target for an RNAi-based therapeutic approach (Llovet et al. 2008 , Hepatology October: 48: 1312-1327).
  • RNAi RNA interference
  • siNA short interfering nucleic acids
  • siRNA short interfering RNA
  • siRNA inhibitors silence the expression of messenger RNAs (“mRNAs”) that share sequence homology to the siNA. This can occur via cleavage of the mRNA mediated by an endonuclease complex containing a siNA, commonly referred to as an RNA-induced silencing complex (RISC).
  • RISC RNA-induced silencing complex
  • RNA interference can also involve small RNA (e.g., micro-RNA or miRNA) mediated gene silencing, presumably through cellular mechanisms that either inhibit translation or that regulate chromatin structure and thereby prevent transcription of target gene sequences (see for example Allshire, 2002 , Science, 297:1818-1819; Volpe et al., 2002 , Science, 297:1833-1837: Jenuwein, 2002 , Science, 297:2215-2218: and Hall et al., 2002 , Science, 297:2232-2237).
  • the invention provides a solution to the problem of treating diseases that respond to the modulation of the CTNNB1 gene expression using novel short interfering nucleic acid (siNA) molecules to modulate CTNNB1 expression.
  • siNA short interfering nucleic acid
  • the present invention provides compounds, compositions, and methods useful for modulating the expression of CTNNB1 genes, specifically those CTNNB1 genes associated with cancer and for treating such conditions by RNA interference (RNAi) using small nucleic acid molecules.
  • RNAi RNA interference
  • the instant invention features small nucleic acid molecules, i.e., short interfering nucleic acid (siNA) molecules including, but not limited to, short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA) and circular RNA molecules and methods used to modulate the expression of CTNNB1 genes and/or other genes involved in pathways of CTNNB1 gene expression and/or activity.
  • siNA short interfering nucleic acid
  • the invention provides double-stranded short interfering nucleic acid (siNA) molecules that inhibit the expression of a CTNNB1 gene in a cell or mammal, wherein the double-stranded siNAs comprise a sense and an antisense stand.
  • the antisense strand comprises a sequence that is complementary to at least a part of an RNA associated with the expression of the CTNNB1 gene.
  • the sense strand comprises a sequence that is complementary to the antisense strand.
  • at least one strand comprises at least a 15 nucleotide sequence selected from the group of sequences consisting of SEQ ID NOS:1-6374.
  • the antisense strand comprises at least 15, 16, 17, 18, or 19 nucleotides having sequence complementarity to a target sequence set forth in Table 1a. In other and/or in the same embodiments, the antisense strand comprises at least a 15, 16, 17, 18, or 19 nucleotide sequence of one of the antisense sequences set forth in Table 1b. In some embodiments, the sense strand comprises at least a 15, 16, 17, 18, or 19 nucleotide sequence of a sense strand sequence as set forth in Table 1b.
  • double-stranded short interfering nucleic acid (siNA) molecules wherein the antisense stand comprises a modified sequence as set forth in Table 1c that has sequence complementarity to a target sequence of the invention.
  • the sense strand also comprises a modified sequence as set for in Table 1c.
  • the present invention provides a double-stranded short interfering nucleic acid (siNA) molecule that modulates the expression of CTNNB1, wherein the siNA comprises a sense strand and an antisense strand; each strand is independently 15 to 30 nucleotides in length; and the antisense strand comprises at least 15, 16, 17, 18, or 19 nucleotides having sequence complementary to any of:
  • siNA short interfering nucleic acid
  • the antisense strand of a siNA molecule comprises at least a 15, 16, 17, 18, or 19 nucleotide sequence of
  • the sense strand of a siNA molecule of the invention comprises at least a 15, 16, 17, 18, or 19 nucleotide sequence of:
  • a siNA molecule of the invention comprises any of:
  • a siNA molecule of the invention comprises SEQ ID NOS: 6372 and 6374.
  • a siNA molecule of the invention comprises SEQ ID NOS: 6370 and 6369.
  • a siNA molecule of the invention comprises SEQ ID NOS: 2021 and 2068.
  • a siNA molecule of the invention comprises SEQ ID NOS: 6372 and 6373.
  • a siNA molecule of the invention comprises SEQ ID NOS: 2147 and 6368
  • the invention features a composition comprising:
  • the invention features a composition comprising:
  • siNA double-stranded short interfering nucleic acid
  • the invention features a composition comprising:
  • she invention features a composition comprising:
  • the invention features a composition comprising:
  • the invention features a composition comprising:
  • the invention features a composition comprising:
  • composition of the invention comprises any Cationic Lipid having any of compound numbers 1-46 in the following molar ratios:
  • a composition of the invention comprises (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine, cholesterol, DSPC, and PEG-DMG, having a molar ratio of 50:30:10:2 respectively.
  • a composition of the invention further comprises a cryo-protectant.
  • the cryoprotectant is Sucrose, Trehalose, Raffinose, Stachyose, Verbascose, Mannitol, Glucose, Lactose, Maltose, Maltotriose-heptose, Dextran, hydroxyethyl Starch, Insulin, Sorbitol, Glycerol, Arginine, Histidine, Lysine, Praline, Dimethylsulfoxide or any combination thereof.
  • the cryoprotectant is Sucrose.
  • the cryoprotectant is Trehalose.
  • the cryoprotectant is a combination of Sucrose and Trehalose.
  • nucleotides of siNAs of the invention are unmodified.
  • one or more (e.g., 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of the nucleotide positions independently in either one or both strands of an siNA molecule are modified.
  • Modifications include nucleic acid sugar modifications, base modifications, backbone (internucleotide linkage) modifications, non-nucleotide modifications, and/or any combination thereof.
  • purine and pyrimidine nucleotides are differentially modified.
  • purine and pyrimidine nucleotides can be differentially modified at the 2′-sugar position (i.e., at least one purine has a different modification from at least one pyrimidine in the same or different strand at the 2′-sugar position).
  • the purines are unmodified in one or both strands, while the pyrimidines in one or both strands are modified.
  • the pyrimidines are unmodified in one or both strands, while the purines in one or both strands are modified.
  • At least one modified nucleotide is a 2′-deoxy-2′-fluoro nucleotide, a 2′-deoxy nucleotide, or a 2′-O-alkyl nucleotide.
  • at least 5 or more of the pyrimidine nucleotides in one or both stands are either all 2′-deoxy-2′-fluoro or all 2′-O-methyl pyrimidine nucleotides.
  • at least 5 or more of the purine nucleotides in one or both stands are either all 2′-deoxy-2′-fluoro or all 2′-O-methyl purine nucleotides.
  • the siNA molecules comprise one or more modifications as described herein, the nucleotides at positions 1, 2, and 3 at the 5′ end of the guide (antisense) strand are unmodified.
  • the siNA molecules of the invention have 3′ overhangs of one, two, three, or tour nucleotide(s) on one or bath of the strands.
  • the siNA molecules lack overhangs (i.e., have blunt ends).
  • the siNA molecule has 3′ overhangs of two nucleotides on both the sense and antisense strands. The overhangs can be modified or unmodified.
  • modified nucleotides in the overhangs include, but are not limited to, 2′-O-alkyl nucleotides, 2′-deoxy-2′-fluoro nucleotides, locked nucleic acid (LNA) nucleotides, or 2′-deoxy nucleotides.
  • the overhang nucleotides in the antisense strand can comprise nucleotides that are complementary to nucleotides in the CTNNB1 target sequence.
  • the overhangs in the sense stand can comprise nucleotides that are in the CTNNB1 target sequence.
  • the siNA molecules of the invention have two 3′ overhang nucleotides on the antisense stand that are 2′-O-alkyl (e.g., 2′-O-methyl) nucleotides and two 3′ overhang nucleotides on the sense stand that are 2′-deoxy nucleotides. In other instances, the siNA molecules of the invention have two 3′ overhang nucleotides that are 2′-O-alkyl 2′-O-methyl) nucleotides on both the antisense stand and on the sense stand. In certain embodiments, the 2′-O-alkyl nucleotides are 2′-O-methyl uridine nucleotides. In certain instances, the overhangs also comprise one or more phosphorothioate linkages between nucleotides of the overhang.
  • the overhangs also comprise one or more phosphorothioate linkages between nucleotides of the overhang.
  • the siNA molecules of the invention have caps (also referred to herein as “terminal caps.”
  • the cap can be present at the 5′-terminus (5′-cap) or at the 3′-terminus (3′-cap) or can be present on both termini, such as at the 5′ and 3′ termini of the sense strand of the siNA.
  • the siNA molecules of the invention are phosphorylated at the 5′ end of the antisense strand.
  • the phosphate group can be a phosphate, a diphosphate or a triphosphate.
  • siNA molecules of the invention when double stranded can be symmetric or asymmetric.
  • Each strand of these double stranded siNAs independently can range in nucleotide length between 3 and 30 nucleotides.
  • each strand of the siNA molecules of the invention is about 15 to 30 (i.e., about 19, 20, 21, 22, 23 or 24) nucleotides in length.
  • the siNA molecules of the invention which are double stranded or have a duplex structure, independently comprise about 3 to about 30 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) base pairs.
  • the duplex structure of siNAs of the invention is between 15 and 30, more generally between 18 and 25, yet more generally between 19 and 24, and most generally between 19 and 21 base pairs in length.
  • double-stranded short interfering nucleic acid (siNA) molecules wherein the molecule has a sense strand and an antisense strand and comprises formula (A):
  • the invention features a double-stranded short interfering nucleic acid (siNA) of formula (A); wherein
  • compositions comprising the double-stranded nucleic acid molecules described herein with optionally a pharmaceutically acceptable carrier or diluent.
  • composition can be carried out by known methods, wherein the nucleic acid is introduced into a desired target cell in vitro or in vivo.
  • Non-limiting examples of such carrier systems suitable for use in the present invention include conjugates, nucleic-acid-lipid particles, lipid nanoparticles (LNP), liposomes, lipoplexes, micelles, virosomes, virus like particles (VLP), nucleic acid complexes, and mixtures thereof.
  • LNP lipid nanoparticles
  • VLP virus like particles
  • compositions of the invention can be in the form of an aerosol, dispersion, solution (e.g., an injectable solution), a cream, ointment, tablet, powder, suspension or the like. These compositions may be administered in any suitable way, e.g. orally, sublingually, buccally, parenterally, nasally, or topically. In some embodiments, the compositions are aerosolized and delivered via inhalation.
  • the molecules and compositions of the present invention have utility over a broad range of therapeutic applications. Accordingly another aspect of this invention relates to the use of the compounds and compositions of the invention in treating a subject.
  • the invention thus provides a method for treating a subject, such as a human, suffering from a condition which is mediated by the action, or by the loss of action, of CTNNB1, wherein the method comprises administering to the subject an effective amount of a double-stranded short interfering nucleic acid (siNA) molecule of the invention.
  • the condition is cancer.
  • FIG. 1 shows a non-limiting proposed mechanistic representation of target RNA degradation involved in RNAi, Double-stranded RNA (dsRNA), which is generated by RNA-dependent.
  • dsRNA Double-stranded RNA
  • RdRP RNA polymerase
  • DICER DICER enzyme
  • siNA duplexes RNA polymerase
  • synthetic or expressed siNA can be introduced directly into a cell by appropriate means.
  • An active siNA complex forms that recognizes a target RNA, resulting in degradation of the target RNA by the RISC endonuclease complex or in the synthesis of additional RNA by RNA-dependent RNA polymerase (RdRP), which can activate DICER and result in additional siNA molecules, thereby amplifying the RNAi response,
  • RdRP RNA-dependent RNA polymerase
  • FIG. 2 shows non-limiting examples of chemically modified siNA constructs of the present invention using a generalized structure of a representative siNA duplex.
  • the specific modifications shown in the figure can be utilized alone or in combination with other modifications of the figure, in addition to other modifications and features described herein with reference to any siNA molecule of the invention.
  • N stands for any nucleotide or optionally a non-nucleotide as described here.
  • the upper strand, having B—N X3 —(N) X2 —B-3′ is the sense (or passenger) strand of the siNA
  • the lower strand, having B(N) X1 —N X4 —[N] X5 -5′ is the antisense (or guide) strand of the siNA.
  • Nucleotides (or optional non-nucleotides) of internal portions of the sense strand are designated N X3 and nucleotides (or optional non-nucleotides) of internal portions of the antisense strand are designated N X4 .
  • Nucleotides (or optional non-nucleotides) of the internal portions are generally base paired between the two strands, but can optionally lack base pairing (e.g. have mismatches or gaps) in some embodiments.
  • Nucleotides (or optional non-nucleotides) of overhang regions are designated by parenthesis (N).
  • Nucleotides of the 5′-terminal portion of the antisense strand are designated [N]. Terminal caps are optionally present at the 5′ and/or 3′ end of the sense strand and further optionally present at the 3′-end of the antisense strand.
  • each strand can independently range from about 15 to about 30 nucleotides in length, but can vary depending on the presence of any overhang nucleotides.
  • X1 and X2 are independently integers front 0 to 4; X3 is an integer from 15 to 30; X4 is an integer from 9 to 30; X5 is an integer from 0 to 6, provided that the sum of X4 and X5 is 15-30.
  • Various modifications are shown for the nucleotides of the sense and antisense strands of the siNA constructs.
  • the (N) overhang nucleotide positions can be chemically modified as described herein (e.g., 2′-O-methyl, 2′-deoxy-2′-fluoro, 2′-deoxy, UNA, universal bases etc.) and can be either derived from a corresponding target nucleic acid sequence or not.
  • the constructs shown in the figure can also comprise phosphorothioate linkages as described herein.
  • phosphorothioate linkages can exist between any N, (N), and/or [N] positions.
  • Such phosphorothioate incorporation can be utilized between purine “R” and pyrimidine “Y” positions, or for stabilization of pyrimidine linkages in general.
  • the constructs shown in the figure can optionally include a ribonucleotide at the 9 th position from the 5′-end of the sense strand or the 11 th position based on the 5′-end of the guide strand by counting 11 nucleotide positions in from the 5′-terminus of the guide strand.
  • the antisense strand can include a ribonucleotide at the 14 th position from the 5′-end, or alternately can be selected or designed so that a 2′-O-alkyl nucleotide (e.g., a 2′-O-methyl purine) is not present at this position.
  • the 5′-terminal position of the antisense strand can comprise a terminal phosphate group as described herein.
  • the antisense strand generally comprises sequence complementary to any target nucleic acid sequence of the invention, such as those set forth in Table 1a herein.
  • FIG. 3 shows non-limiting examples of certain combinations of modifications applied to the representative siNA, duplex described in FIG. 2 .
  • the table shown below the representative structure provides specific combinations of (N) X1 , (N) X2 , N X3 , N X4 , and/or [N] X5 nucleotide (and optional non-nucleotide) positions.
  • N X3 and 5 or more (e.g., 5, 6, 7, 8, 9, or 10 or more) N X4 pyrimidine “Y” and purine “R” nucleotides are specified, each of which can independently have specific (N) X1 , and/or (N) X2 , substitutions as shown in the figure, in addition to optional phosphorothioate substitutions.
  • the 5′-terminal antisense strand [N] nucleotides are generally ribonucleotides, but can also be modified or unmodified depending on if they are purine “R” or pyrimidine “Y” nucleotides
  • FIG. 4 A-C shows non-limiting examples of different siNA constructs of the invention.
  • the criteria of the representative structures shown in FIGS. 2 and 3 can be applied to any of the structures shown in FIG. 4 A-C .
  • constructs 1, 2, and 3 have 19 representative base pairs; however, different embodiments of the invention include any number of base pairs described herein. Bracketed regions represent nucleotide overhangs, for example, comprising about 1, 2, 3, or 4 nucleotides in length, preferably about 2 nucleotides.
  • Constructs 1 and 2 can be used independently for RNAi activity.
  • Construct 2 can comprise a polynucleotide or non-nucleotide linker, which can optionally be designed as a biodegradable linker.
  • the loop structure shown in construct 2 can comprise a biodegradable linker that results in the formation of construct 1 in vivo and/or in vitro.
  • construct 3 can be used to generate construct 2 under the same principle wherein a linker is used to generate the active siNA construct 2 in vivo and/or in vitro, which can optionally utilize another biodegradable linker to generate the active siNA construct 1 in vivo and/or in vitro.
  • a linker is used to generate the active siNA construct 2 in vivo and/or in vitro, which can optionally utilize another biodegradable linker to generate the active siNA construct 1 in vivo and/or in vitro.
  • the stability and/or activity of the siNA constructs can be modulated based on the design of the siNA construct for use in vivo or in vitro and/or in vitro.
  • FIG. 4 B represent different variations of double-stranded nucleic acid molecule of the invention, such as microRNA, that can include overhangs, bulges, loops, and stem-loops resulting from partial complementarity.
  • Such motifs having bulges, loops, and stem-loops are generally characteristics of miRNA.
  • the bulges, loops, and stem-loops can result from any degree of partial complementarily, such as mismatches or bulges of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more nucleotides in one or both strands of the double-stranded nucleic acid molecule of the invention.
  • the example shown in FIG. 4 C represents a model double-stranded nucleic acid molecule of the invention comprising a 19 base pair duplex of two 21 nucleotide sequences having dinucleotide 3′-overhangs.
  • the top strand (1) represents the sense strand (passenger strand)
  • the middle strand (2) represents the antisense (guide strand)
  • the lower strand (3) represents a target polynucleotide sequence.
  • the dinucleotide overhangs (NN) can comprise a sequence derived from the target polynucleotide.
  • the 3′-(NN) sequence in the guide strand can be complementary to the 5′-[NN] sequence of the target polynucleotide.
  • the 5′-(NN) sequence of the passenger strand can comprise the same sequence as the 5′-[NN] sequence of the target polynucleotide sequence.
  • the overhangs (NN) are not derived from the target polynucleotide sequence, for example where the 3′-(NN) sequence in the guide strand are not complementary to the 5′-[NN] sequence of the target polynucleotide and the 5′-(NN) sequence of the passenger strand can comprise different sequence from the 5′-[NN] sequence of the target polynucleotide sequence.
  • any (NN) nucleotides are chemically modified, e.g., as 2′-O-methyl, 2′-deoxy-2′-fluoro, and/or other modifications herein.
  • the passenger strand can comprise a ribonucleotide position N of the passenger strand.
  • position N can be 9 nucleotides in from the 3′ end of the passenger strand.
  • the position. N is determined based on the 5′-end of the guide strand by counting 11 nucleotide positions in from the 5′-terminus of the guide strand and picking the corresponding base paired nucleotide in the passenger strand.
  • Cleavage by Agog takes place between positions 10 and 11 as indicated by the arrow.
  • FIG. 5 shows non-limiting examples of different stabilization chemistries (1-10) that can be used, for example, to stabilize the 5′ and/or 3′-ends of siNA sequences of the invention, including (1) [3-3′]-inverted deoxyribose, (2) deoxyribonucleotide; (3) [5′-3′]-3′-deoxyribonucleotide; (4) [5′-3]-ribonucleotide; (5) [5′-3′]-3′-O-methyl ribonucleotide; (6) 3′-glyceryl; (7) [3′-5′]-3′-deoxyribonucleotide; (8) [3′-3′]-deoxyribonucleotide; (9) [5′-2′]-deoxyribonucleotide; and (10) [5′-3′]-dideoxyribonucleotide (when X ⁇ O).
  • these chemistries indicated in the figure these chemistries indicated in the figure, these
  • FIG. 6 shows a non-limiting example of a strategy used to identify chemically modified siNA constructs of the invention that are nuclease resistant while preserving the ability to mediate RNAi activity.
  • Chemical modifications are introduced into the siNA construct based on educated design parameters (e.g. introducing 2′-modifications, base modifications; backbone modifications, terminal cap modifications etc).
  • the modified construct is tested in an appropriate system (e.g., human serum for nuclease resistance, shown, or an animal model for PK/delivery parameters).
  • the siNA construct is tested for RNAi activity, for example in a cell culture system such as a luciferase reporter assay and/or against endogenous mRNA).
  • siNA constructs are then identified which possess a particular characteristic while maintaining RNAi activity, and can be further modified and assayed once again. This same approach can be used to identify siNA-conjugate molecules with improved pharmacokinetic profiles, delivery, and RNAi activity.
  • FIG. 7 shows non-limiting examples of phosphotylated siNA molecules of the invention, including linear and duplex constructs and asymmetric derivatives thereof.
  • FIG. 8 shows non-limiting examples of chemically modified terminal phosphate groups of the invention.
  • FIG. 9 shows a non-limiting example of a cholesterol linked phosphoramidite that can be used to synthesize cholesterol conjugated siNA molecules of the invention.
  • An example is shown with the cholesterol moiety linked to the 5′-end of the sense strand of an siNA molecule.
  • FIG. 10 depicts an embodiment of 5′ and 3′ inverted abasic cap linked to a nucleic acid strand.
  • an abasic moiety of the invention is a ribose, deoxyribose, or dideoxyribose sugar.
  • acyclic nucleotide refers to its meaning as is generally accepted in the art.
  • the term generally refers to any nucleotide having an acyclic ribose sugar, for example where any of the ribose carbon/carbon or carbon/oxygen bonds are independently or in combination absent from the nucleotide.
  • alkyl refers to its meaning as is generally accepted in the art.
  • the term generally refers to a saturated or unsaturated hydrocarbons, including straight-chain, branched-chain, alkenyl, alkynyl groups and cyclic groups, but excludes aromatic groups. Notwithstanding the foregoing, alkyl also refers to non-aromatic heterocyclic: groups.
  • the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, more preferably 1 to 4 carbons.
  • the alkyl group can be substituted or unsubstituted.
  • the substituted group(s) is preferably, hydroxyl, halogen, cyano C1-C4 alkoxy, ⁇ O, ⁇ S, —NO 2 , SH, NH 2 , or NR 1 R 2 , where R 1 and R 2 independently are H or C1-C4 alkyl.
  • agents that interfere with cell cycle checkpoints refers to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents.
  • RTKs receptor tyrosine kinases
  • androgen receptor modulators refers to compounds that interfere or inhibit the binding of androgens to the receptor, regardless of mechanism.
  • angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • aryl refers to its meaning as is generally accepted in the art.
  • the term generally refers to an aromatic group that has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which can be optionally substituted.
  • the preferred substituent(s) of aryl groups are halogen, trihalomethyl, hydroxyl, SH, OH, cyano, C1-C4 alkoxy, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, NH 2 , and NR 1 , R 2 groups, where R 1 and R 2 independently are H or C1-C4
  • alkylaryl refers to its meaning as is generally accepted in the art.
  • the term generally refers to an alkyl group (as described above) covalently joined to an aryl group (as described above).
  • Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms. The carbon atoms are optionally substituted.
  • Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms.
  • Suitable heteroatoms include oxygen, sulfur, and nitrogen, and examples of heterocyclic aryl groups having such heteroatoms include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted.
  • the alkyl group is a C1-C4 alkyl group.
  • amide refers to its meaning as is generally accepted in the art.
  • the term generally refers to an —C(O)—NH—R, where R is either alkyl, aryl, alkylaryl or hydrogen.
  • antisense region refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to a nucleotide sequence of an siNA molecule having complementarity to a target nucleic acid sequence.
  • the antisense region of an siNA molecule can optionally comprise a nucleic acid sequence having complementarily to a sense region of the siNA molecule. In one embodiment, the antisense region of the siNA molecule is referred to as the antisense strand or guide strand.
  • asymmetric hairpin refers to a linear siNA molecule comprising an antisense region, a loop portion that can comprise nucleotides or non-nucleotides, and a sense region that comprises fewer nucleotides than the antisense region to the extent that the sense region has enough complementary nucleotides to base pair with the antisense region and form a duplex with loop.
  • an asymmetric hairpin siNA molecule or the invention can comprise an antisense region having length sufficient to mediate RNAi in a cell or in vitro system (e.g.
  • the asymmetric hairpin siNA molecule can also comprise a 5′-terminal phosphate group that can be chemically modified.
  • the loop portion of the asymmetric hairpin siNA molecule can comprise nucleotides, non-nucleotides, linker molecules, or conjugate molecules as described herein.
  • biodegradable refers to its meaning as is generally accepted in the art.
  • the term generally refers to degradation in a biological system, for example, enzymatic degradation or chemical degradation.
  • biodegradable linker refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to a linker molecule that is designed to connect one molecule to another molecule, and which is susceptible to degradation in a biological system.
  • the linker can be a nucleic acid or non-nucleic acid based linker.
  • a biodegradable linker can be used to attach a ligand or biologically active molecule to an siNA molecule of the invention. Alternately, biodegradable linker can be used to connect the sense and antisense strands of an siNA molecule of the invention.
  • the biodegradable linker is designed such that its stability can be modulated for a particular purpose, such as delivery to a particular tissue or cell type.
  • the stability of a nucleic acid-based biodegradable linker molecule can be modulated by using various chemistries, for example combinations of ribonucleotides, deoxyribonucleotides, and chemically modified nucleotides, such as 2′-O-methyl, 2′-fluoro, 2′-amino, 2′-O-amino, T-C-allyl, 2′-O-allyl, and other 2′-modified or base modified nucleotides.
  • the biodegradable nucleic acid linker molecule can be a dirtier, trimer, tetramer or longer nucleic acid molecule, for example, an oligonucleotide of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, or can comprise a single nucleotide with a phosphorus-based linkage, for example, a phosphoramidate or phosphodiester linkage.
  • the biodegradable nucleic acid linker molecule can also comprise nucleic acid backbone, nucleic acid sugar, or nucleic acid base modifications.
  • biologically active molecule refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to compounds or molecules that are capable of eliciting or modifying a biological response in a system and/or are capable of modulating the pharmacokinetics and/or pharmacodynamics of other biologically active molecules.
  • biologically active molecules include siNA molecules alone or in combination with other molecules including, but not limited to therapeutically active molecules such as antibodies, cholesterol, hormones, antivirals, peptides, proteins, chemotherapeutics, small molecules, vitamins, co-factors, nucleosides, nucleotides, oligonucleotides, enzymatic nucleic acids, antisense nucleic acids, triplex forming oligonucleotides, polyamines, polyamides, polyethylene glycol, other polyethers, 2-5A chimeras, siNA, dsRNA, allozymes, aptamers, decoys and analogs thereof.
  • therapeutically active molecules such as antibodies, cholesterol, hormones, antivirals, peptides, proteins, chemotherapeutics, small molecules, vitamins, co-factors, nucleosides, nucleotides, oligonucleotides, enzymatic nucleic acids, antisense nucleic acids, triplex forming oligon
  • biological system refers to its meaning as is generally accepted in the art.
  • the term generally refers to material, in a purified or unpurified form, from biological sources including, but not limited to, human or animal, wherein the system comprises the components required for RNAi activity.
  • the phrase includes, for example, a cell, tissue, subject, or organism, or extract thereof.
  • the term also includes reconstituted material from a biological source.
  • blunt end refers to its meaning as is generally accepted in the art.
  • the term refers to termini of a double-stranded siNA molecule having no overhanging nucleotides.
  • the two strands of a double-stranded siNA molecule having blunt ends align with each other with matched base-pairs without overhanging nucleotides at the termini.
  • a siNA duplex molecule of the invention can comprise blunt ends at one or both termini of the duplex, such as termini located at the 5′-end of the antisense strand, the 5′-end of the sense strand, or both termini of the duplex.
  • cap also referred to herein as “terminal cap,” as used herein refers to its meaning as is generally accepted in the art.
  • the term refers to a moiety, which can be a chemically modified nucleotide or non-nucleotide that can be incorporated at one or more termini of one or more nucleic acid molecules of the invention.
  • These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and can help in delivery and/or localization within a cell.
  • the cap can be present at the 5′-terminus (5′-cap) or at the 3′-terminal (3′-cap) or can be present on both termini of any nucleic acid molecule of the invention.
  • a cap can be present at the 5′-end, 3-end and/or 5′ and 3′-ends of the sense strand of a nucleic acid molecule of the invention. Additionally, a cap can optionally be present at the 3′-end of the antisense strand of a nucleic acid molecule of the invention.
  • the 5′-cap includes, but is not limited to, LNA; glyceryl; inverted deoxy abasic residue (moiety); 4°,5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide, 4′-thio nucleotide; carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides; alpha-nucleotides; modified base nucleotide; phosphorodithioate linkage; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic 3,5-dihydroxypentyl nucleotide; 3′-3′-inverted nucleotide moiety; 3′-3′-inverted abasic moiety;
  • Non-limiting examples of the 3′-cap include, but are not limited to, LNA; glyceryl; inverted deoxy abasic residue (moiety); 4′, 5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide; 4′-thio nucleotide; carbocyclic nucleotide; 5′-amino-alkyl phosphate; 1,3-diamino-2-propyl phosphate; 3-aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco
  • the term “cell” as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term is used in its usual biological sense, and does not refer to an entire multicellular organism, e.g., specifically does not refer to a human being.
  • the cell can be present in an organism, e.g., birds, plants and mammals, such as humans, cows, sheep, apes, monkeys, swine, dogs, and cats.
  • the cell can be prokaryotic (e.g., bacterial cell) or eukaryotic (e.g., mammalian or plant cell).
  • the cell can be of somatic or germ line origin, totipotent or pluripotent, dividing or non-dividing.
  • the cell can also be derived from or can comprise a gamete or embryo, a stem cell, or a fully differentiated cell.
  • chemical modification refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to any modification of the chemical structure of the nucleotides that differs from nucleotides of native siRNA or RNA in general.
  • the term “chemical modification” encompasses the addition, substitution, or modification of native siRNA or RNA at the sugar, base, or internucleotide Linkage, as described herein or as is otherwise known in the art.
  • the term “chemical modification” can refer to certain forms of RNA that are naturally occurring in certain biological systems, for example 2′-O-methyl modifications or inosine modifications.
  • CTNNB1 refers to catering (cadherin-associated protein), beta 1 which is gene that encodes CTNNB1 proteins, CTNNB1 peptides, CTNNB1 polypeptides, CTNNB1 regulatory polynucleotides CTNNB1 miRNAs and siNAs), mutant CTNNB1 genes, and splice variants of a CTNNB1 genes, as well as other genes involved in CTNNB1 pathways of gene expression and/or activity.
  • each of the embodiments described herein with reference to the term “CTNNB1” are applicable to all of the protein, peptide, polypeptide, and/or polynucleotide molecules covered by the term “CTNNB1”, as that term is defined herein.
  • nucleic acid molecules of the invention refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the terms generally refer to the formation or existence of hydrogen bond(s) between one nucleic acid sequence and another nucleic acid sequence by either traditional Watson-Crick or other non-traditional types of bonding as described herein. In reference to the nucleic molecules of the present invention, the binding free energy for a nucleic acid molecule with its complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., RNAi activity.
  • Partial complementarity can include various mismatches or non-based paired nucleotides (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more mismatches, non-nucleotide linkers, or non-based paired nucleotides) within the nucleic acid molecule, which can result in bulges, loops, or overhangs that result between the sense strand or sense region and the antisense strand or antisense region of the nucleic acid molecule or between the antisense strand or antisense region of the nucleic acid molecule and a corresponding target nucleic acid molecule.
  • mismatches or non-based paired nucleotides e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more mismatches, non-nucleotide linkers, or non-based paired nucleotides
  • Such partial complementarity can be represented by a % complementarity that is determined by the number of non-base paired nucleotides, i.e., about 50%, 60%, 70%, 80%, 90% etc, depending on the total number of nucleotides involved.
  • Such partial complementarity is permitted to the extent that the nucleic acid molecule (e.g., siNA) maintains its function, for example the ability to mediate sequence specific RNAi.
  • compositions or “formulation” as used herein refer to their generally accepted meaning in the art. These terms generally refer to a composition or formulation, such as in a pharmaceutically acceptable carrier or diluent, in a form suitable for administration, e.g., systemic or local administration, into a cell or subject, including, for example, a human. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, inhalation, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell (i.e., a cell to which the negatively charged nucleic acid is desirable for delivery). For example, compositions injected into the blood stream should be soluble.
  • compositions include formulations for human and veterinary use.
  • agents suitable for formulation with the nucleic acid molecules of the instant invention include: Lipid Nanoparticles (see for example Semple et al., 2010 , Nat Biotechnol ., February; 28(2):172-6); P-glycoprotein inhibitors (such as Pluronic P85); biodegradable polymers, such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery (Einerich, D F et al, 1999 , Cell Transplant, 8, 47-58); and loaded nanoparticles, such as those made of polybutylcyanoacrylate.
  • a “pharmaceutically acceptable composition” or “pharmaceutically acceptable formulation” can refer to a composition or formulation that allows fir the effective distribution of the nucleic acid molecules of the instant invention to the physical location most suitable for their desired activity.
  • cytotoxic/cytostatic agents refer to compounds that cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mytosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors; microtubule-stabilizing agents, inhibitors of mitotic kinesins, inhibitors of histone deacetylase, inhibitors of kinases involved in mitotic progression, antimetabolites; biological response modifiers; hormonal/anti-hormonal therapeutic agents, hematopoetic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligase inhibitors.
  • estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism.
  • gene or “target gene” as used herein refers to their meaning as is generally accepted in the art.
  • the terms generally refer a nucleic acid (e.g., DNA or RNA) sequence that comprises partial length or entire length coding sequences necessary for the production of a polypeptide.
  • the target gene can also include the UTR or non-coding region of the nucleic acid sequence.
  • a gene or target gene can also encode a functional RNA (fRNA) or non-coding RNA (ncRNA), such as small temporal RNA (stRNA), micro RNA (miRNA), small nuclear RNA (snRNA), short interfering RNA (siRNA), small nucleolar RNA (snRNA), ribosomal RNA (rRNA), transfer RNA (tRNA) and precursor RNAs thereof.
  • fRNA functional RNA
  • ncRNA non-coding RNA
  • stRNA small temporal RNA
  • miRNA micro RNA
  • snRNA small nuclear RNA
  • siRNA small nucleolar RNA
  • rRNA ribosomal RNA
  • tRNA transfer RNA
  • siNA molecules targeting fRNA and ncRNA can also be used to manipulate or alter the genotype or phenotype of a subject, organism or cell, by intervening in cellular processes such as genetic imprinting, transcription, translation, or nucleic acid processing (e.g., transamination, methylation etc.).
  • the target gene can be a gene derived from a cell, an endogenous gene, a transgene, or exogenous genes such as genes of a pathogen, for example a virus, which is present in the cell after infection thereof.
  • the cell containing the target gene can be derived from or contained in any organism, for example a plant, animal, protozoan, virus, bacterium, or fungus.
  • Non-limiting examples of plants include monocots, divots, or gymnosperms.
  • Non-limiting examples of animals include vertebrates or invertebrates.
  • Non-limiting examples of fungi include molds or yeasts.
  • HMG-CoA reductase inhibitors refers to inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase.
  • HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds that have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
  • homologous sequence refers to its meaning as is generally accepted in the art.
  • the term generally refers a nucleotide sequence that is shared by one or more polynucleotide sequences, such as genes, gene transcripts and/or non-coding polynucleotides.
  • a homologous sequence can be a nucleotide sequence that is shared by two or more genes encoding related but different proteins, such as different members of a gene family, different protein epitopes, different protein isoforms or completely divergent genes.
  • a homologous sequence can be a nucleotide sequence that is shared by two or more non-coding polynucleotides, such as noncoding DNA or RNA, regulatory sequences, introns, and sites of transcriptional control or regulation. Homologous sequences can also include sequence regions shared by more than one polynucleotide sequence. Homology does not need to be perfect identity (100%), as partially homologous sequences are also contemplated by and within the scope of the instant invention (e.g., at least 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80% etc.). Percent homology is the number of matching nucleotides between two sequences divided by the total length being compared, multiplied by 100.
  • RNAi activity refers to an increase in RNAi activity measured in vitro and/or in vivo, where the RNAi activity is a reflection of both the ability of the siNA to mediate RNAi and the stability of the siNAs of the invention.
  • the product of these activities can be increased in vitro and/or in vivo compared to an all RNA siNA or an siNA containing a plurality of ribonucleotides.
  • the activity or stability of the siNA molecule can be decreased (i.e., less than ten-fold), but the overall activity of the siNA molecule is enhanced in vitro and/or in vivo.
  • inhibitor refers to its meaning as is generally accepted in the art.
  • exemplary nucleic acid molecules of the invention generally refers the reduction in the expression of the gene, or level of RNA molecules or equivalent RNA molecules encoding one or more proteins or protein subunits, or activity of one or more proteins or protein subunits, below that observed in the absence of the nucleic acid molecules (e.g., siNA) of the invention.
  • Down-regulation can also be associated with post-transcriptional silencing, such as, RNAi mediated cleavage or by alteration in DNA methylation patterns or DNA chromatin structure.
  • Inhibition, down-regulation or reduction with an siNA molecule can be in reference to an inactive molecule, an attenuated molecule, an siNA molecule with a scrambled sequence, or an siNA molecule with mismatches or alternatively, it cart be in reference to the system in the absence of the nucleic acid.
  • inhibitors of cell proliferation and survival signaling pathway refers to pharmaceutical agents that inhibit cell surface receptors and signal transduction cascades downstream of those surface receptors.
  • integrated circuit blockers refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ ⁇ ⁇ 3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ ⁇ ⁇ 5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the ⁇ ⁇ ⁇ 3 integrin and the ⁇ ⁇ ⁇ 5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the ⁇ ⁇ ⁇ 6 ⁇ ⁇ ⁇ 8 ⁇ 1 ⁇ 1 ⁇ 2 ⁇ 1 ⁇ 5 ⁇ 1 ⁇ 6 ⁇ 1 and ⁇ 6 ⁇ 4 integrins.
  • the term also refers to antagonists of any combination of ⁇ ⁇ ⁇ 3 , ⁇ ⁇ ⁇ 5 , ⁇ ⁇ ⁇ 6 ⁇ ⁇ ⁇ 8 ⁇ 1 ⁇ 1 ⁇ 2 ⁇ 1 ⁇ 5 ⁇ 1 ⁇ 6 ⁇ 1 and ⁇ 6 ⁇ 4 integrins.
  • internucleoside linkage or “internucleoside linker” or “internucleotide linkage” or “internucleotide linker” are used herein interchangeably and refer to any linker or linkage between two nucleoside units, as is known in the art, including, for example, but not limitation, phosphate, analogs of phosphate, phosphonate, guanidium, hydroxylamine, hydroxylhydrazinyl, amide, carbamate, alkyl, and substituted alkyl linkages.
  • the internucleoside linkages constitute the backbone of a nucleic acid molecule.
  • mammalian or “mammal” as used herein refers to its meaning as is generally accepted in the art.
  • the term generally refers to any warm blooded vertebrate species, such as a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit, livestock, and the like.
  • MDI refers to a unit comprising a can, a secured cap covering the can and a formulation metering valve situated in the cap
  • MDI systems includes a suitable channeling device.
  • Suitable channeling devices comprise for example, a valve actuator and a cylindrical or cone-like passage through which medicament can be delivered from the filled canister via the metering valve to the nose or mouth of a patient such as a mouthpiece actuator.
  • microRNA or “miRNA” as used herein refers to its meaning as is generally accepted in the art.
  • the term generally refers a small double-stranded RNA that regulates the expression of target messenger RNAs either by mRNA cleavage, translational repression/inhibition or heterochromatic silencing (see for example Ambros, 2004, Nature, 431, 350-355; Bartel, 2004, Cell, 116, 281-297; Cullen, 2004, Virus Research., 102, 3-9; He et al., 2004, Nat. Rev. Genet., 5, 522-531; Wing at al., 2004, Gene, 342, 25-28; and Sethupathy et al., 2006, RNA, 12:192-197).
  • modulate refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to when the expression of a gene, or level of one or more RNA molecules (coding or non-coding), or activity of one or more RNA molecules or proteins or protein subunits, is up-regulated or down-regulated, such that expression, level, or activity is greater than or less than that observed in the absence of the molecule that effects modulation.
  • the term “modulate” in some embodiments can refer to inhibition and in other embodiments can refer to potentiation or up-regulation, e.g., of gene expression.
  • modified nucleotide refers to its meaning as is generally accepted in the art.
  • the term generally refers a nucleotide, which contains a modification in the chemical structure of the base, sugar and/or phosphate of the unmodified (or natural) nucleotide as is generally known in the art.
  • modified nucleotides are described herein and in U.S. application Ser. No. 12/064,014.
  • NSAIDs that are selective COX-2 inhibitors refers to NSAIDs, which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC 50 for COX-2 over IC 50 for COX-1 evaluated by cell or microsomal assays.
  • non-base paired refers to nucleotides that are not base paired between the sense strand or sense region and the antisense strand or antisense region of an double-stranded siNA molecule; and can include for example, but not limitation, mismatches, overhangs, single stranded loops, etc.
  • non-nucleotide refers to any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, such as for example hut not limitation abasic moieties or alkyl chains.
  • the group or compound is “abasic” in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine and therefore lacks a nucleobase at the 1′-position.
  • nucleotide is used as is generally recognized in the art. Nucleotides generally comprise a nucleobase, a sugar, and an internucleoside linkage, e.g., a phosphate.
  • the base can be a natural bases (standard), modified bases, or a base analog, as are well known in the art. Such bases are generally located at the 1′ position of a nucleotide sugar moiety.
  • nucleotides can be unmodified or modified at the sugar, internucleoside linkage, and/or base moiety, (also referred to interchangeably as nucleotide analogs, modified nucleotides, non-natural nucleotides, non-standard nucleotides and others; see, for example, U.S. application Ser. No. 12/064,014.
  • overhang refers to its meaning as is generally accepted in the art. With reference to exemplary double stranded nucleic acid molecules, the term generally refers to the terminal portion of a nucleotide sequence that is not base paired between the two strands of a double-stranded nucleic acid molecule (see for example, FIG. 4 ). Overhangs, when present, are typically at the 3′-end of one or both strands in a siNA duplex.
  • parenteral refers to its meaning as is generally accepted in the art.
  • the term generally refers methods or techniques of administering a molecule, drug, agent, or compound in a manner other than through the digestive tract, and includes epicutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like.
  • pathway target refers to any target involved in pathways of gene expression or activity.
  • any given target can have related pathway targets that can include upstream, downstream, or modifier genes in a biologic pathway.
  • pathway target genes can provide additive or synergistic effects in the treatment of diseases, conditions, and traits herein.
  • phosphorothioate refers to an internucleotide phosphate linkage comprising one or more sulfur atoms in place of an oxygen atom. Hence, the term phosphorothioate refers to both phosphorothioate and phosphorodithioate internucleotide linkages.
  • Prenyl-protein transferase inhibitor refers to a compound that inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
  • FPTase farnesyl-protein transferase
  • GGPTase-I geranylgeranyl-protein transferase type I
  • GGPTase-II geranylgeranyl-protein transferase type-II
  • retinoid receptor modulators refers to compounds that interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • ribonucleotide refers to its meaning as is generally accepted in the art.
  • the term generally refers to a nucleotide with a hydroxyl group at the 2′ position of a ⁇ -D-ribofuranose moiety.
  • RNA refers to its generally accepted meaning in the art.
  • RNA refers to a molecule comprising at least one ribofuranoside moiety.
  • the term can include double-stranded RNA, single-stranded RNA, isolated RNA such as partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA, as well as altered RNA that differs from naturally occurring RNA by the addition, deletion, substitution and/or alteration of one or more nucleotides.
  • Such alterations can include addition of non-nucleotide material, such as to the end(s) of the siNA or internally, for example at one or more nucleotides of the RNA.
  • Nucleotides in the RNA molecules of the instant invention can also comprise non-standard nucleotides, such as non-naturally occurring nucleotides or chemically synthesized nucleotides or deoxynucleotides. These altered RNAs can be referred to as analogs or analogs of naturally-occurring RNA.
  • RNA interference refers to the biological process of inhibiting or down regulating gene expression in a cell, as is generally known in the art, and which is mediated by short interfering nucleic acid molecules, see for example Zamore and Haley, 2005 , Science, 309, 1519-1524; Vaughn and Martienssen, 2005 , Science, 309, 1525-1526; Zamore et al., 2000 , Cell, 101, 25-33; Bass, 2001 , Nature, 411, 428-429; Elbashir et al., 2001 , Nature, 411, 191-498; and Kreutzer et al., international PCT Publication No.
  • RNAi is meant to be equivalent to other terms used to describe sequence specific RNA interference, such as post transcriptional gene silencing, translational inhibition, transcriptional inhibition, or epigenetics.
  • siNA molecules of the invention can be used to epigenetically silence genes at either the post-transcriptional level or the pre-transcriptional level.
  • epigenetic modulation of gene expression by siNA molecules of the invention can result from siNA mediated modification of chromatin structure or methylation patterns to alter gene expression (see, for example, Verdel et al., 2004 , Science, 303, 672-676; Pal-Bhadra et al., 2004 , Science, 303, 669-672; Alishire, 2002 , Science, 297, 1818-1819; Volpe et al., 2002 , Science, 297, 1833-1837; Jenuwein, 2002 , Science, 297, 2215-2218; and Hall et al., 2002 , Science, 297, 2232-2237).
  • modulation of gene expression by siNA molecules of the invention can result from siNA mediated cleavage of RNA (either coding or non-coding RNA) via RISC, or via translational inhibition, as is known in the art or modulation can result from transcriptional inhibition (see for example Janowski et al., 2005 , Nature Chemical Biology, 1, 216-222).
  • RNAi inhibitor refers to any molecule that can down regulate, reduce or inhibit RNA interference function or activity in a cell or organism.
  • An RNAi inhibitor can down regulate, reduce or inhibit.
  • RNAi e.g., RNAi mediated cleavage of a target polynucleotide, translational inhibition, or transcriptional silencing
  • protein components such as RISC
  • nucleic acid components such as miRNAs or siRNAs.
  • a RNAi inhibitor can be an siNA molecule, an antisense molecule, an aptamer, or a small molecule that interacts with or interferes with the function of RISC, a miRNA, or an siRNA or any other component of the RNAi pathway in a cell or organism.
  • RNAi e.g., RNAi mediated cleavage of a target polynucleotide, translational inhibition, or transcriptional silencing
  • a RNAi inhibitor of the invention can be used to modulate (e.g., up-regulate or down regulate) the expression of a target gene.
  • sense region refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to a nucleotide sequence of an siNA molecule having complementarity to an antisense region of the siNA molecule.
  • the sense region of an siNA molecule can comprise a nucleic acid sequence having homology or sequence identity with a target nucleic acid sequence.
  • the sense region of the siNA molecule is also referred to as the sense strand or passenger strand.
  • short interfering nucleic acid refers to any nucleic acid molecule capable of inhibiting or down regulating gene expression or viral replication by mediating RNA interference (“RNAi”) or gene silencing in a sequence-specific manner. These terms can refer to both individual nucleic acid molecules, a plurality of such nucleic acid molecules, or pools of such nucleic acid molecules.
  • RNAi RNA interference
  • the siNA can be a double-stranded nucleic acid molecule comprising self-complementary sense and antisense strands, wherein the antisense strand comprises a nucleotide sequence that is complementary to a nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense strand comprises a nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof.
  • the siNA can be a polynucleotide with a duplex, asymmetric duplex, hairpin or asymmetric hairpin secondary structure, having self-complementary sense and antisense regions, wherein the antisense region comprises a nucleotide sequence that is complementary to a nucleotide sequence in a separate target nucleic acid molecule or a portion thereof and the sense region comprises a nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof.
  • the siNA can be a circular single-stranded polynucleotide having two or more loop structures and a stem comprising self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to a nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region comprises a nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof, and wherein the circular polynucleotide can be processed either in vivo or in vitro to generate an active siNA molecule capable of mediating RNAi.
  • the siNA can also comprise a single-stranded polynucleotide having a nucleotide sequence complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof (for example, where such siNA molecule does not require the presence within the siNA molecule of a nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof), wherein the single-stranded polynucleotide can further comprise a terminal phosphate group, such as a 5′-phosphate (see for example, Martinez et al., 2002 , Cell 110, 563-574 and Schwarz et al., 2002 , Molecular Cell, 10, 537-568), or 5′,3′-diphosphate.
  • a terminal phosphate group such as a 5′-phosphate (see for example, Martinez et al., 2002 , Cell 110, 563-574 and Schwarz et al., 2002 , Molecular Cell, 10, 537-568), or 5′,3′-
  • subject refers to its meaning as is generally accepted in the art.
  • the term generally refers an organism to which the nucleic acid molecules of the invention can be administered.
  • a subject can be a mammal or mammalian cells, including a human or human cells.
  • the term also refers to an organism, which is a donor or recipient of explanted cells or the cells themselves.
  • systemic administration refers to its meaning as is generally accepted in the art.
  • the term generally refers in vivo systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body.
  • target refers to any CTNNB1 target protein, peptide, or polypeptide, such as encoded by Genbank Accession Nos. shown in Table 5.
  • the term also refers to nucleic acid sequences or target polynucleotide sequence encoding any target protein, peptide, or polypeptide, such as proteins, peptides, or polypeptides encoded by-sequences having Genbank Accession Nos, shown in Table 5.
  • the target of interest can include target polynucleotide sequences, such as target DNA or target RNA.
  • target is also meant to include other sequences, such as differing isoforms, mutant target genes, splice variants of target polynucleotides, target polymorphisms, and non-coding (e.g., ncRNA, miRNA, stRNA, sRNA) or other regulatory polynucleotide sequences as described herein.
  • non-coding e.g., ncRNA, miRNA, stRNA, sRNA
  • target site refers to its meaning as is generally accepted in the art.
  • the term generally refers to a sequence within a target nucleic acid molecule, (e.g., RNA) that is “targeted”, e.g., for cleavage mediated by an siNA construct, which contains sequences within its antisense region that are complementary to the target sequence.
  • terapéuticaally effective amount refers to its meaning as is generally accepted in the art.
  • the term generally refers to the amount of the compound or composition that will elicit the biological or medical response of a cell, tissue, system, animal or human that is be sought by the researcher, veterinarian, medical doctor or other clinician. For example, if a given clinical treatment is considered effective when there is at least a 25% reduction in a measurable parameter associated with a disease or disorder, a therapeutically effective amount of a drug for the treatment of that disease or disorder is that amount necessary to effect at least a 25% reduction in that parameter.
  • universal base refers to its meaning as is generally accepted in the art.
  • the term universal base generally refers to nucleotide base analogs that form base pairs with each of the natural DNA/RNA bases with little or no discrimination between them.
  • Non-limiting examples of universal bases include C-phenyl, C-naphthyl and other aromatic derivatives, inosine, azole carboxamides, and nitroazole derivatives such as 3-nitropyrrole, 4-nitroindole, 5-nitroindole, and 6-nitroindole as known in the art (see for example, Loakes, 2001 , Nucleic Acids Research, 29, 2437-2447).
  • up-regulate refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to an increase in the expression of a gene, or level of RNA molecules or equivalent RNA molecules encoding one or more proteins or protein subunits, or activity of one or more RNAs, proteins or protein subunits, above that observed in the absence of the nucleic acid molecules (e.g., siNA) of the invention. In certain instances, up-regulation or promotion of gene expression with an siNA molecule is above that level observed in the presence of an inactive or attenuated molecule.
  • siNA nucleic acid molecules
  • up-regulation or promotion of gene expression with siNA molecules is above that level observed in the presence of, for example, an siNA molecule with scrambled sequence or with mismatches.
  • up-regulation or promotion of gene expression with a nucleic acid molecule of the instant invention is greater in the presence of the nucleic acid molecule than in its absence.
  • up-regulation or promotion of gene expression is associated with inhibition of RNA mediated gene silencing, such as RNAi mediated cleavage or silencing of a coding or non-coding RNA target that down regulates, inhibits, or silences the expression of the gene of interest to be up-regulated.
  • the down regulation of gene expression can, for example, be induced by a coding RNA or its encoded protein, such as through negative feedback or antagonistic effects.
  • the down regulation of gene expression can, for example, be induced by a non-coding RNA having regulatory control over a gene of interest, for example by silencing expression of the gene via translational inhibition, chromatin structure, methylation, RISC mediated RNA cleavage, or translational inhibition.
  • inhibition or down regulation of targets that down regulate, suppress, or silence a gene of interest can be used to up-regulate expression of the gene of interest toward therapeutic use.
  • vector refers to its meaning as is generally accepted in the art.
  • vector generally refers to any nucleic acid- and/or viral-based expression system or technique used to deliver one or more nucleic acid molecules.
  • the present invention provides compositions and methods comprising siNAs targeted to CTNTNB1 that can be used to treat diseases, malignancies and/or cancers associated with CTNNB1 expression.
  • the nucleic acid molecules of the invention comprise at least a 15 nucleotide sequence of the sequences shown in Table 1a and Table 1b.
  • the siNAs can be provided in several forms.
  • the siNA can be isolated as one or more siNA compounds, or it may be in the form of a transcriptional cassette in a DNA plasmid.
  • the siNA may also be chemically synthesized and can include modifications as shown, for example, but not limitation, in Table 1c and Table 6.
  • At least one strand or region of the nucleic acids of the invention comprises at least a 15 nucleotide sequence selected from the group of sequences consisting of SEQ ID NOS:1-6374.
  • the siNAs can be administered alone or co-administered with other siNA molecules or with conventional agents that treat a CTNNB1 related disease or condition.
  • the siNA molecules of the invention can be used to mediate gene silencing, specifically CTNNB1, via interaction with RNA transcripts or alternately by interaction with particular gene sequences, wherein such interaction results in modulation of gene silencing either at the transcriptional level or post-transcriptional level such as, for example, but not limited to, RNAi or through cellular processes that modulate the chromatin structure or methylation patterns of the target and prevent transcription of the target gene, with the nucleotide sequence of the target thereby mediating silencing.
  • the target is any of CTNNB1 RNA, DNA, or mRNA,
  • the invention provides short interfering nucleic acid (siNA) molecules for inhibiting the expression of the CTNNB1 gene in a cell or mammal.
  • the siNA can be single-stranded or double-stranded. When double-stranded, the siNA comprising a sense and an antisense stand.
  • the antisense strand is complementary to at least a part of an mRNA formed in the expression of the CTNNB1 gene.
  • the sense strand comprises a region that is complementary to the antisense strand.
  • the antisense strand comprises at least a 15 nucleotide sequence of an antisense sequence listed in Table 1b.
  • the double-stranded siNA comprises at least a 15 nucleotide sequence of the sense strand in Table 1b and at least a 15 nucleotide sequence of the antisense strand in Table 1b.
  • One or more of the nucleotides of the siNAs of the invention are optionally modified.
  • some siNAs of the invention comprises at least one nucleotide sequence selected from the groups of sequences provide in Table 1c.
  • the siNA comprises at least two sequences selected from the group of sequences provided in Table 1c, wherein one of the at least two sequences is complementary to another of the at least two sequences and one of the at least two sequences is complementary to a sequence of a mRNA generated in the expression of the CTNNB1 gene.
  • Examples of certain modified siNAs of the invention are in Table 1c.
  • the double stranded RNA molecules of the invention can comprise two distinct and separate strands that can be symmetric or asymmetric and are complementary, i.e., two single-stranded RNA molecules, or can comprise one single-stranded molecule in which two complementary portions, e.g., a sense region and an antisense region, are base-paired, and are covalently linked by one or more single-stranded “hairpin” areas (i.e. loops) resulting in, for example, a single-stranded short-hairpin polynucleotide or a circular single-stranded polynucleotide.
  • two complementary portions e.g., a sense region and an antisense region
  • hairpin i.e. loops
  • the linker can be polynucleotide linker or a non-nucleotide linker.
  • the linker is a non-nucleotide linker
  • a hairpin or circular siNA molecule of the invention contains one or more loop motifs, wherein at least one of the loop portions of the siNA molecule is biodegradable.
  • a single-stranded hairpin siNA molecule of the invention is designed such that degradation of the loop portion of the siNA molecule in vivo can generate a double-stranded siNA molecule with 3′-terminal overhangs, such as 3′-terminal nucleotide overhangs comprising 1, 2, 3 or 4 nucleotides.
  • a circular siNA molecule of the invention is designed such that degradation of the loop portions of the siNA molecule in vivo can generate a double-stranded siNA molecule with 3′-terminal overhangs, such as 3′-terminal nucleotide overhangs comprising about 2 nucleotides.
  • each strand, the sense (passenger) strand and antisense (guide) strand are independently about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides in length.
  • each strand of the symmetric siNA molecules of the invention are about 19-24 (e.g., about 19, 20, 21, 22, 23 or 24) nucleotides in length.
  • the antisense region or strand of the molecule is about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, or 30) nucleotides in length, wherein the sense region is about 3 to about 25 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, or 25) nucleotides in length.
  • each strand of the asymmetric siNA molecules of the invention is about 19-24 (e.g., about 19, 20, 21, 22, 23 or 24) nucleotides in length.
  • siNA molecules of the invention comprise single stranded hairpin siNA molecules, wherein the siNA molecules are about 25 to about 70 (e.g., about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 40, 45, 50, 55, 60, 65, or 70) nucleotides in length.
  • siNA molecules of the invention comprise single-stranded circular siNA molecules, wherein the siNA molecules are about 38 to about 70 (e.g., about 38, 40, 45, 50, 55, 60, 65, or 70) nucleotides in length.
  • siNA molecules of the invention comprise single-stranded non-circular siNA molecules, wherein the siNA molecules are independently about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides in length.
  • the siNA duplexes of the invention independently comprise about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) base pairs.
  • the duplex structure of siNAs of the invention is between 15 and 30, more generally between 18 and 25, yet more generally between 19 and 24, and most generally between 19 and 21 base pairs in length.
  • the siNA molecules of the invention comprise about 3 to 25 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) base pairs.
  • the duplex structure of siNAs of the invention is between 15 and 25, more generally between 18 and 25, yet more generally between 19 and 24, and most generally between 19 and 21 base pairs in length.
  • the siNA molecules of the invention comprise about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) base pairs.
  • the sense strand and antisense strand, or the sense region and antisense region, of the siNA molecules of the invention can be complementary.
  • the antisense strand or antisense region can be complementary to a nucleotide sequence or a portion thereof of the CTNNB1 target RNA.
  • the sense strand or sense region of the siNA can comprise a nucleotide sequence of a CTNNB1 gene or a portion thereof.
  • the sense region or sense strand of an siNA molecule of the invention is complementary to that portion of the antisense region or antisense strand of the siNA molecule that is complementary to a CTNNB1 target polynucleotide sequence, such as for example, but not limited to, those sequences represented by GENBANK Accession Nos. shown in Table 5.
  • siNA molecules of the invention have perfect complementarity between the sense strand or sense region and the antisense strand or antisense region of the siNA molecule.
  • the antisense strand of the siNA molecules of the invention are perfectly complementary to a corresponding target nucleic acid molecule.
  • siNA molecules of the invention have partial complementarity (i.e., less than 100% complementarity) between the sense strand or sense region and the antisense strand or antisense region of the siNA molecule or between the antisense strand or antisense region of the siNA molecule and a corresponding target nucleic acid molecule.
  • the double-stranded nucleic acid molecules of the invention have between about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides in one strand that are complementary to the nucleotides of the other strand.
  • the molecules have between about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides in the sense region that are complementary to the nucleotides of the antisense region of the double-stranded nucleic acid molecule.
  • the double-stranded nucleic acid molecules of the invention have between about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides in the antisense strand that are complementary to a nucleotide sequence of its corresponding target nucleic acid molecule.
  • the siNA molecule can contain one or more nucleotide deletions, substitutions, mismatches and/or additions; provided, however, that the siNA molecule maintains its activity, for example, to mediate RNAi.
  • the deletion, substitution, mismatch and/or addition can result in a loop or bulge, or alternately a wobble or other alternative (non Watson-Crick) base pair.
  • the double-stranded nucleic acid molecules of the invention have 1 or more (e.g., 1, 2, 3, 4, 5, or 6) nucleotides, in one strand or region that are mismatches or non-base-paired with the other strand or region.
  • the double-stranded nucleic acid molecules of the invention have 1 or more (e.g., 1, 2, 3, 4, 5, or 6) nucleotides in each strand or region that are mismatches or non-base-paired with the other strand or region.
  • the siNA of the invention contains no more than 3 mismatches. If the antisense strand of the siNA contains mismatches to a target sequence, it is preferable that the area of mismatch not be located in the center of the region of complementarity.
  • the siNA molecule can contain one or more nucleotide deletions, substitutions, mismatches and/or additions to a sequence in Table 1b provided, however, that the siNA molecule maintains its activity, for example, to mediate RNAi.
  • the deletion, substitution, mismatch and/or addition can result in a loop or bulge, or alternately a wobble or other alternative (non Watson-Crick) base pair.
  • the invention also comprises double-stranded nucleic acid (siNA) molecules as otherwise described hereinabove in which the first strand and second strand are complementary to each other and wherein at least one strand is hybridisable to the polynucleotide sequence of a sequence in Table 1b under conditions of high stringency, and wherein any of the nucleotides is unmodified or chemically modified.
  • siNA double-stranded nucleic acid
  • Hybridization techniques are well known to the skilled artisan (see for instance, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)).
  • Preferred stringent hybridization conditions include overnight incubation at 42° C. in a solution comprising: 50% formamide, 5 ⁇ SSC (150 mM NaCl, 1.5 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5 ⁇ Denhardt's solution, 10% dextran sulfate, and 20 microgram/ml denatured, sheared salmon sperm DNA; followed by washing the filters in 0.1 ⁇ SSC at about 65° C.
  • the first strand has about 15, 16, 17, 18, 19, 20 or 21 nucleotides that are complementary to the nucleotides of the other strand and at least one strand is hybridisable to a polynucleotide sequence in Table 1b.
  • the first strand has about 15, 16, 17, 18, 19, 20 or 21 nucleotides that are complementary to the nucleotides of the other strand and at least one strand is hybridisable to SEQ ID NO: 1, SEQ NO: 1049, SEQ ID NO: 43, SEQ ID NO: 1091, SEQ ID NO: 51, SEQ ID NO: 1099, SEQ ID NO: 53, or SEQ ID NO:1101; under conditions of high stringency, and wherein any of the nucleotides is unmodified or chemically modified.
  • the siNA molecules of the invention comprise overhangs of about 1 to about 4 (e.g., about 1, 2, 3 or 4) nucleotides.
  • the nucleotides in the overhangs can be the same or different nucleotides.
  • the overhangs occur at the 3′-end at one or both strands of the double-stranded nucleic acid molecule.
  • a double-stranded nucleic acid molecule of the invention can comprise a nucleotide or non-nucleotide overhang at the 3′-end of the antisense strand/region, the 3′-end of the sense strand/region, or both the antisense strand/region and the sense strand/region of the double-stranded nucleic acid molecule.
  • the nucleotides comprising the overhang portion of an siNA molecule of the invention comprise sequences based on the CTNNB1 target polynucleotide sequence in which nucleotides comprising the overhang portion of the antisense strand/region of an siNA molecule of the invention can be complementary to nucleotides in the CTNNB1 target polynucleotide sequence and/or nucleotides comprising the overhang portion of the sense strand/region of an siNA molecule of the invention can comprise the nucleotides in the CTNNB1 target polynucleotide sequence.
  • the overhang comprises a two nucleotide overhang that is complementary to a portion of the CTNNB1 target polynucleotide sequence. In other embodiments, however, the overhang comprises a two nucleotide overhang that is not complementary to a portion of the CTNNB1 target polynucleotide sequence. In certain embodiments, the overhang comprises a overhang that is not complementary to a portion of the CTNNB1 target polynucleotide sequence. In other embodiments, the overhang comprises a UU overhang at the 3′ end of the antisense strand and a TT overhang at the 3′ end of the sense strand. In other embodiments, the overhang comprises nucleotides as described in the examples, Tables, and Figures herein.
  • the overhangs are optionally chemically modified at one or more nucleic acid sugar, base, or backbone positions.
  • modified nucleotides in the overhang portion of a double-stranded nucleic acid (siNA) molecule of the invention include: 2′-O-alkyl (e.g., 2′-O-methyl), 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-deoxy-2′-fluoroarabino (FANA), 4′-thio, 2′-O-trifluoromethyl, 2′-O-ethyl-trifluoromethoxy, 2′4)-difluoromethoxy-ethoxy, universal base, acyclic, or 5-C-methyl nucleotides.
  • the overhang nucleotides are each independently, a 2′-O-alkyl nucleotide, a 2′-O-methyl nucleotide, a 2′-dexoy-2-fluoro nucleotide, or a 2′-deoxy ribonucleotide. In some instances the overhang nucleotides are linked by a one or more phosphorothioate linkages.
  • siNA molecules of the invention comprise duplex nucleic acid molecules with blunt ends (i.e., without nucleotide overhangs), where both ends are blunt, or alternatively, where one of the ends is blunt.
  • the siNA molecules of the invention can comprises one blunt end, for example wherein the 5′-end of the antisense strand and the 3′-end of the sense strand do not have any overhanging nucleotides.
  • the siNA molecule comprises one blunt end, for example wherein the 3′-end of the antisense strand and the 5′-end of the sense strand do not have any overhanging nucleotides.
  • siNA molecules of the invention comprise two blunt ends, for example wherein the 3′-end of the antisense strand and the 5′-end of the sense strand as well as the 5′-end of the antisense strand and 3′-end of the sense strand do not have any overhanging nucleotides.
  • the sense strand and/or the antisense strand can further have a cap, such as described herein or as known in the art, at the 3′-end, the 5′-end, or both of the 3′ and 5′-ends of the sense strand and/or antisense strand.
  • the cap can be at either one or both of the terminal nucleotides of the polynucleotide.
  • the cap is at one of both of the ends of the sense strand of a double-stranded siNA molecule.
  • the cap is at the 3′-end of antisense (guide) strand.
  • the caps are at the 3′-end of the sense strand and the 5′-end of the sense strand.
  • terminal caps include an inverted abasic nucleotide, an inverted deoxy abasic nucleotide, an inverted nucleotide moiety, a group shown in FIG. 5 , a glyceryl modification, an alkyl or cycloalkyl group, a heterocycle, or any other cap as is generally known in the art.
  • any of the embodiments of the siNA molecules of the invention can have a 5′ phosphate termini.
  • the siNA molecules lack terminal phosphates.
  • siNA molecule or construct of the invention can comprise one or more chemical modifications. Modifications can be used to improve in vitro or in vivo characteristics such as stability, activity, toxicity, immune response (e.g., prevent stimulation of an interferon response, an inflammatory or pro-inflammatory cytokine response, or a Toll-like Receptor (TlF) response), and/or bioavailability.
  • Modifications can be used to improve in vitro or in vivo characteristics such as stability, activity, toxicity, immune response (e.g., prevent stimulation of an interferon response, an inflammatory or pro-inflammatory cytokine response, or a Toll-like Receptor (TlF) response), and/or bioavailability.
  • TlF Toll-like Receptor
  • RNAi activity RNAi activity
  • stability RNAi activity
  • Various chemically modified siNA motifs disclosed herein provide the capacity to maintain RNAi activity that is substantially similar to unmodified or minimally modified active siRNA (see for example Elbashir et al., 2001, EMBO J., 20:6877-6888) while at the same time providing nuclease resistance and pharmacokinetic properties suitable for use in therapeutic applications.
  • the siNA molecules of the invention comprise modifications wherein any (e.g., one or more or all) nucleotides present in the sense and/or antisense strand are modified nucleotides (e.g., wherein one nucleotide is modified, some nucleotides (i.e., plurality or more than one) are modified, or all nucleotides are modified nucleotides.
  • the siNA molecules of the invention are partially modified (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, or 59 nucleotides are modified) with chemical modifications.
  • an siNA molecule of the invention comprises at least about 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or 60 nucleotides that are modified nucleotides.
  • the siNA molecules of the invention are completely modified (e.g., 100% modified) with chemical modifications, i.e., the siNA molecule does not contain any, ribonucleotides.
  • one or more of the nucleotides in the sense strand of the siNA molecules of the invention are modified.
  • one or more of the nucleotides in the antisense strand of the siNA molecules of the invention are modified.
  • the chemical modification within a single siNA molecule can be the same or different.
  • at least one strand has at least one chemical modification.
  • each strand has at least one chemical modifications, which can be the same or different, such as, sugar, base, or backbone (i.e., internucleotide linkage) modifications.
  • siNA molecules of the invention contain at least 2, 3, 4, 5, or more different chemical modifications.
  • Non-limiting examples of chemical modifications that are suitable for use in the present invention are disclosed in U.S. patent application Ser. Nos. 10/444,853; 10/981,966; 12/064,014 and in references cited therein and include sugar, base, and phosphate, non-nucleotide modifications, and/or any combination thereof.
  • At least one modified nucleotide is a 2′-deoxy-2-fluoro nucleotide, a 2′-deoxy nucleotide, a 2′-O-alkyl (e.g., 2′-O-methyl) nucleotide, or a locked nucleic acid (LNA) nucleotide as is generally recognized in the art.
  • LNA locked nucleic acid
  • At least one nucleotide has a ribo-like, Northern or A form helix configuration (see e.g., Saenger, Principles of Nucleic Acid Structure, Springer-Verlag ed., 1984).
  • Non-limiting examples of nucleotides having a Northern configuration include locked nucleic acid (LNA) nucleotides (e.g., 2′-O, 4′-C-methylene-(D-ribofuranosyl) nucleotides); 2′-methoxyethoxy (MOE) nucleotides; 2′-methyl-thio-ethyl nucleotides, 2′-deoxy-2′-fluoro nucleotides; 2′-deoxy-2′-chloro nucleotides; 2′-azido nucleotides; 2′-O-trifluoromethyl nucleotides; 2′-O-ethyl-trifluoromethoxy nucleotides; 2′4)-difluoromethoxy-ethoxy nucleotides; 4′-thio nucleotides and 2′-O-methyl nucleotides.
  • LNA locked nucleic acid
  • MOE 2′-methoxyethoxy
  • a majority (e.g., greater than 50%) of the pyrimidine nucleotides present in the double-stranded siNA molecule comprises a sugar modification.
  • a majority (e.g., greater than 50%) of the purine nucleotides present in the double-stranded siNA molecule comprises a sugar modification.
  • the pyrimidine nucleotides in the antisense strand are 2′-O-methyl or 2′-deoxy-2′-fluoro pyrimidine nucleotides and the purine nucleotides present in the antisense strand are 2′-O-methyl nucleotides or 2′-deoxy nucleotides.
  • the pyrimidine nucleotides in the sense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides and the purine nucleotides present in the sense strand are 2′-O-methyl or 2′-deoxy purine nucleotides.
  • all the pyrimidine nucleotides in the complementary region on the sense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides. In certain embodiments, all of the pyrimidine nucleotides in the complementary region of the antisense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides. In certain embodiments, all the purine nucleotides in the complementary region on the sense strand are 2′-deoxy purine nucleotides.
  • all of the purines in the complementary region on the antisense strand are 2′-O-methyl purine nucleotides
  • all of the pyrimidine nucleotides in the complementary regions on the sense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides
  • all of the pyrimidine nucleotides in the complementary region of the antisense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides
  • all the purine nucleotides in the complementary region on the sense strand are 2′-deoxy purine nucleotides and all of the purines in the complementary region on the antisense strand are 2′-O-methyl purine nucleotides.
  • At least 5 or more of the pyrimidine nucleotides in one or both stands are 2′-deoxy-2′-fluoro pyrimidine nucleotides, in some embodiments, at least 5 or more of the pyrimidine nucleotides in one or both stands are 2′-O-methyl pyrimidine nucleotides. In some embodiments, at least 5 or more of the purine nucleotides in one or both stands are 2′-deoxy-2′-fluoro purine nucleotides In some embodiments, at least 5 or more of the purine nucleotides in one or both stands are 2′-O-methyl purine nucleotides.
  • the purines and pyrimidines are differentially modified at the 2′-sugar position (i.e., at least one purine has a different modification from at least one pyrimidine in the same or different strand at the 2′-sugar position).
  • at least 5 or more of the pyrimidine nucleotides in one or both stands are 2′-deoxy-2′-fluoro pyrimidine nucleotides and at least 5 or more purine nucleotides in one or both strands are 2′-O-methyl purine nucleotides.
  • At least 5 or more of the pyrimidine nucleotides in one or both stands are 2′-O-methyl pyrimidine nucleotides and at least 5 or more purine nucleotides in one or both strands are 2′-deoxy-2′-fluoro purine nucleotides.
  • FIGS. 2 and 3 Further non-limiting examples of sense and antisense strands of such siNA molecules having various modifications and modifications patterns are shown in FIGS. 2 and 3 .
  • the modified siNA molecules of the invention can comprise modifications at various locations within the siNA molecule.
  • the double-stranded siNA molecule of the invention comprises modified nucleotides at internal base paired positions within the siNA duplex.
  • a double-stranded siNA molecule of the invention comprises modified nucleotides at non-base paired or overhang regions of the siNA molecule.
  • a double-stranded siNA molecule of the invention comprises modified nucleotides at terminal positions of the siNA molecule.
  • such terminal regions include the 3′-position and/or 5′-position of the sense and/or antisense strand or region of the siNA molecule.
  • any of the modified siNA molecules of the invention can have a modification in one or both oligonucleotide strands of the siNA duplex, for example in the sense strand, the antisense strand, or both strands.
  • each strand of the double-stranded siNA molecules of the invention can have one or more chemical modifications, such that each strand comprises a different pattern of chemical modifications.
  • each strand of a double-stranded siNA molecule of the invention comprises a different pattern of chemical modifications, such as any Stab modification chemistries described herein (see Table 9) or any combination thereof, i.e., different combinations of defined Stabilization chemistry (Stab) sense and antisense strands.
  • Stab Stabilization chemistry
  • the stabilization chemistries referred to in Table 9 as Stab cart be combined in any combination of sense/antisense chemistries, such as Slab 7/8, Stab 7/11, Stab 8/8, Stab 18/8, Stab 18/11, Stab 12/13, Stab 7/13, Stab 18/13, Stab 7/19, Stab 8/19, Stab 18/19, Stab 7/20, Stab 8/20, Stab 18/20, Stab 7/32, Stab 8/32, or Stab 18/32 or any other combination of Stabilization chemistries.
  • one or more (for example 1, 2, 3, 4 or 5) nucleotides at the 5′-end of the guide strand or guide region (also known as antisense strand or antisense region) of the siNA molecule are ribonucleotides.
  • the present invention provides a double-stranded short interfering nucleic acid (siNA) molecule that modulates the expression of CTNNB1, wherein the siNA comprises a sense strand and an antisense strand; each strand is independently 15 to 30 nucleotides in length; and the antisense strand comprises at least 15, 16, 17, 18, or 19 nucleotides having sequence complementary to any of:
  • siNA short interfering nucleic acid
  • the antisense strand of a siNA molecule of the invention comprises at least a 15, 16, 17, 18, or 19 nucleotide sequence of:
  • the sense strand of a siNA molecule of the invention comprises at least a 15, 16, 17, 18, or 19 nucleotide sequence of:
  • a siNA molecule of the invention comprises any of:
  • the nucleotides of the at least a 15, 16, 17, 18, or 19 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064 form a contiguous stretch of nucleotides.
  • the siNA molecule can contain one or more nucleotide deletions, substitutions, mismatches and/or additions to the at least 15, 16, 17, 18, or 19 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, SEQ ID NO: 5064; provided, however, that the siNA molecule maintains its activity, for example, to mediate RNAi.
  • the deletion, substitution, mismatch and/or addition can result in a loop or bulge, or alternately a wobble or other alternative (non Watson-Crick) base pair.
  • double-stranded siNA molecules wherein the molecule has a sense strand and an antisense strand and comprises the following formula (A):
  • nucleotides of the at least a 15, 16, 17, 18, or 19 nucleotide sequence of SEQ ID NO: 4918, SEQ ID NO: 5107, SEQ NO: 5109, or SEQ NO: 5064 form a contiguous stretch of nucleotides.
  • the siNA molecule of formula A can contain one or more nucleotide deletions, substitutions, mismatches and/or additions to the at least 15, 16, 17, 18, or 19 nucleotide sequence of SEQ ID NO: 4918, SEQ ID NO: 5107, SEQ ID NO: 5109, or SEQ ID NO: 5064; provided, however, that the siNA molecule maintains its activity, for example, to mediate RNAi.
  • the deletion, substitution, mismatch and/or addition can result in a loop or bulge, or alternately a wobble or other alternative (non Watson-Crick) base pair.
  • the invention features a double-stranded short interfering nucleic acid (siNA) of formula (A); wherein
  • the invention features a double-stranded short interfering nucleic acid (siNA) molecule of formula (A); wherein
  • the invention features a double-stranded short interfering nucleic acid (siNA) molecule of formula (A); wherein
  • the invention features a double-stranded short interfering nucleic acid (siNA) molecule of formula (A); wherein
  • the invention features a double-stranded short interfering nucleic acid (siNA) molecule of formula (A) further comprising one or more phosphorothioate internucleotide linkages.
  • siNA short interfering nucleic acid
  • siNA molecules having formula A comprise a terminal phosphate group at the 5′-end of the antisense strand or antisense region of the nucleic acid molecule.
  • siNA molecules having formula A comprise caps B at the 3′ and 5′ ends of the sense strand or sense region.
  • siNA molecules having formula A comprise caps (B) at the 3′-end of the antisense strand or antisense region.
  • siNA molecules having formula A comprise caps (B) at the 3′ and 5′ ends of the sense strand or sense region and caps (B) at the 3′-end of the antisense strand or antisense region.
  • siNA molecules having formula A comprise caps (B) only, at the 5′-end of the sense (upper) strand of the double-stranded nucleic acid molecule.
  • siNA molecules having formula A further comprise one or more phosphorothioate internucleotide linkages between the nucleotides. In certain embodiments, siNA molecules having formula A comprise one or more phosphorothioate internucleotide linkages between the first terminal (N) and the adjacent nucleotide on the 3′ end of the sense strand, antisense strand, or both sense strand and antisense strands of the nucleic acid molecule.
  • one or more of the nucleotides of siNA molecules having formula A have a universal base.
  • siNA molecules having formula A have at position 14 from the 5′-end of the antisense strand a ribonucleotide when the nucleotide at that position 14 is a purine. In other embodiments, siNA molecules having formula A have at position 14 from the 5′-end of the antisense strand a ribonucleotide, a 2′-deoxy-2′-fluoro nucleotide or a 2′-O-methyl nucleotide when the nucleotide at that position 14 is a pyrimidine nucleotide.
  • siNA molecules having formula. A comprises (N) nucleotides in the antisense strand (lower strand) that are complementary to nucleotides in a CTNNB1 target polynucleotide sequence, which also has complementarity to the N and [N] nucleotides of the antisense (lower) strand.
  • one or more siNA molecules of the invention are modified according to modification criteria as shown and described in U.S. Ser. No. 61/408,428 and U.S. Ser. No. 61/408,303, both of which are incorporated by reference herein.
  • siNAs of the invention can be obtained using a number of techniques known to those of skill in the art.
  • the siNA can be chemically synthesized or may be encoded by plasmid (e.g., transcribed as sequences that automatically fold into duplexes with hairpin loops).
  • siNA can also be generated by cleavage of longer dsRNA dsRNA greater than about 25 nucleotides in length) by the E. coli RNase II or Dicer. These enzymes process the dsRNA into biologically active siNA (see, e.g., Yang et al., PNAS USA 99:9942-9947 (2002); Calegari et al. PNAS USA 99:14236 (2002) Byron el al.
  • siNA of the invention are chemically synthesized.
  • Oligonucleotides e.g., certain modified oligonucleotides or portions of oligonucleotides lacking ribonucleotides
  • Oligonucleotides are synthesized using protocols known in the art, for example as described in Caruthers et al., 1992 , Methods in Enzymology 211, 3-19, Thompson et al., International PCT Publication No. WO 99/54459, Wincott et al., 1995 , Nucleic Acids Res. 23, 2677-2684, Wincott et al., 1997 , Methods Mol.
  • oligonucleotides intakes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end.
  • siNA molecules without modifications are synthesized using procedures as described in Usinan et al., 1987 J. Am. Chem. Soc., 109, 7845; Scaringe et al., 1990 , Nucleic Acids Res., 18, 5433. These syntheses makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end that can be used for certain siNA molecules of the invention.
  • the siNA molecules of the invention are synthesized, deprotected, and analyzed according to methods described in U.S. Pat. Nos. 6,995,259, 6,686,463, 6,673,918, 6,649,751, 6,989,442, and U.S. patent application Ser. No. 10/190,359.
  • small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 ⁇ mol scale protocol with a 2.5 min coupling step for 2′-O-methylated nucleotides and a 45 second coupling step for 2′-deoxy nucleotides or 2′-deoxy-2′-fluoro nucleotides.
  • Table 10 outlines the amounts and the contact times of the reagents used in the synthesis cycle.
  • siNA molecules of the present invention can be synthesized separately and joined together post-synthetically, for example, by ligation (Moore et al., 1992 , Science 256, 9923; Draper et al., International PCT Publication No. WO 93/23569; Shaharova et al., 1991 , Nucleic Acids Research 19, 4247; Bellon et al., 1997 , Nucleosides & Nucleotides, 16, 951; Belton et al., 1997 , Bioconjugate Chem. 8, 204), or by hybridization following synthesis and/or deprotection.
  • siNA molecules of the invention can also be synthesized using the teachings of Scaringe et al., U.S. Pat. Nos. 5,889,136; 6,008,400; and 6,111,086.
  • siNA molecules of the invention that interact with and down-regulate gene encoding target CTNNB1 molecules can be expressed and delivered from transcription units (see for example Couture et al., 1996 , TIG., 12, 510) inserted into DNA or RNA vectors.
  • the recombinant vectors can be DNA plasmids or viral vectors.
  • siNA expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus.
  • pol III based constructs are used to express nucleic acid molecules of the invention. Transcription of the siNA molecule sequences can be driven from a promoter for eukaryotic RNA polymerase I (pol I), RNA polymerase II (pot II), or RNA polymerase III (pol III).
  • poly I eukaryotic RNA polymerase I
  • pot II RNA polymerase II
  • RNA polymerase III polymerase III
  • Transcripts from pol II or pol III promoters are expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type depends on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby.
  • Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990 , Proc. Natl, Acad. Sci. USA, 87, 6743-7; Ciao and Huang 1993 , Nucleic Acids Res., 21, 2867-72; Lieber et al. 1993 , Methods Enzymol., 217, 47-66; Zhou et al., 1990 , Mol. Cell. Biol., 10, 4529-37).
  • nucleic acid molecules expressed from such promoters can function in mammalian cells (e.g.
  • transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA are useful in generating high concentrations of desired RNA molecules such as siNA in cells (Thompson et at, supra; Couture and Stinchcomb, 1996, supra; Noonberg et at, 1994 , Nucleic Acid Res., 22, 2830; Noonberg et al., U.S. Pat. No.
  • siNA transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (for a review see Couture and Stinchcomb, 1996, supra).
  • viral DNA vectors such as adenovirus or adeno-associated virus vectors
  • viral RNA vectors such as retroviral or alphavirus vectors
  • Vectors used to express the siNA molecules of the invention can encode one or both strands of an siNA duplex, or a single self-complementary strand that self hybridizes into an siNA duplex.
  • the nucleic acid sequences encoding the siNA molecules of the instant invention can be operably linked in a manner that allows expression of the siNA molecule (see for example Paul et al., 2002 , Nature Biotechnology, 19, 505; Miyagishi and Taira, 2002, Nature Biotechnology, 19, 497; Lee et al., 2002 , Nature Biotechnology, 19, 500; and Novina et al., 2002 , Nature Medicine , advance online publication doi:10.1038/nm725).
  • siNA molecules of the invention are added directly, or can be complexed with cationic lipids, packaged within liposomes, or as a recombinant plasmid or viral vectors which express the siNA molecules, or otherwise delivered to target cells or tissues.
  • Methods for the delivery of nucleic acid molecules are described in Akhtar et al., 1992 , Trends Cell Bio., 2, 139 ; Delivery Strategies for Antisense Oligonucleotide Therapeutics , ed. Akhtar, 1995, Maurer et al., 1999 , Mol. Membr. Biol., 16, 129-140; Holland and Huang, 1999 , Handb. Exp.
  • Nucleic acid molecules can be administered to cells by a variety of methods known to those of skill in the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as biodegradable polymers, hydrogels, cyclodextrins (see for example, Gonzalez et al., 1999 , Bioconjugate Chem., 10, 1068-1074; Wang et al., International PCT Publication Nos. WO 03/47518 and WO 03/46185), poly(lactic-co-glycolic)acid (PLGA) and PLCA microspheres (see for example U.S. Pat. No. 6,447,796 and US Patent Application Publication No. US 2002130430), biodegradable nanocapsules, and bioadhesive microspheres, or by proteinaceous vectors (O'Hare and Normand, International PCT Publication No. WO 00/53722).
  • biodegradable polymers such as poly
  • the present invention provides carrier systems containing the siNA molecules described herein.
  • the carrier system is a lipid-based carrier system, cationic lipid, or liposome nucleic acid complexes, a liposome, a micelle, a virosome, a lipid nanoparticle or a mixture thereof.
  • the carrier system is a polymer-based carrier system such as a cationic polymer-nucleic acid complex.
  • the carrier system is a cyclodextrin-based carrier system such as a cyclodextrin polymer-nucleic acid complex.
  • the carrier system is a protein-based carrier system such as a cationic peptide-nucleic acid complex.
  • the carrier system is a lipid nanoparticle (“LNP”) formulation.
  • the siNA molecules of the invention are formulated with a lipid nanoparticle composition such as is described in U.S. patent application Ser. Nos. 11/353,630, 11/586,102, 61/189,295, 61/204,878, 61/235,476, 61/249,807, 61/298,022, 61/351,373, 61/347,640, 61/345,754, 61/322,054, 12/640,342, and 12/617,079, and PCT Applications Nos. PCT/US10/020013 and PCT/US09/053336.
  • the siNA molecules of the invention are formulated with a lipid nanoparticle composition comprising a cationic lipid/Cholesterol/PEG-C-DMA/DSPC in a 40/48/2/10 ratio or a cationic lipid/Cholesterol/PEG-DMG/DSPC in a 40/48/2/10 ratio.
  • the cationic lipid is DLinDMA (see Table 12)
  • the PEG is PEG-DMG
  • the N/P ratio of the formulation is 2.8.
  • the cationic lipid is DLinDMA (see Tables 11 & 12).
  • lipid nanoparticle formulations described in Table 11 are applied to any siNA molecule or combination of siNA molecules herein.
  • the invention features a composition comprising an siNA molecule of the invention formulated as any of formulation LNP-051; LNP-053; LNP-054; LNP-069; LNP-073; LNP-077; LNP-080; LNP-082; LNP-083; LNP-060; LIMP-061; LNP-086; LNP-097; LNP-098; LNP-099; LNP-100; LNP-101; LNP-102; LNP-103; or LNP-104 (see Table 11).
  • the invention features a composition comprising an siNA molecule of the invention formulated with any of the cationic lipid formulations described in U.S. Patent Application Nos. 61/189,295, 61/204,878, 61/235,476, 61/249,807, and 61/298,022.
  • the invention features conjugates and/or complexes of siNA molecules of the invention.
  • Such conjugates and/or complexes can be used to facilitate delivery siNA molecules into a biological system, such as a cell.
  • the conjugates and complexes provided by the instant invention can impart therapeutic activity by transferring therapeutic compounds across cellular membranes, altering the pharmacokinetics, and/or modulating the localization of nucleic acid molecules of the invention.
  • Non-limiting, examples of such conjugates are described in U.S. Publication Nos. US2008/0152661 A1 and US 2004/0162260 A1 (e.g., CDM-LBA, CDM-Pip-LBA, CDM-PEG, CDM-NAG, etc) and U.S. patent application Ser.
  • polyethylene glycol can be covalently attached to siNA compounds of the present invention.
  • the attached PEG can be any molecular weight, preferably from about 100 to about 50,000 daltons (Da).
  • the invention features compositions or formulations comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes) and siNA molecules of the invention, such as is disclosed in for example, International PCT Publication No, WO 96/10391; Anson at al., International PCT Publication No, WO 96/10390; Holland et al., International PCT Publication No. WO 96/10392.
  • the siNA molecules of the invention can also be formulated or complexed with polyethyleneimine and derivatives thereof, such as polyethyleneimine-polyethyleneglycol-N-acetylgalactosamine (PEI-PEG-GAL) or polyethyleneimine-polyethyleneglycol-tri-N-acetyl galactosamine (PEI-PEG-triGAL) derivatives.
  • polyethyleneimine and derivatives thereof such as polyethyleneimine-polyethyleneglycol-N-acetylgalactosamine (PEI-PEG-GAL) or polyethyleneimine-polyethyleneglycol-tri-N-acetyl galactosamine (PEI-PEG-triGAL) derivatives.
  • the nucleic acid molecules of the invention are formulated as described in U.S. Patent Application Publication No. 20030077829.
  • siNA molecules of the invention are complexed with membrane disruptive agents such as those described in U.S. Patent Application Publication No. 20010007666.
  • the membrane disruptive agent or agents and the siNA molecule are also complexed with a cationic lipid or helper lipid molecule, such as those lipids described in U.S. Pat. No. 6,235,310.
  • siNA, molecules of the invention are complexed with delivery systems as described in U.S. Patent Application Publication Nos. 2003077829; 20050287551; 20050164220; 20050191627; 20050118594; 20050153919; 20050085486; and 20030158133; and International PCT Publication Nos. WO 00/03683 and WO 02/087541.
  • a liposomal formulation of the invention comprises an siNA molecule of the invention (e.g., siNA) formulated or complexed with compounds and compositions described in U.S. Pat. Nos. 6,858,224; 6,534,484; 6,287,591; 6,835,395; 6,586,410; 6,858,225; 6,815,432; 6,586,001; 6,120,798; 6,977,223; 6,998,115; 5,981,501; 5,976,567; 5,705,385; and U.S. Patent Application Publication Nos.
  • siNA siNA
  • siNA molecule expressing vectors can be systemic, such as by intravenous or intra-muscular administration, by administration to target cells ex-planted from a subject followed by, reintroduction into the subject, or by any other means that would allow for introduction into the desired target cell (for a review see Couture el al., 1996 , TIG., 12, 510).
  • Such recombinant plasmids can also be administered directly or in conjunction with a suitable delivery reagents, including, for example, the Mirus Transit LT1 lipophilic reagent; lipofectin; lipofectamine; cellfectin; polycations polylysine) or liposomes lipid-based carrier system, cationic lipid, or liposome nucleic acid complexes, a micelle, a virosome, a lipid nanoparticle.
  • a suitable delivery reagents including, for example, the Mirus Transit LT1 lipophilic reagent; lipofectin; lipofectamine; cellfectin; polycations polylysine
  • liposomes lipid-based carrier system cationic lipid, or liposome nucleic acid complexes, a micelle, a virosome, a lipid nanoparticle.
  • the present invention also provides nucleic acids in kit form.
  • the kit may comprise a container.
  • the kit typically contains a nucleic acid of the invention with instructions for its administration.
  • the nucleic acids may have a targeting moiety attached. Methods of attaching targeting moieties (e.g. antibodies, proteins) are known to those of skill in the art.
  • the nucleic acids are chemically modified.
  • the kit contains more than one siNA molecule of the invention.
  • the kits may comprise an siNA molecule of the invention with a pharmaceutically acceptable carrier or diluent.
  • the kits may further comprise excipients.
  • the present body of knowledge in CTNNB1 research indicates the need for methods to assay CTNNB1 activity and for compounds that can regulate CTNNB1 expression for research, diagnostic, and therapeutic use.
  • the nucleic acid molecules of the present invention can be used in assays to diagnose disease state related of CTNNB1 levels.
  • the nucleic acid molecules and pharmaceutical compositions can be used to treat disease states related to CTNNB1 RNA levels.
  • cancers including solid tumors.
  • cancers include: bilary tract cancer, bladder cancer, transitional cell carcinoma, urothelial carcinoma, osteosarcoma, brain cancer, gliomas, astrocytomas, breast carcinoma, metaplastic carcinoma, cervical cancer, cervical squamous cell carcinoma, rectal cancer, colorectal carcinoma, colon cancer, hereditary nonpolyposis colorectal cancer, colorectal adenocarcinomas, gastrointestinal stromal tumors (GISTs), endometrial carcinoma, endometrial stromal sarcomas, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, ocular melanoma, uveal melanoma, gallbladder carcinomas, gallbladder adenocarcinoma, renal cell carcinoma, clear cell renal cell carcinoma, transitional cell carcinoma, transitional cell carcinoma, transitional cell carcinoma, transitional cell carcinoma, transitional cell carcinoma
  • the siNA molecules of the invention can degrade the target CTNNB1 mRNA (and thus inhibit the diseases stated above). Inhibition of a disease can be evaluated by directly measuring the progress of the disease in a subject. It can also be inferred through observing a change or reversal in a condition associated with the disease. Additionally, the siNA molecules of the invention can be used as a prophylaxis. Thus, the use ref the nucleic acid molecules and pharmaceutical compositions of the invention can be used to ameliorate, treat, prevent, and/or cure these diseases and others associated with regulation of CTNNB1 gene expression.
  • siNA molecules of the instant invention provide useful reagents and methods for a variety of therapeutic, prophylactic, cosmetic, veterinary, diagnostic, target validation, genomic discovery, genetic engineering, and pharmacogenomic applications.
  • compositions of the siNA molecules described i.e., compositions in a pharmaceutically acceptable carrier or diluent.
  • pharmaceutical compositions include salts, esters, or salts of such esters, of the above compounds, e.g., acid addition salts, for example, salts of hydrochloric, hydrobromic, hydroiodic, acetic acid, and benzene sulfonic acid.
  • Other salts include for example, sodium, potassium, manganese, ammonium, and calcium salts.
  • formulations or compositions can comprise a pharmaceutically acceptable carrier or diluent as is generally known in the art.
  • the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5. In another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 4918. In yet another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 194. In still another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5107.
  • the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 196. In another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5109. In another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 151. In yet another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5064. In still another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising formula (A).
  • the siNA molecules of the invention are preferably formulated as pharmaceutical compositions prior to administering to a subject, according to techniques known in the art.
  • Pharmaceutical compositions of the present invention are characterized as being at least sterile and pyrogen-free. Methods for preparing pharmaceutical compositions of the invention are within the skill in the art for example as described in Remington's Pharmaceutical Science, 17 th ed., Mack Publishing Company, Easton, Pa. (1985).
  • compositions of the invention further comprise conventional pharmaceutical excipients and/or additives.
  • suitable pharmaceutical excipients include preservatives, flavoring agents, stabilizers, antioxidants, osmolality adjusting agents, buffers, and pH adjusting agents.
  • Suitable additives include physiologically biocompatible buffers (e.g., trimethylamine hydrochloride), addition of chelants (such as, for example, DTPA or DTPA-bisamide) or calcium chelate complexes (as for example calcium DTPA, CaNaDTPA-bisamide), or, optionally, additions of calcium or sodium salts (for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate).
  • chelants such as, for example, DTPA or DTPA-bisamide
  • calcium chelate complexes as for example calcium DTPA, CaNaDTPA-bisamide
  • calcium or sodium salts for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate.
  • antioxidants and suspending agents can be used.
  • Non-limiting examples of various types of formulations for local administration include ointments, lotions, creams, gels, foams, preparations for delivery by transdermal patches, powders, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (for example eye or nose drops), solutions/suspensions for nebulization, suppositories, pessaries, retention enemas and chewable or suckable tablets or pellets (for example for the treatment of aphthous ulcers) or liposome or microencapsulation preparations.
  • Ointments, creams and gels can, for example, can be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents.
  • suitable thickening and/or gelling agent and/or solvents can thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol.
  • Various thickening agents and gelling agents can be used depending on the nature of the base.
  • Non-limiting examples of such agents include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.
  • lotions can be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.
  • powders for external application can be formed with the aid of any suitable powder base, for example, talc, lactose or starch.
  • Drops can be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents, suspending agents or preservatives.
  • compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more such sweetening agents, flavoring agents, coloring agents or preservative agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients can be, for example, inert diluents; such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets can be uncoated or they can be coated by known techniques. In some cases such coatings can be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate; or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate
  • the aqueous suspensions can also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents and flavoring agents can be added to provide palatable oral preparations.
  • These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid
  • compositions of the invention can also be in the form of oil-in-water emulsions.
  • the oily phase can be a vegetable oil or a mineral oil or mixtures of these.
  • Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions can also contain sweetening and flavoring agents.
  • Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the nucleic acid molecules of the invention can also be administered in the form of suppositories, e.g., for rectal administration of the drug.
  • suppositories e.g., for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials include cocoa butter and polyethylene glycols.
  • Nucleic acid molecules of the invention can be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • the siNA and LNP compositions and formulations provided herein for use in pulmonary delivery further comprise one or more surfactants.
  • Suitable surfactants or surfactant components for enhancing the uptake of the compositions of the invention include synthetic and natural as well as full and truncated forms of surfactant protein A, surfactant protein B, surfactant protein C, surfactant protein D and surfactant Protein E, di-saturated phosphatidylcholine (other than dipalmitoyl), dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine; phosphatidic acid, ubiquinones, lysophosphatidylethanolamine, lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, dehydroepiandrosterone, dolic
  • siNAs and pharmaceutical formulations according to the invention can be administered to a subject alone or used in combination with or include one or more other therapeutic agents, for example, anticancer agents.
  • anticancer agents for example, anticancer agents.
  • combinations of the presently disclosed compounds with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), 6 th edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers.
  • a person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Such anti-cancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents and agents that interfere with cell cycle checkpoints.
  • the siNAs of the invention are also useful in combination with any therapeutic agent used in the treatment of HCC, for example, but not limitation sorafenib.
  • the instant compounds are particularly useful when co-administered with radiation therapy.
  • the invention provides a combination comprising an siNA molecule of the invention, such as for example, but not limitation, an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064; or formula (A) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof together with one or more anti-cancer or chemotherapeutic agents.
  • an siNA molecule of the invention such as for example, but not limitation, an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064; or formula (A) or
  • the instant siNA molecules of the invention are useful in combination with known anti-cancer agents including the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors.
  • known anti-cancer agents including the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors.
  • estrogen receptor modulators examples include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.
  • Examples of androgen receptor modulators that can be used in combination with the compounds of the invention include, hut are not limited to, finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • retinoid receptor modulators examples include, but are not limited to, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, ⁇ -difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
  • cytotoxic agents examples include, but are not limited to, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminediehloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu-(hex)platinum, benzylguanine
  • hypoxia activatable compound that can be used in combination with the compounds of the invention is tirapazamine.
  • proteasome inhibitors examples include, but are not limited to, lactacystin and bortezomib.
  • microtubule inhibitors/microtubule-stabilising agents that can be used in combination with the compounds of the invention include, but are not limited to, paclitaxel, vindesine sulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-prolyl-L-proline-t-butylamide, TDX258, the epothilones (see for example U.S. Pat. No
  • topoisomerase inhibitors that can be used in combination with the compounds of the invention include, but are not limited to, are topotecan, hycaptatmine, irinotecan, rubitecan, 6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1
  • inhibitors of mitotic kinesins include, but are not limited to, inhibitors described in PCT Publications WO 01/30768, WO 01/98278, WO 03/050,064, WO 03/050,122, WO 03019,527, WO 03/049,679, WO 03/049,678, WO04/039774, WO03/079973, WO03/099211, WO03/105855, WO03/106417, 5004/037171, WO04/058148, WO04/058700, WO04/126699, WO05/018638, WO05/019206, WO05/019205, WO05/018547, 4005/017190, US2005/0176776.
  • inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKIP1, inhibitors of CENP-E, inhibitors of MCAK, inhibitors of Kif14, inhibitors of Mphosph1 and inhibitors of Rabb-KIFL.
  • histone deacetylase inhibitors examples include, but are not limited to, TSA, oxamflatin, PXD101, MG98, valproic acid and scriptaid. Further reference to other histone deacetylase inhibitors may be found m the following manuscript; Miller, T. A. et al. J. Med. Chem. 216(24):5097-5116 (2003).
  • Inhibitors of kinases involved in mitotic progression include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK) (in particular inhibitors of PLK-1), inhibitors of bub-1 and inhibitors of bub-R1.
  • PLK Polo-like kinases
  • Antiproliferative agents that can be used in combination with the compounds of the invention include, but are not limited to, antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2′-deoxy-2′-methylidenecytidine, 2′-fluoromethylene-2′-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl
  • monoclonal antibody targeted therapeutic agents that can be used in combination with the compounds of the invention include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody, such as, for example, Bexxar.
  • HMG-CoA reductase inhibitors examples include, but are not limited to, lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®; see U.S. Pat. Nos.
  • prenyl-protein transferase inhibitors examples include, but are not limited to, can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. Nos. 5,420,245, 5,523,430, 5,532,359, 5,510,510, 5,589,485, 5,602,098, European Patent Publ. 0 618 221, European Patent 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.
  • angiogenesis inhibitors examples include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon- ⁇ , interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib ( PNAS , Vol, 89, p, 7384 (1992); JNCI , Vol, 69, p.
  • tyrosine kinase inhibitors such as inhibitors of the tyrosine
  • steroidal anti-inflammatories such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone
  • carboxyamidotriazole combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)
  • VEGF see, Nature Biotechnology , Vol. 17, pp. 963-968 (October 1999); Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).
  • agents that modulate or inhibit angiogenesis may also be used in combination with the compounds of the instant invention and include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. 38:679-692 (2000)).
  • agents that modulate or inhibit the coagulation and fibrinolysis pathways that can be used in combination with the compounds of the invention include, but are not limited to, heparin (see Thromb. Haemost. 80:10-23 (1998)), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res, 101:329-354 (2001)).
  • TAFIa inhibitors have been described in PCT Publication WO 03/013,526 and U.S. Ser. No. 60/349,925 (filed Jan. 18, 2002).
  • Agents that interfere with cell cycle checkpoints that can be used in combination with the compounds of the invention include, but are not limited to, inhibitors of ATR, ATM, the Chk1 and Chk2 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
  • RTKs receptor tyrosine kinases
  • agents that interfere with receptor tyrosine kinases (RTKs) include, but are not limited to, inhibitors of c-Kit, Eph, PDGF, Flt3 and CTNNB1.
  • Further agents include inhibitors of RTKs as described by Bunco-Jensen and Hunter, Nature, 41.1:355-365, 2001.
  • Inhibitors of cell proliferation and survival signaling pathway that can be used in combination with the compounds of the invention include, but are not limited to, inhibitors of EGER (for example gefitinib and erlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors of IGFR, inhibitors of cytokine receptors, inhibitors of CTNNB1, inhibitors of PI3K (for example LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in WO 02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US 2004-0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO 03/086403, WO 2004/041162, WO 2004/096131, WO 2004/096129, WO 2004/096135, WO 2004/096130,
  • Apoptosis inducing agents that can be used in combination with the compounds of the invention include, but are not limited to, activators of TNF receptor family members (including the TRAIL receptors).
  • NSAIDs that are selective COX-2 inhibitors that can be used in combination with the compounds of the invention include, but are not limited to, those NSAIDs disclosed in U.S. Pat. Nos. 5,474,995, 5,861,419, 6,001,843, 6,020,343, 5,409,944, 5,436,265, 5,536,752, 5,550,142, 5,604,260, 5,698,584, 5,710,140, WO 94/15932, U.S. Pat. Nos. 5,344,991, 5,134,142, 5,380,738, 5,393,790, 5,466,823, 5,633,272, and 5,932,598, all of which are hereby incorporated by reference.
  • Inhibitors of COX-2 that are particularly useful in combination with the compounds of the invention include: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and 5-chloro-3-(4-methylsulfonyl)-phenyl-2-(2-methyl-5-pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof.
  • Angiogenesis inhibitors that can be used in combination with the compounds of the invention include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)-phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino
  • Tyrosine kinase inhibitors that can be used in combination with the compounds of the invention include, but are not limited to, N-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one, 17-(allylamino)-17-demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-
  • Combinations with compounds other than anti-cancer compounds are also encompassed in the instant compositions and methods.
  • combinations of the instantly claimed compounds with PPAR- ⁇ (i.e., PPAR-gamma) agonists and PPAR- ⁇ (i.e., PPAR-delta) agonists are useful in the treatment of certain malignancies.
  • PPAR- ⁇ and PPAR- ⁇ are the nuclear peroxisome proliferator-activated receptors ⁇ and ⁇ .
  • the expression of PPAR- ⁇ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc, Pharmacol, 31:909-913 (1993); J. Biol. Chem. 274:9116-9121 (1999): Invest.
  • Examples of PPAR- ⁇ agonists and PPAR- ⁇ / ⁇ agonists that can be used in combination with the compounds of the invention include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, HT-501, MCC-555, GW2331, (GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionic acid (disclosed in U.S.
  • thiazolidinediones such as DRF2725, CS-011,
  • Another embodiment of the instant invention is the use of the presently disclosed compounds in combination with gene therapy for the treatment of cancer.
  • Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Pat. No.
  • a uPA/uPAR antagonist (“Adenovirus-Mediated Delivery of a uPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice,” Gene Therapy , August 5(8):1105-13 (1998)), and interferon gamma ( J Immunol 164:217-222 (2000)).
  • the compounds of the instant invention may also be administered in combination with an inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins.
  • MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (vaispodar).
  • a compound of the present invention may be employed in conjunction with anti-emetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy.
  • a compound of the present invention may be used in conjunction with other anti-emetic agents, especially neurokinin-1 receptor antagonists, 5H T3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Pat. Nos.
  • neurokinin-1 receptor antagonists especially 5H T3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Pat. Nos.
  • an antidopaminergic such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol.
  • an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is administered as an adjuvant for the treatment or prevention of emesis that may result upon administration of the instant compounds.
  • Neurokinin-1 receptor antagonists of use in conjunction with the compounds of the present invention are fully described, for example, in U.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European Patent Publication Nos.
  • the neurokinin-1 receptor antagonist for use in conjunction with the compounds of the present invention is selected from: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Pat. No. 5,719,147.
  • a compound of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids).
  • bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ihandronate (Boniva), incadronate or cimadronate clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.
  • a compound of the instant invention may also be administered with an agent useful in the treatment of anemia.
  • an anemia treatment agent is, for example, a continuous eyttropolesis receptor activator (such as epoetin alfa).
  • a compound of the instant invention may also be administered with an agent useful in the treatment of neutropenia.
  • a neutropenia treatment agent is, for example, a hematopoletic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF).
  • G-CSF human granulocyte colony stimulating factor
  • Examples of a G-CSF include filgrastim and PEG-filgrastim.
  • a compound of the instant invention may also be administered with an immunologic-enhancing drug, such as levamisole, isoprinosine and Zadaxin.
  • an immunologic-enhancing drug such as levamisole, isoprinosine and Zadaxin.
  • a compound of the instant invention may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors.
  • aromatase inhibitors include but are not limited to: anastrozole, letrozole and exemestane.
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with other siNA therapeutics.
  • the compounds of the instant invention may also be administered in combination with ⁇ -secretase inhibitors and/or inhibitors of NOTCH signaling.
  • Such inhibitors include compounds described in WO 01/90084, WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO 03/093264, WO 03/093251, WO 03/093253, WO 2004/039800, WO 2004/039370, WO 2005/030731, WO 2005/014553, U.S. Ser. No.
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with PARP inhibitors.
  • a compound of the instant invention may also be useful for treating cancer in combination with the following therapeutic agents: abarelix (Plenaxis Depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumahh (Carripath®); alitretinoin (Panretin®); allopurinol (Zyloprin®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine.
  • the invention also provides a combination comprising an siNA molecule of the invention comprising at least a 15 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064; or formula (A) and/or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with another CTNNB1 inhibitor.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.
  • the individual compounds of such combinations can be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.
  • the described molecules could be used in combination with one or more known compounds, treatments, or procedures to prevent or treat diseases, disorders, conditions, and traits described herein in a subject or organism as are known in the art, such as other CTNNB1 inhibitors.
  • one aspect of the invention comprises a method of treating a subject including, but not limited to, a human suffering from a condition which is mediated by the action, or by loss of action, of CTNNB1 gene expression, which method comprises administering to said subject an effective amount of a double-stranded siNA molecule of the invention.
  • the siNA molecules comprises at least a 15 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064; or formula (A).
  • the condition is or is caused by cancer.
  • the molecules and compositions of the instant invention are useful in a method for treating cancer.
  • Cancers treatable according to this aspect of the invention include bilary tract cancer, bladder cancer, transitional cell carcinoma, urothelial carcinoma, osteosarcoma, brain cancer, gliomas, astrocytomas, breast carcinoma, metaplastic carcinoma, cervical cancer, cervical squamous cell carcinoma, rectal cancer, colorectal carcinoma, colon cancer, hereditary nonpolyposis colorectal cancer, colorectal adenocarcinomas, gastrointestinal stromal tumors (GISTs), endotnetrial carcinoma, endometrial stromal sarcomas, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, ocular melanoma, uveal melanoma, gallbladder carcinomas, gallbladder adenocarcinoma, renal cell carcinoma, clear cell renal cell carcinoma,
  • the siNA molecules of the instant invention are useful in a method for treating or preventing cancer selected from: brain cancer, breast carcinoma, cervical cancer, colorectal carcinoma, renal cell carcinoma, leukemia, hepatocellular carcinoma, lung cancer, B-cell lymphomas, multiple myeloma, ovarian carcinoma, pancreatic cancer, prostate cancer, melanoma, and gastric carcinoma.
  • cancer selected from: brain cancer, breast carcinoma, cervical cancer, colorectal carcinoma, renal cell carcinoma, leukemia, hepatocellular carcinoma, lung cancer, B-cell lymphomas, multiple myeloma, ovarian carcinoma, pancreatic cancer, prostate cancer, melanoma, and gastric carcinoma.
  • the compounds of the instant invention are useful for treating breast carcinoma, colorectal carcinoma, hepatocellular carcinoma, lung cancer; and prostate cancer.
  • the compounds of the instant invention are useful for treating hepatocellular carcinoma.
  • the siNA molecules of the instant invention are useful in a method for the prevention or modulation of the metastases of cancer cells and cancer.
  • the siNA molecules of the instant invention are useful in a method to prevent or modulate the metastases of brain cancer, breast carcinoma, cervical cancer, colorectal carcinoma, renal cell carcinoma, leukemia, hepatocellular carcinoma, lung cancer, B-cell lymphomas, multiple myeloma, ovarian carcinoma, pancreatic cancer, prostate cancer, melanoma, and gastric carcinoma.
  • the administration of the siNA molecule is via local administration or systemic administration.
  • the invention features contacting the subject or organism with an siNA molecule of the invention via local administration to relevant tissues or cells, such as lung cells and tissues, such as via pulmonary delivery.
  • the invention features contacting the subject or organism with an siNA molecule of the invention via systemic administration (such as via intravenous or subcutaneous administration of siNA) to relevant tissues or cells, such as cancerous tissues or cells in a subject or organism.
  • siNA molecules of the invention are also used as reagents in ex vivo applications.
  • siNA reagents are introduced into tissue or cells that are transplanted into a subject for therapeutic effect.
  • the cells and/or tissue can be derived from an organism or subject that later receives the explant, or can be derived from another organism or subject prior to transplantation.
  • the siNA molecules can be used to modulate the expression of one or more genes in the cells or tissue, such that the cells or tissue obtain a desired phenotype or are able to perform a function when transplanted in vivo.
  • certain CTNNB1 target cells from a patient are extracted.
  • CTNNB1 siNAs targeting a specific nucleotide sequence within the cells under conditions suitable for uptake of the siNAs by these cells (e.g., using delivery reagents such as cationic lipids, liposomes and the like or using techniques such as electroporation to facilitate the delivery of siNAs into cells).
  • delivery reagents such as cationic lipids, liposomes and the like or using techniques such as electroporation to facilitate the delivery of siNAs into cells.
  • the cells are then reintroduced back into the same patient or other patients.
  • a pharmaceutically effective dose of the siNA molecules or pharmaceutical compositions of the invention is administered to the subject.
  • a pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) a disease state.
  • One skilled in the art can readily determine a therapeutically effective dose of the siNA of the invention to be administered to a given subject, by taking into account factors, such as the size and weight of the subject, the extent of the disease progression or penetration, the age, health, and sex of the subject, the route of administration, and whether the administration is regional or systemic. Generally, an amount between 0.1 ⁇ g/kg and 100 mg/kg body weight/day of active ingredients is administered dependent upon potency of the negatively charged polymer. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient.
  • the siNA molecules of the invention can be administered in a single dose or in multiple doses.
  • siNA molecules of the instant invention can be administered once monthly, once weekly, once daily (QD), or divided into multiple monthly, weekly, or daily doses, such as, for example, but not limitation, twice daily (BID), three times daily (TID), once every two weeks.
  • BID twice daily
  • TID three times daily
  • Persons of ordinary skill in the art can easily estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues.
  • the administration can be continuous, i.e., every day, or intermittently.
  • intermittent administration of a compound of the instant invention may be administration one to six days per week or it may mean administration in cycles (e.g. daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week) or it may mean administration on alternate days.
  • compositions or formulations can be administered in a variety of sways.
  • administration methods of the invention include oral, buccal, sublingual, parenteral (i.e., intraarticularly, intravenously, intraperitoneally, subcutaneously, or intramuscularly), local rectal administration or other local administration.
  • the composition of the invention can be administered by insufflation and inhalation. Administration can be accomplished via single or divided doses.
  • the pharmaceutical compositions are administered intravenously or intraperitoneally by a bolus injection (see, e.g., U.S. Pat. No. 5,286,634).
  • Lipid nucleic acid particles can be administered by direct injection at the site of disease or by injection at a site distal from the site of disease (see, e.g., Culver, HUMAN GENE THERAPY, MaryAnn Liebert, Inc., Publishers, New York. pp. 70-71 (1994)).
  • the siNA molecules of the invention and formulations or compositions thereof are administered to a cell, subject, or organism as is described herein and as is generally known in the art.
  • the siNA can be administered to the subject systemically as described herein or otherwise known in the art, either alone as a monotherapy or in combination with additional therapies described herein or as are known in the art.
  • Systemic administration can include, for example, pulmonary (inhalation, nebulization etc.) intravenous, subcutaneous, intramuscular, catheterization, nasopharangeal, transdermal, or oral/gastrointestinal administration as is generally known in the art.
  • the siNA can be administered to the subject locally or to local tissues as described herein or otherwise known in the art, either alone as a monotherapy or in combination with additional therapies as are known in the art.
  • Local administration can include, for example, inhalation, nebulization, catheterization, implantation, direct injection, dermal/transdermal application, patches, stenting, ear/eye drops, or portal vein administration to relevant tissues, or any other local administration technique, method or procedure, as is generally known in the art.
  • the siNA molecules of the invention and formulations or compositions thereof are administered to the liver as is generally known in the art (see for example Wen et al., 2004 , World J Gastroenterol., 10, 244-9; Murao et al., 2002 , Pharm Res., 19, 1808-14; Liu et al., 2003 , gene Ther., 10, 180-7; Hong et al., 2003, J Pharm Pharmacol., 54, 51-8; Herrmann et al., 2004 , Arch Virol., 149, 1611-7; and Matsuno et al., 2003 , gene Ther, 10, 1559-66).
  • the invention features the use of methods to deliver the siNA molecules of the instant invention to hematopoietic cells, including monocytes and lymphocytes. These methods are described in detail by Hartmann et al., 1998 , J. Phamacol. Exp. Ther., 285(2), 920-928; Kronenwett et al., 1998 , Blood, 91(3), 852-862; Rion and Phillips, 1997 , Biochim. Biophys. Acta., 1329(2), 345-356; Ma and Wei, 1996 , Leuk. Res., 20(11/12), 925-930; and Bongartz et al., 1994 , Nucleic Acids Research, 22(22), 4681-8.
  • the siNA molecules of the invention and formulations or compositions thereof are administered directly or topically (e.g., locally) to the dermis or follicles as is generally known in the art (see for example Brand, 2001 , Curr. Opin. Mol. Ther., 3, 244-8; Regnier et al., 1998 , J. Drug Target, 5, 275-89; Kanikkannan, 2002 , BioDrugs, 16, 339-47; Wraight et al., 2001 , Pharmacol. Ther., 90, 89-104; and Preat and Dujardin, 2001, STP PharmaSciences, 11, 57-68).
  • the siNA molecules of the invention and formulations or compositions thereof are administered directly or topically using a hydroalcoholic gel formulation comprising an alcohol (e.g., ethanol or isopropanol), water, and optionally including additional agents such isopropyl myristate and carbomer 980.
  • a hydroalcoholic gel formulation comprising an alcohol (e.g., ethanol or isopropanol), water, and optionally including additional agents such isopropyl myristate and carbomer 980.
  • the siNA are formulated to be administered topically to the nasal cavity.
  • Topical preparations can be administered by one or more applications per day to the affected area; over skin areas occlusive dressings can advantageously be used. Continuous or prolonged delivery can be achieved by an adhesive reservoir system.
  • an siNA molecule of the invention is administered iontophoretically, for example to a particular organ or compartment (e.g., the eye, back of the eye, heart, liver, kidney, bladder, prostate, tumor, CNS etc.).
  • a particular organ or compartment e.g., the eye, back of the eye, heart, liver, kidney, bladder, prostate, tumor, CNS etc.
  • iontophoretic delivery are described in, for example, WO 03/043689 and WO 03/030989, which are incorporated by reference in their entireties herein.
  • the siNA molecules of the invention and formulations or compositions thereof are administered to the lung as is described herein and as is generally known in the art.
  • the siNA molecules of the invention and formulations or compositions thereof are administered to lung tissues and cells as is described in U.S. Patent Publication Nos, 2006/0062758; 2006/0011289; and 2004/0077540.
  • compositions of the present invention can be made into aerosol formulations (i.e., they can be “nebulized”) to be administered via inhalation (e.g., intranasally or intratracheally) (see, Brigham et al, Am. J. Sci., 298:278 (1989)). Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
  • the siNA molecules of the invention and formulations thereof are administered via pulmonary delivery, such as by inhalation of an aerosol or spray dried formulation administered by an inhalation device or nebulizer, providing rapid local uptake of the nucleic acid molecules into relevant pulmonary tissues.
  • Solid particulate compositions containing respirable dry particles of micronized nucleic acid compositions can be prepared by grinding dried or lyophilized nucleic acid compositions, and then passing the micronized composition through, for example, a 400 mesh screen to break up or separate out large agglomerates.
  • a solid particulate composition comprising the siNA compositions of the invention cart optionally contain a dispersant which serves to facilitate the formation of an aerosol as well as other therapeutic compounds.
  • a suitable dispersant is lactose, which can be blended with the nucleic acid compound in any suitable ratio, such as a 1 to 1 ratio by weight.
  • Spray compositions comprising siNA molecules or compositions of the invention can, for example, be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurized packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.
  • aerosol compositions of the invention suitable for inhalation can be either a suspension or a solution and generally contain an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064; or formula (A), and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof.
  • a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-
  • the aerosol composition can optionally contain additional formulation excipients well known in the art such as surfactants.
  • additional formulation excipients well known in the art such as surfactants.
  • Non-limiting examples include oleic acid, lecithin or an oligolactic acid or derivative such as those described in WO94/21229 and WO98/34596 and co-solvents for example ethanol.
  • a pharmaceutical aerosol formulation of the invention comprising a compound of the invention and a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof as propellant, optionally in combination with a surfactant and/or a co-solvent.
  • the aerosol formulations of the invention can be buffered by the addition of suitable buffering agents.
  • Aerosol formulations can include optional additives including preservatives if the formulation is not prepared sterile.
  • Non-limiting examples include, methyl hydroxybenzoate, anti-oxidants, flavorings, volatile oils, buffering agents and emulsifiers and other formulation surfactants.
  • fluorocarbon or perfluorocarbon carriers are used to reduce degradation and provide safer biocompatible non-liquid particulate suspension compositions of the invention siNA and/or LNP formulations thereof).
  • a device comprising a nebulizer delivers a composition of the invention (e.g., siNA and/or LNP formulations thereof) comprising fluorochemicals that are bacteriostatic thereby decreasing the potential for microbial growth in compatible devices.
  • Capsules and cartridges comprising the composition of the invention for use in an inhaler or insufflator, of for example gelatine, can be formulated containing a powder mix for inhalation of a compound of the invention and a suitable powder base such as lactose or starch.
  • each capsule or cartridge contains an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064; or formula (A), and one or more excipients.
  • the compound of the invention can be presented without excipients such as lactose
  • the aerosol compositions of the present invention can be administered into the respiratory system as a formulation including particles of respirable size, particles of a size sufficiently small to pass through the nose, mouth and larynx upon inhalation and through the bronchi and alveoli of the lungs.
  • respirable particles range from about 0.5 to 10 microns in size.
  • the particulate range can be from 1 to 5 microns.
  • the particulate range can be from 2 to 3 microns. Particles of non-respirable size which are included in the aerosol tend to deposit in the throat and be swallowed, and the quantity of non-respirable particles in the aerosol is thus minimized.
  • a particle size in the range of 10-500 um is preferred to ensure retention in the nasal cavity.
  • an siNA composition of the invention is administered topically to the nose for example, for the treatment of rhinitis via pressurized aerosol formulations, aqueous formulations administered to the nose by pressurized pump or by nebulization.
  • Suitable formulations contain water as the diluent or carrier for this purpose.
  • the aqueous formulations for administration of the composition of the invention to the lung or nose can be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like.
  • siNA molecules of the invention can be formulated and delivered as particles and/or aerosols as discussed above and dispensed from various aerosolization devices known by, those of skill in the art.
  • Aerosols of liquid or non-liquid particles comprising an siNA molecule or formulation of the invention can be produced by any suitable means, such as with a device comprising a nebulizer (see for example U.S. Pat. No. 4,501,729) such as ultrasonic or air jet nebulizers.
  • a nebulizer see for example U.S. Pat. No. 4,501,729
  • ultrasonic or air jet nebulizers such as ultrasonic or air jet nebulizers.
  • Solid particle aerosols comprising an siNA molecule or formulation of the invention and surfactant can be produced with any solid particulate aerosol generator.
  • One type of solid particle aerosol generator used with the siNA molecules of the invention is an insufflator.
  • a second type of illustrative aerosol generator comprises a metered dose inhaler (“MDI”). MDIs containing siNA molecules or formulations taught herein can be prepared by methods of the art (for example, see Byron, above and WO96/32099).
  • the siNA molecules can also be formulated as a fluid formulation for delivery from a fluid dispenser, such as those described and illustrated in WO05/044354.
  • nebulizer devices are used in applications for conscious, spontaneously breathing subjects, and for controlled ventilated subjects of all ages.
  • the nebulizer devices can be used for targeted topical and systemic drug delivery to the lung.
  • a device comprising a nebulizer is used to deliver an siNA molecule or formulation of the invention locally to lung or pulmonary tissues.
  • a device comprising a nebulizer is used to deliver a an siNA molecule or formulation of the invention systemically.
  • siNA molecules of the invention can also be used for diagnostic applications, research applications, and/or manufacture of medicants.
  • the invention features a method for diagnosing a disease, trait, or condition in a subject comprising administering to the subject a composition of the invention under conditions suitable for the diagnosis of the disease, trait, or condition in the subject.
  • siNA molecules of the invention are used to down regulate or inhibit the expression of CTNNB1 proteins arising from haplotype polymorphisms that are associated with a trait, disease or condition in a subject or organism.
  • Analysis of CTNNB1 genes, or CTNNB1 protein or RNA levels can be used to identify subjects with such polymorphisms or those subjects who are at risk of developing traits, conditions, or diseases described herein. These subjects are amenable to treatment, for example, treatment with siNA molecules of the invention and any other composition useful in treating diseases related to target gene expression.
  • analysis of CTNNB1 protein or RNA levels can be used to determine treatment type and the course of therapy in treating a subject.
  • Monitoring of CTNNB1 protein or RNA levels can be used to predict treatment outcome and to determine the efficacy of compounds and compositions that modulate the level and/or activity of certain CTNNB1 proteins associated with a trait, disorder, condition, or disease.
  • the invention comprises use of a double-stranded nucleic acid according to the invention for use in the manufacture of a medicament.
  • the medicament is for use in treating a condition that is mediated by the action, or by loss of action, of CTNNB1.
  • the medicament is for use for the treatment of cancer.
  • the medicament is for use for the treatment of brain cancer, breast carcinoma, cervical cancer, colorectal carcinoma, renal cell carcinoma, leukemia, hepatocellular carcinoma, lung cancer, B-cell lymphomas, multiple myeloma, ovarian carcinoma, pancreatic cancer, prostate cancer, melanoma, and gastric carcinoma.
  • the compounds of the instant invention are useful for treating hepatocellular carcinoma.
  • siNAs wherein at least one strand comprises at least a 15 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064; or formula (A), are for use in a method for treating a cancer, such as, for example but not limitation, brain cancer, breast carcinoma, cervical cancer, colorectal carcinoma, renal cell carcinoma, leukemia, hepatocellular carcinoma, lung cancer, B-cell lymphomas, multiple myeloma, ovarian carcinoma, pancreatic cancer, prostate cancer, melanoma, and gastric carcinoma.
  • a cancer such as, for example but not limitation, brain cancer, breast carcinoma, cervical cancer, colorectal carcinoma, renal cell carcinoma, leukemia, hepatocellular carcinoma, lung cancer, B-cell lymphomas, multiple myeloma, ovarian carcinoma, pancreatic
  • siNA molecules were designed, synthesized and evaluated for efficacy against CTNNB1 gene expression.
  • Certain CTNNB1 sequences were designed and selected by methods set forth in U.S. Application No. 60/182,604. Other sequences were designed and selected using a proprietary algorithm.
  • the primary criteria for design of certain of the CTNNB1 sequences for human siNAs were (i) homology between two species (human and rhesus monkey) and (ii) high efficacy scores as determined by a proprietary algorithm.
  • the target sequences of the siNAs that were selected are set forth in Table 1a (target sequences).
  • the sense and antisense strands of the siNA, sequences corresponding to the target sequences in Table 1a are set forth in Table 1b.
  • Various chemically modified siNAs that were synthesized are set forth in Table 1c.
  • Target Site SEQ ID Target Sequence (human) NO: 1 UCGAGCUCAGAGGGUACGA 535 1 GAGGCUCUUGUGCGUACUG 1601 2 GCCCAGAAUGCAGUUCGCC 1709 3 CGAGCUCAGAGGGUACGAG 536 4 CUGUUGGAUUGAUUCGAAA 1797 5 GUCUGCUAUUGUACGUACC 853 6 AAUUCUUGGCUAUUACGAC 1143 7 GGAUGUUCACAACCGAAUU 2014 8 ACAGUAUGCAAUGACUCGA 520 9 AGCUUCCAGACACGCUAUC 814 10 UGUCUGCUAUUGUACGUAC 852 11 ACUGUUGGAUUGAUUCGAA 1796 12 CAGGAUACCCAGCCGUA 1901 13 GACACGCUAUCAUGCGUUC 822 14 UACUGUUGGAUUGAUUCGA 1795 15 UUCUUGGCUAUUACGACAG 1145 16 ACACGCUAUCAUGCGUU
  • Target Site human
  • SEQ ID NO: Sense Sequence Antisense Sequence SEQ ID NO: 535 1 UCGAGCUCAGAGGGUACGA UCGUACCCUCUGAGCUCGA 4914 1601 2 GAGGCUCUUGUGCGUACUG CAGUACGCACAAGAGCCUC 4915 1709 3 GCCCAGAAUGCAGUUCGCC GGCGAACUGCAUUCUGGGC 4916 536 4 CGAGCUCAGAGGGUACGAG CUCGUACCCUCUGAGCUCG 4917 1797 5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAG 4918 853 6 GUCUGCUAUUGUACGUACC GGUACGUACAAUAGCAGAC 4919 1143 7 AAUUCUUGGCUAUUACGAC GUCGUAAUAGCCAAGAAUU 4920 2014 8 GGAUGUUCACAACCGAAUU AAUUC
  • the two individual, complementary strands of the siNA were synthesized separately using solid phase synthesis, then purified separately by reversed phase solid phase extraction (SPE).
  • SPE reversed phase solid phase extraction
  • the complementary strands were annealed to form the double strand (duplex) and delivered in the desired concentration and buffer of choice.
  • the single strand oligonucleotides were synthesized using phosphoramidite chemistry on an automated solid-phase synthesizer, using procedures as are generally known in the art (see for example U.S. application Ser. No. 12/064,014).
  • a synthesis column was packed with solid support derivatized with the first nucleoside residue (natural or chemically modified). Synthesis was initiated by detritylation of the acid labile 5′-O-dimethoxytrityl group to release the 5′-hydroxyl.
  • a suitably protected phosphoramidite and a suitable activator in acetonitrile were delivered simultaneously to the synthesis column resulting in coupling of the amidite to the 5′-hydroxyl.
  • the column was then washed with a solvent, such as acetonitrile.
  • An oxidizing solution such as an iodine solution was pumped through the column to oxidize the phosphite triester linkage P(III) to its phosphotriester P(V) analog.
  • Unreacted 5′-hydroxyl groups were capped using reagents such as acetic anhydride in the presence of 2,6-lutidine and N-methylimidazole.
  • the elongation cycle was resumed with the detritylation step for the next phosphoramidite incorporation. This process was repeated until the desired sequence was synthesized.
  • the synthesis concluded with the final 5′-terminus protecting group (trityl or 5′-O-dimethoxytrityl).
  • the solid-support and associated oligonucleotide were dried under argon pressure or vacuum.
  • Aqueous base was added and the mixture was heated to effect cleavage of the succinyl linkage, removal of the cyanoethyl phosphate protecting group, and deprotection of the exocyclic amine protection.
  • the trityl-on solution of each crude single strand was purified using chromatographic purification, such as SPE RPC purification.
  • the hydrophobic nature of the trityl group permits stronger retention of the desired full-length oligo than the non-tritylated truncated failure sequences.
  • the failure sequences were selectively washed from the resin with a suitable solvent, such as low percent acetonitrile. Retained oligonucleotides were then detritylated on-column with trifluoroacetic acid to remove the acid-labile trityl group. Residual acid was washed from the column, a salt exchange was performed, and a final desalting of the material commenced.
  • the full-length oligo was recovered in a purified form with an aqueous-organic solvent. The final product was then analyzed for purity (HPLC), identity (Maldi-TOF MS), and yield (UV A 260 ). The oligos were dried via lyophilization or vacuum condensation.
  • Annealing Based on the analysis of the product, the dried oligos were dissolved in appropriate buffers followed by mixing equal molar amounts (calculated using the theoretical extinction coefficient) of the sense and antisense oligonucleotide strands. The solution was then analyzed for purity of duplex by chromatographic methods and desired final concentration. If the analysis indicated an excess of either strand, then the additional non-excess strand was titrated until duplexing was complete. When analysis indicated that the target product purity has been achieved the material was delivered and ready for use.
  • the material is transferred to the tangential flow filtration (TFF) system for concentration and desalting, as opposed to doing this prior to the annealing step.
  • TMF tangential flow filtration
  • Ultrafiltration The annealed product solution is concentrated using a TFF system containing an appropriate molecular weight cut-off membrane. Following concentration, the product solution is desalted via diafiltration using water until the conductivity of the filtrate is that of water.
  • Lyophilization The concentrated solution is transferred to a bottle, flash frozen and attached to a lyophilizer. The product is then freeze-dried to a powder. The bottle is removed from the lyophilizer and is now ready for use.
  • Human hepatoma cell line, HepG2, rhesus kidney epithelial cell line, LLC-MK2 Derivative, and the Huh7 cell line were grown in modified Eagle's medium. All the culture media were supplemented with 10% fetal bovine serum, 100 ⁇ g/ML streptomycin, 100 U/ml, penicillin, and 1% sodium bicarbonate.
  • Cells were plated in all wells of tissue-culture treated, plates at a final count of 3500 (HepG2 find LLC-MK2 Derivative and Huh7) cells/well in 100 ⁇ L of the appropriate culture media. The cells were cultured for overnight after plating at 37° C. in the presence of 5% CO 2 .
  • RNAiMax complexes containing siNA and RNAiMax (invitrogen) were created as follows. A solution of RNAiMax diluted 33-fold in OPTI-MEM was prepared. In parallel, solutions of the siNAs for testing were prepared to a final concentration of 120 nM in OPTI-MEM. After incubation of RNAiMax/OPTI-MEM solution at room temperature for 5 ruin, an equal volume of the siNA solution and the RNAiMax solution were added together for each of the siNAs.
  • siNA/RNAiMax where the concentration of siNA was 60 nM. This solution was incubated at room temperature for 20 minutes. After incubation, 20 ⁇ K of the solution was added to each of the relevant wells. The final concentration of siNA in each well was 10 nM and the final volume of RNAiMax in each well was 0.3 ul.
  • siNAs were transfected at 200, 150, 100 or 75 pM per well.
  • the siNA series are 6-fold serial dilution starting at 300 nM or 4-fold serial dilution starting at 40 nM. All transfections were set up as multiple biological replicates.
  • the time of incubation with the RNAiMax-siNA complexes was 24 hours and there was no change in media between transfection and harvesting for screening and dose response curve studies.
  • the time of incubation with the RNAiMax-siNA complexes was 24, 72, and 120 hours. There was no change in media between transfection and harvesting for 24- and 72-hour time points. Media was replaced with fresh media 72 hours after transfection for 120-hour time point.
  • the culture medium was aspirated and discarded from the wells of the culture plates at the desired time points.
  • the transfected cells were washed once with 50 uL DPBS solution per well.
  • Fifty microliters per well of the Lysis Solution from the TaqMan® Gene Expression Cells-to-CTTM Kit (Applied Biosystems, Cat #4399002) supplemented with DNase I was added directly to the plates to lyse the cells.
  • Five microliters per well of Stop Solution from the same kit was added to the plates to inactivate DNase I 5 minutes later.
  • the lysis plates were incubated for at least 2 minutes at room temperature. The plates can be stored for 2 hours at 4° C., or ⁇ 80° C. tor two months.
  • Each well of the reverse transcription plate required 10 uL of 2 ⁇ reverse transcriptase buffer, 1 uL of 20 ⁇ reverse transcription enzyme and 2 uL of nuclease-free water.
  • the reverse transcription master mix was prepared by mixing 2 ⁇ reverse transcription buffer, 20 ⁇ reverse transcription enzyme mix, and nuclease-free water. 13 uL of the reverse transcription master mix was dispensed into each well of the reverse transcription plate (semi-skirted). A separate reverse transcription plate was prepared for each cell plate. A separate reverse transcription plate was prepared for each cell plate. Seven microliters per lysate from the cell lysis procedure described above was added into each well of the reverse transcription plate.
  • the plate was sealed and spun on a centrifuge (1000 rpm for 30 seconds) to settle the contents to the bottom of the reverse transcription plate.
  • the plate was placed in a thermocycler at 37° C. for 60 min, 95° C. for 5 min, and 4° C. until the plate is removed from the thermocycler. Upon removal, if not used immediately, the plate was frozen at ⁇ 20° C.
  • the assays were performed on an ABI 7900 instrument, according to the manufacturer's instructions.
  • a TagMan Gene Expression Master Mix (provided in the Cells-to-CTTM Kit, Applied Biosystems, Cat #4399002) was used.
  • the PCR reactions were carried out at 50° C. for 2 min, 95° C. for 10 min followed by 40 cycles at 95° C. for 15 sees and 60° C. for 1 minute.
  • the baseline was set in the exponential phase of the amplification curve, and based on the intersection point of the baselines with the amplification curve, a Ct value was assigned by the instrument.
  • the non-targeting control siNA was, unless otherwise indicated, chosen as the value against which to calculate the percent inhibition (knockdown) of gene expression, because it is the most relevant control.
  • the level of protein was quantified using the Bio-Rad VersaDoc Imager according to the protocols of that piece of equipment. A pixel count was performed in each lane using an area of identical size. Each sample was then compared to the appropriate control treated sample and converted to a percent of protein remaining compared to control.
  • the CTNNB1 siNAs were designed and synthesized as described previously. Various siNAs were screened in HepG2, MK2D and Huh7 cells. The log 2 (fold change) in CTNNB1 gene expression data upon treatment with various modified CTNNB1 siNAs in human cells is shown in Table 3a. Each screen was performed at 24 hrs. Quantitative RT-PCR was used to assess the level of CTNNB1 mRNA and the data were normalized to the expression level of GAPDH (an ubiquitously expressed ‘house-keeping’ gene). Each treatment was then normalized against the non-CTNNB1 targeting control.
  • GAPDH an ubiquitously expressed ‘house-keeping’ gene
  • Huh7 Huh7 Mean SD siNA Duplex ID ⁇ Ct ⁇ Ct
  • R-008362791-000B 4.24 0.05
  • R-008362812-000F 4.17 0.02
  • R-008362689-000U 4.17 0.01
  • R-008362722-000N 4.17 0.04
  • R-008362932-000A 4.07 0.17
  • R-008363043-000H 4.05 0.02
  • R-008362875-000L 4.03 0.12
  • R-008308997-000F 3..99 0.35
  • R-008362947-000L 3..99 0.18
  • R-008362821-000P 3.95 0.11
  • R-008363070-000J 3.91 0.08
  • R-008362785-000U 3.88 0.06 R-008363031-000Y 3.88 0.10
  • the CTNNB1 siNAs were designed and synthesized as described previously. Various siNAs were screened in M1K2D cells. The log 2 (fold change) in CTNNB1 gene expression data upon treatment with various modified CTNNB1 siNAs in human cells is shown in Table 3c. Each screen was performed at 24 hrs. Quantitative RT-PCR was used to assess the level of CTNNB1 mRNA and the data were normalized to the expression level of GAPDH (a ubiquitously expressed ‘house-keeping’ gene). Each treatment was then normalized against the non-CTNNB1 targeting control.
  • GAPDH ubiquitously expressed ‘house-keeping’ gene
  • siNAs from Tables 3a & 3b were further analyzed for efficacy and potency in Huh7 cells use dose response curves. The results for these siNAs are shown in Table 4.
  • the potency 50 is the calculated siNA transfection concentration that produces 50% target mRNA knockdown. The IC50 was determined after 24 hour exposure time.
  • siNAs from Tables 3a & 3b were farther analyzed for efficacy and potency in MK2D cells using dose response curves. The results for these siNAs are shown in Table 5.
  • the potency 50 is the calculated siNA transfection concentration that produces 50% target mRNA knockdown. The IC50 was determined after 24 hour exposure time.
  • siNAs are reconstituted as 50 ⁇ M to 100 ⁇ M stock solution with H 2 O and added to human serum pre-warmed to 37° C. to a final concentration of 20 ⁇ g/mL. The mixture is then incubated at 37° C. for 0, 1 and 2 hours. At the end of each time point, the reactions are stopped by mixing with equal volume of Phenomenex Lysis-Loading Buffer. Oligotrucleotides are purified in 96-well format by Phenomenex Solid Phase Extraction and lyophilized until dry with Labconco Triad Lyo-00417. The lyophilized samples are reconstituted in 150 ⁇ L, of 1 mM EDTA prepared with RNase-free H 2 O.
  • sample solutions re then diluted 5 fold with 1 mM EDTA for liquid chromatography/mass spectrometry (LC/MS) analysis on ThermoFisher Orbitrap.
  • Scrum metabolites of the siNAs were determined based on the measured molecular weights.
  • C57Bl/6 mice are dosed with a single 3 mpk dose of LNP formulated siNAs through tail vein injection.
  • Serum or plasma samples are collected at 3 and 24 hours post-dose.
  • the cytokine and chemokine levels in these samples is measured with the SearchLight IR Cytokine Array from Aushon Biosciences according to the manufacturer's instruction.
  • the cytokines and chemokines measured are IL-1 ⁇ , IL-1 ⁇ , IL-6, KC, IL-10, IFN ⁇ , TNF, GMCSF, MIP-1 ⁇ , MCP-1/JE, and RANTES.
  • mice are dosed IV via tail vein injections with LNP encapsulated siNAs or vehicle control using 2 different 3-week dosing schemes: one 1 mg/kg dose for 3 consecutive days or a single 6 mg/kg does per week.
  • the mice are co-dosed with sorafertib at a dose of 100 mg/kg BID every day for 3 weeks.
  • Total tumor burden is measured by micro-CT scan imaging.
  • the animals are sacrificed 5 days after the last siNA dose (Day 23), and normal liver and tumor tissues from each animal is collected for RNA purification.
  • RNA is purified using RNeasy 96 kit (Qiagen, Cat #74182), cDNA is generated from total RNA using High Capacity cDNA Reverse Transcription Kit (Cat #: 4368813). Quantitative PCR reactions are performed with TaqMan. Universal PCR Master Mix (Cat #:4304437). Human CTNNB1 TaqMan Gene Expression Assay (Hs00355045_m1) and human GAPDH TaqMan. Gene Expression Assay is used to monitor the mRNA level of both transcripts in tumor tissue. Mouse CTNNB1 TaqMan. Gene Expression Assay (Mm00483033_m1) and mouse GAPDH TaqMan Gene Expression Assay is used to monitor the mRNA level of both transcripts in liver tissue. The expression level of CTNNB1 is normalized against GAPDH to minimize technical variations.
  • RNA from the liver biopsy tissue was purified using RNeasy 96 kit (Qiagen, Cat; 74182).
  • cDNA was generated from total RNA using High Capacity cDNA Reverse Transcription Kit (Cat #: 4368813). Quantitative PCR reactions were performed with TagMan Universal PCR Master Mix (Cat #: 4304437), Human CTNNB1 TaqMan Gene Expression Assay (Hs00355045_ml) and rhesus GAPDH TagMan Gene Expression Assay (Rh02621745_g1) is used to monitor the mRNA level of both transcripts in liver biopsy tissue. The expression level of CTNNB1 is normalized against GAPDH to minimize technical variations.
  • LNP formulations (DLinDMA/Cholesterol/S-PEG-C-DMA/DSPC in a 40/48/2/10 ratio) comprising the siNA are tested.
  • Log 2 (fold change) in CTNNB1 gene expression is determined on days 3, 7, 11, and 28 days post-dosing.
  • Pre-dose CTNNB1 expression levels for the monkey is measured 7 days before the first dosing.
  • mice were dosed IV via tail vein injections with LNP encapsulated siNAs or vehicle control using a single 0.33 mg/kg.
  • Five animals which received each treatment were sacrificed 2, 7, 14 and 21 days after the siNA dose, and liver tissues from each animal was collected for RNA purification.
  • Total RNA was purified using RNeasy 96 kit (Qiagen, Cat #74182).
  • cDNA was generated from total RNA using High Capacity cDNA Reverse Transcription Kit (Cat #: 4368813). Quantitative PCR reactions were performed with TagMan Universal PCR Master Mix (Cat #: 4304437).
  • Mouse CTNNB1 TaqMan Gene Expression Assay (Mm00483033_ml) and mouse GAPDH TaqMan Gene Expression Assay was used to monitor the mRNA level of both transcripts.
  • the expression level of CTNNB1 was normalized against GAPDH to minimize technical variations. Data is shown in Table 6.
  • Rhesus macaque monkeys were dosed with a single 3.34 mg/m 2 of body surface area dose of siNA loaded lipid nanoparticles through intravenous infusion.
  • liver biopsies were performed at various time points pre- and post-dose with 16T gauge Menghini needles for about 20 mg tissue per animal.
  • Whole blood and serum/plasma is also collected at different time points pre- and post-dose to monitor potential toxicity associated with the treatments. All procedures adhered to the regulations outlined in the USDA Animal Welfare Act (9 CFR, Parts 1, 2 and 3) and the conditions specified in The Guide for Care and Use of Laboratory Animals (ILAR publication, 1996, National Academy Press).
  • RNA from the liver biopsy tissue was purified using RNeasy 96 kit (Qiagen, Cat #74182), cDNA was generated from total RNA using High Capacity cDNA Reverse Transcription Kit (Cat #: 4368813). Quantitative PCR reactions were, performed with TaqMan Universal PCR Master Mix (Cat #: 4304437). Human CTNNB1 TaqMan Gene Expression Assay (Hs00355045_m1) and rhesus GAPDH TaqMan Gene Expression Assay (Rh02621745_g1) was used to monitor the mRNA level of both transcripts in liver biopsy tissue. The expression level of CTNNB1 was normalized against GAPDH to minimize technical variations. Data is shown in Table 7.
  • LNP formulations (DLinDMA/Cholesterol/S-PEG-C-DMA/DSPC in a 40/48/2/10 ratio) comprising the siNA were tested.
  • Log 2 (fold change) in CTNNB1 gene expression was determined on days 2 and 7 days post-dosing.
  • Pre-dose CTNNB1 expression levels for the monkey is measured 6 days before the first dosing.
  • the lipid nanoparticles were prepared by an impinging jet process.
  • the particles were formed by mixing lipids dissolved in alcohol with siNA dissolved in a citrate buffer.
  • the lipid solution contained a cationic lipid, a helper lipid (cholesterol), PEG (e.g. PEG-C-DMA, PEG-DMG) lipid, and DSPC at a concentration of 5-15 mg/mL with a target of 9-12 mg/mL in an alcohol (for example ethanol).
  • the ratio of the lipids had a mole percent range of 25-98 for the cationic lipid with a target of 35-65, the helper lipid had a mole percent range from 0-75 with a target of 30-50, the PEG lipid has a mole percent range from 1-15 with a target of 1-6, and the DSPC had a mole percent range of 0-15 with a target of 0-12.
  • the siNA solution contained one or more siNA sequences at a concentration range from 0.3 to 0.6 mg/mL with a target of 0.3-0.9 mg/mL in a sodium citrate buffered salt solution with pH in the range of 3.5-5.
  • the two solutions were heated to a temperature in the range of 15-40° C., targeting 30-40° C., and then mixed in an impinging jet mixer instantly forming the LNP.
  • the teeID had a range from 0.25 to 1.0 mm and a total flow rate from 10-600 mL/minute.
  • the combination of flow rate and tubing ID had the effect of controlling the particle size of the LNPs between 30 and 200 inn.
  • the LNP suspension was then mixed with a buffered solution at a higher pH with a mixing ratio in the range of 1:1 to 1:3 vol:vol, but targeting 1:2 vol:vol. This buffered solution was at a temperature in the range of 15-40° C., targeting 30-40° C.
  • This LNP suspension was further mixed with a buffered solution at a higher pH and with a mixing ratio in the range of 1:1 to 1:3 vol:vol, but targeting 1:2 vol:vol.
  • the buffered solution was at a temperature in the range of 15-40° C., targeting 30-40° C.
  • the mixed LNPs were held from 30 minutes to 2 hrs prior to an anion exchange filtration step.
  • the temperature during incubating was in the range of 15 ⁇ 40° C., targeting 30-40° C.
  • the LNP suspension was filtered through a 0.8 um filter containing an anion exchange separation step.
  • This process used tubing IDs ranging from 1 mm ID to 5 mm ID and a flow rate from 10 to 2000 mL/minute
  • the LNPs were concentrated and diafiltered via an ultrafiltration process where the alcohol was removed and the citrate buffer was exchanged for the final buffer solution such as phosphate buffered saline.
  • the ultrafiltration process used a tangential flow filtration format (TFF).
  • TFF tangential flow filtration format
  • This process used a membrane nominal molecular weight cutoff range from 30-500 KD.
  • the membrane format was hollow fiber or flat sheet cassette.
  • the TFF processes with the proper molecular weight cutoff retained the LNP in the retentate and the filtrate or permeate contained the alcohol; citrate buffer; and final buffer wastes.
  • the TFF process is a multiple step process with an initial concentration to a siNA concentration of 1-3 mg/mL. Following concentration, the LNP suspension was diafiltered against the final buffer for 10-20 volumes to remove the alcohol and perform buffer exchange. The material was then concentrated an additional 1-3 fold. The final steps of the LNP process were to sterile filter the concentrated LNP solution and vial the product.
  • the siNA duplex concentrations were determined by Strong Anion-Exchange High-Performance Liquid Chromatography (SAX-H PLC) using Waters 2695 Alliance system (Water Corporation, Milford Mass.) with a 2996 PDA detector.
  • the LNPs otherwise referred to as RNAi Delivery Vehicles (RDVs)
  • RDVs RNAi Delivery Vehicles
  • SAX separation using a Dionex BioLC DNAPac PA 200 (4 ⁇ 250 mm) column with UV detection at 254 nm.
  • Mobile phase was composed of A: 25 mM NaClO 4 , 10 mM Tris, 20% EtOH, pH 7.0 and B: 250 mM. NaClO 4 , 10 mM Tris, 20% EtOH, pH 7.0 with a liner gradient from 0-15 min and a flow rate of 1 ml/minute.
  • the siNA amount was determined by comparing to the siNA standard curve.
  • Fluorescence reagent SYBR Gold was employed for RNA quantitation to monitor the encapsulation rate of RDVs.
  • RDVs with or without Triton X-100 were used to determine the free siNA and total siNA amount.
  • the assay is performed using a SpectraMax M5e microplate spectrophotometer from Molecular Devices (Sunnyvale, Calif.). Samples were excited at 485 nm and fluorescence emission was measured at 530 nm. The siNA amount is determined by comparing to an siNA standard curve.
  • Encapsulation rate (1 ⁇ free siNA/total SiNA) ⁇ 00%
  • RDVs containing 1 ⁇ g siNA were diluted to a final volume of 3 ml with 1 ⁇ PBS.
  • the particle size and polydispersity of the samples was measured by a dynamic light scattering method using ZetaPALS instrument (Brookhaven instruments Corporation, Holtsville, N.Y.).
  • the scattered intensity was measured with He—Ne laser at 25° C. with a scattering angle of 90°.
  • RDVs containing 1 ⁇ g siNA were diluted to a final volume of 2 ml with 1 mM Tris buffer (pH 7.4). Electrophoretic mobility of samples was determined using ZetaPALS instrument (Brookhaven instruments Corporation, Holtsville, N.Y.) with electrode and He—Ne laser as a light source. The Smoluchowski limit was assumed in the calculation of zeta potentials,
  • lipid concentrations were determined by Reverse Phase High-Performance Liquid Chromatography (RP-HPLC) using Waters 2695 Alliance system (Water Corporation, Milford Mass.) with a Corona charged aerosol detector (CAD) (ESA Biosciences, Inc, Chelmsford, Mass.). Individual lipids in RDVs were analyzed using an Agilent Zorbax SB-C18 (50 ⁇ 4.6 runt, 1.8 ⁇ m particle size) column with CAD at 60° C. The mobile phase was composed of A: 0.1% TEA in H 2 O and B: 0.1% TEA in IPA.
  • the individual lipid concentration was determined by comparing to the standard curve with all the lipid components in the RDVs with a quadratic curve fit. The molar percentage of each lipid was calculated based on its molecular weight.
  • siNA nanoparticle suspensions in Table 11 were prepared by dissolving siNAs and/or carrier molecules in 20 mM sodium citrate buffer (pH 5.0) at a concentration of about 0.40 mg/mL.
  • Lipid solutions were prepared by dissolving a mixture of cationic lipid (e.g., (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine, see structure in Table 12), DSPC, Cholesterol, and PEG-DMG (ratios shown in Table 11) in absolute ethanol at a concentration of about 8 mg/mL. The nitrogen to phosphate ratio was approximated to 6:1.
  • cationic lipid e.g., (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine, see structure in Table 12
  • DSPC DSPC
  • Cholesterol Cholesterol
  • PEG-DMG ratios shown
  • LNPs were prepared in bulk as follows. The process consisted of (1) preparing a lipid solution; (2) preparing an siNA/carrier solution; (3) mixing/particle formation; (4) incubation; (5) dilution; (6) ultrafiltration and concentration.
  • siNA siNA styrene-maleic anhydride copolymer
  • the siNA was transferred to a depyrogenated 2 L glass reagent bottle.
  • the weighing container was rinsed 3 ⁇ with citrate buffer (20 mM, pH 5.0) and the rinses were placed into the 2 L glass bottle, QS with citrate buffer to 1 L.
  • the concentration of the siNA solution was determined with a UV spectrometer using the following procedure. 20 ⁇ L at was removed from the solution, diluted 50 times to 1000 ⁇ L, and the UV reading recorded at A260 nm after blanking with citrate buffer. This was repeated.
  • the concentration can be adjusted by adding more siNA/carrier powder, or adding more citrate buffer. This process can be repeated for the second siNA, if applicable
  • siNA/carrier solution comprised a single siNA duplex instead of a cocktail of two or more siNA duplexes and/or carriers
  • siNA/carrier was dissolved in 20 mM citrate buffer (pH 5.0) to give a final concentration of 0.4 mg/mL.
  • the lipid and ethanol solutions were then sterile filtered through a Pall Acropak 20 0.8/0.2 ⁇ m sterile filter PN 12203 into a depyrogenated glass vessel using a Master Flex Peristaltic Pump Model 7520-40 to provide a sterile starting material for the encapsulation process.
  • the filtration process was run at an 80 ml, scale with membrane area of 20 cm 2 .
  • the flow rate was 280 mL/minute. This process can be scaled by increasing the tubing diameter and the filtration area.
  • the sterile lipid/ethanol solution and the sterile siNA/carrier or siNA/carrier cocktail/citrate buffer (20 mM citrate buffer, pH 5.0) solutions were mixed in a 0.5 mm ID T-mixer (Mixing Stage 1) at equal, or nearly equal, flow rates.
  • the resulting outlet LNP suspension contained 40-50 vol % ethanol.
  • the sterile lipid/ethanol and the sterile siNA/carrier or siNA/carrier cocktail/citrate buffer solutions were mixed at flow rates of 54 mL/min and 66 mL/min, respectively, such that the total flow rate of the mixing outlet is 120 mL/min.
  • the outlet stream of Mixing Stage I was fed directly into a 4 mm ID T-mixer (Mixing Stage II), where it was diluted with a buffered solution at higher pH (20 mM sodium citrate, 300 mM sodium chloride, pH 6.0) at a ratio of 1:1 vol:vol 1%.
  • This buffered solution was at a temperature in the range of 30-40′C, and was delivered to the 4 mm T-mixer via a peristaltic pump (Cole Parmer Masterflex L/S 600 RPM) at a flow rate of 120 mL/min.
  • the outlet stream of Mixing Stage II was fed directly into a 6 min ID T-mixer (Mixing Stage III), where it was diluted with a buffered solution at higher pH (PBS, pH 7.4) at a ratio of 1:1 vol:vol %.
  • This buffered solution was at a temperature in the range of 15-25° C., and was delivered to the 6 mm T-mixer via peristaltic pump (Cole Parmer MasterFlex L/S 600 RPM) at a flow rate of 240 mil min.
  • the outlet stream of Mixing Stage III was held after mixing for 30 minute incubation.
  • the incubation was conducted at temperature of 35-40° C. and the in-process suspension was protected from light.
  • free (un-encapsulated) siNA was removed via anion exchange with Mustang Q chromatography filters (capsules).
  • the chromatography filters Prior to use, the chromatography filters were pre-treated sequentially with flushes of 1N Na0H, 1M NaCl, and a final solution of 12.5 vol % ethanol in PBS. The pH of the final flush was checked to ensure pH ⁇ 8.
  • the incubated LNP stream was then filtered via Mustang Q filters via peristaltic pump (Cole Partner MasterFlex L/S 600 RPM) at flow rate of approximately 100 mL/min. The filtered stream was received into a sterile glass container for ultrafiltration and concentration as follows.
  • the ultrafiltration process is a timed process and the flow rates must be monitored carefully. This is a two step process; the first is a concentration step taking the diluted material and concentrating approximately 8-fold, to a concentration of approximately 0.3-0.6 mg/mL siNA.
  • a ring-stand with a ultrafiltration membrane 100 kDa PES (Spectrum Labs) installed was attached to a peristaltic pump (Spectrum KrosFloII System).
  • 9.2 L of sterile distilled water was added to the reservoir; 3 L was drained to waste and the remainder was drained through permeate to waste.
  • 5.3 L of 0.25 N sodium hydroxide was added to the reservoir with 1.5 L drained to waste and 3.1 L drained through permeate to waste.
  • the remaining sodium hydroxide was held in the system for sanitization (at least 10 minutes), and then the pump was drained, 9.2 L of 70 (v/v) % isopropyl alcohol was added to the reservoir with 1.5 L drained to waste and the remainder drained through permeate to waste. 6 L of conditioning buffer (12.5% ethanol in phosphate buffered saline) was added with 1.5 L drained to waste and the remainder drained though the permeate until the waste was of neutral pH (7-8). A membrane flux value was recorded, and the pump was then drained.
  • the diluted LNP solution was placed into the reservoir to the 1.1 L mark.
  • the pump was turned on at 2.3 L/min. After 5 minutes of recirculation, the permeate pump was turned on at 62.5 mL/min and the liquid level was constant at approximately 950 mL in the reservoir.
  • the diluted LNP solution was concentrated from 9.8 L to 1.1 L in 140 minutes, and the pump was paused when all the diluted LNP solution has been transferred to the reservoir.
  • the second step was a diafiltration step exchanging the ethanol/aqueous buffer to phosphate buffered saline. During this step, approximately 10-20 diafiltration volumes of phosphate buffered saline were used. Following diafiltration, a second concentration was undertaken to concentrate the LNP suspension 3-fold to approximately 1-1.5 mg/mL siRNA. The concentrated suspension was collected into sterile, plastic PETG bottles. The final suspension was then filtered sequentially via Pall 0.45 um PES and Pall 0.2 um PES titters for terminal sterilization prior to vial filling.
  • the obtained LNPs were characterized in terms of particle size, Zeta potential, alcohol content, total lipid content, nucleic acid encapsulated, and total nucleic acid concentration.
  • Synthesis of the single carbon homologated cationic lipids v is a linear process starting from lipid ketone (iii). Conversion of the ketone to the nitrile (iv) is accomplished via treatment with TOSMIC and potassium tert-butoxide. Reduction of the nitrite to the primary amine followed by reductive amination provides final cationic lipids v.
  • Synthesis of two carbon homologated cationic lipids vii is a linear process starting from lipid ketone (iii). Conversion of the ketone to the ⁇ , ⁇ -unsaturated amide vi is accomplished under Peterson conditions. Conjugate reduction of the ⁇ , ⁇ -unsaturation is performed using LS-Selectride to give amide vii. Reduction of the amide with lithium aluminum hydride provides final cationic lipids viii.
  • Synthesis of allylic amine cationic lipids xv is a linear process starting with aldehyde x. Addition of t-butyl acetate generates P-hydroxy ester xi. Conversion of the hydroxyl functionality to a fluoro group followed by acid treatment generates ⁇ -fluoro acid xii. Conversion of the acid to the Weinreb amide followed by Grignard addition gives the ⁇ -fluoro ketone xiv. Reductive amination results in simultaneous elimination to generate the desired allylic amine xv.
  • 11,14-Eicosadienoic acid, (11Z,14Z)— 50 g, 162 mmol
  • N,O-Dimethythydroxylamine hydrochloride 31.6 g, 324 mmol
  • HOAt 44.1 g, 324 mmol
  • Et 3 N 45.2 mL, 324 mmol
  • EDC 62.1 g, 324 mmol
  • 11,14-eicosadienamide, N-methoxy-N-methyl-, (11Z,14Z)-1 (4 g, 11.38 mmol) was dissolved in dry THF (50.0 ml) in a 250 mL flask then 1 M nonylmagnesium bromide (22.76 22.76 mmol) was added under nitrogen at ambient temperature. After 10 min, the reaction was slowly quenched with excess sat. aq NH 4 Cl. The reaction was washed into a separator), funnel with hexane and water, shaken, the lower aqueous layer discarded, the upper layer dried with sodium sulfate, filtered, and evaporated to give crude ketone as a golden oil.
  • the silyl amide Peterson reagent (3.1 g, 16.7 mmol) was dissolved in THF (35 mL) and cooled to ⁇ 63° C. To this solution was added nBuLi (16.7 mmol, 6.7 mL of a 2,5M solution). The reaction was warmed to ambient temperature for 30 minutes. The ketone (5.0 g, 11.9 mmol) was dissolved in THF (25 mL) in a second flask. The Peterson reagent was transferred to the ketone solution at ⁇ 60 The reaction was warmed to ⁇ 40° C. for 1 hour, then warmed to 0° C. for 30 minutes.
  • ⁇ , ⁇ -unsatured amide vi (1 g, 2.1 mmol) and LS-Selectride (4.1 mmol, 4.1 mL of a 1M solution) were combined in a sealed tube and heated to 60° C. for 24 hours. The reaction was cooled to ambient temperature and partitioned between ammonium chloride solution and heptane. The organics were dried over sodium sulfate, filtered and evaporated in vacuo to give amide vii. This intermediate was carried directly into next reaction crude.
  • Ketone xiv (5.1 g, 11.7 mmol) was treated with dimethylamine (29.3 mmol, 14.7 mL of a 2M solution in THF) and titanium(IV) isopropoxide (6.7 g, 23.5 mmol) and the reaction was stirred at ambient temperature for 16 hours. To the reaction mixture was added ethanol (50 mL) followed by sodium borohydride (0.67 g, 17.6 mmol). The reaction was loaded directly onto a silica column and purified by flash chromatography (0-15% MeOH/DCM).
  • Compound 45 is DLinKC2DMA as described in Nature Biotechnology, 2010, 28, 172-176, WO 2010/042877 A1, WO 2010/048536 A2, WO 2010/088537 A2, and WO 2009/127060 A1.
  • Compound 46 is MC3 as described in WO 2010/054401, and WO 2010/144740 A1.
  • lipid nanoparticle compositions of the instant invention are useful for the delivery of oligonucleotides, specifically siNA molecules of the invention:
  • CTNNB1 Accession Numbers NM_001098210 Homo sapiens catenin (cadherin-associated protein), beta 1, 88 kDa. (CTNNB1), transcript variant 3, mRNA. NM_001098210.1 GI:148227671 NM_007614 Mus musculus catenin (cadherin associated protein), beta 1 (Ctnnb1), transcript variant 1, mRNA NM_007614.2 GI:31560726 NM_001115474 Macaca mulatta catenin (cadherin-associated protein), beta 1, 88 kDa. transcript variant (CTNNB1), mRNA. NM_001115474.1 GI:109041278
  • All Stab chemistries can be used in combination with each other for duplexes of the invention (e.g. as combinations of sense and antisense strand chemistries), or alternately can be used in isolation, e.g., for single stranded nucleic acid molecules of the invention.
  • All Stab chemistries can comprise 3'-overhang nucleotides having 2'-O-alkyl, 2'-deoxy-2'- fluoro, 2’-deoxy, LNA or other modified nucleotides or non-nucleotides.
  • All Stab chemistries typically comprise about 19-21 nucleotides, but can vary as described herein.
  • All Stab chemistries can also include a single ribonucleotide in the sense or passenger strand at the 11 th base paired position of the double-stranded nucleic acid duplex as determined from the 5'-end of the antisense or guide strand. All Stab chemistries can also have in place of the Stab designation above a 2'-deoxy-2'-fluoro modification at position 14 from the 5'end of the antisense strand regardless of whether it is a purine or pyrimidine at that position. All Stab chemistries of the antisense strand presented above can have a thymidine in place of a 2'-deoxy uridine at position 1, 2, and/or 3 from the 5' end of the antisense strand.
  • S sense strand.
  • AS antisense strand.
  • Stab 23 has a single ribonucleotide adjacent to 3'-CAP.
  • Stab 24 and Stab 28 have a single ribonucleotide at 5'-terminus.
  • Stab 25, Stab 26, Stab 27, Stab 35, Stab 35G*, Stab 35N*, Stab 35rev*, Stab 36, Stab 50*, Stab53*, Stab 53N*, and Stab 54 have three ribonucleotides at 5'-terminus.
  • Stab 29, Stab 30, Stab 31, Stab 33, and Stab 34 any purine at first three nucleotide positions from 5’-terminus are ribonucleotides.
  • ⁇ Stab 35 has 2'-O-methyl U at 3'-overhangs and three ribonucleotides at 5'-terminus.
  • ⁇ Stab 36 has 2'-O-methyl overhangs that are complementary to the target sequence, (naturally occurring overhangs) and three ribonucleotides at 5'-terminus.
  • Stab35G*, Stab 35N*, Stab35rev*, Stab50*, Stab53*, and Stab53N* do not allow for a 2'-O- methyl modification at position 14 of the guide strand as determined from the 5'-end.

Abstract

The present invention relates to compounds, compositions, and methods for the study, diagnosis, and treatment of traits, diseases and conditions that respond to the modulation of CTNNB1 gene expression and/or activity, and/or modulate a beta-catenin gene expression pathway. Specifically, the invention relates to double-stranded nucleic acid molecules including small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules that are capable of mediating or that mediate RNA interference (RNAi) against CTNNB1 gene expression.

Description

    SEQUENCE LISTING
  • The sequence listing submitted via EFS, in compliance with 37 CFR § 1.52(e)(5), is incorporated herein by reference. The sequence listing text file submitted via EFS contains the File “SequenceListingSIRONC2”, created on Jul. 25, 2011 which is 2,173,912 bytes in size.
  • BACKGROUND OF THE INVENTION
  • Beta catenin (also known as cadherin-associated protein and β-catenin), is a member of the catenin family of cytosolic proteins. β-catenin is encoded by the CTNNB1 gene.
  • β-catenin is a pivotal player in the Wnt/Wg signaling pathway, mediators of several developmental processes. In the absence of Wnt, glycogen synthase kinase 3 (GSK-3β), a serine/threonine protein kinase constitutively phosphorylates the 3-catenin protein. When Wnt is present and binds to any of the family members of the frizzled receptors (Fz), an intracellular signaling protein known as dishevelled (Dsh) is recruited to the membrane and phosphorylated. GSK-3β is inhibited by the activation of Dsh. As a result, β-catenin levels increase in the cytosol and are translocated into the nucleus to perform a variety of functions. β-catenin acts together with the transcription factors TCF and LEF to activate specific target genes involved in different processes.
  • β-catenin undergoes phosphorylation upon growth factor stimulation resulting in reduced cell adhesion, thereby functioning as a component of adherin junctions which are multiprotein complexes that mediate cell adhesion, cell-cell communication and cytoskeletal anchoring. (Willett et 1998, Curr. Opin, Genet, Dev. 8:95-102).
  • Thompson et al. suggest that β-catenin plays an important role in various aspects of liver biology including liver development (both embryonic and postnatal), liver regeneration following partial hepatectomy, hepatocyte growth factor (HGF)-induced hepatomegaly, liver zonation, and pathogenesis of liver cancer. (Thompson M D., 2007, Hepatology May; 45(5):1298-305).
  • Wang et al, (2008) have shown that β-catenin can function as an oncogene. (Wang et al., 2008, Cancer Epidemiol. Biomarkers Prev. 17 (8):2101-8). In patients with basal cell carcinoma an increased level in β-catenin is present and leads to the increase in proliferation of related tumors. Mutations in the β-catenin gene area cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), hepatoblastoma, and ovarian cancer.
  • The role of β-catenin in the development of colorectal cancer has been shown to be regulated by the expression product of the APC (adenomatous polyposis of the colon) gene, a tumor suppressor. (Korinek et al., Science, 1997, 275:1784-1787; Morin et al., Science, 1997, 275:1787-1790). The APC protein normally binds β-catenin in conjunction with TCF/LEF forming a transcription factor complex. Morin el al. (Morin et al., Science, 1997, 275:1787-1790) report that APC protein down-regulates the transcriptional activation mediated by β-catenin and Tcf-4 in colon cancer. Their results indicate that the regulation of β-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or β-catenin.
  • Mutations in the β-catenin gene are either truncations that lead to deletion of part of the N-terminus of β-catenin, or point mutations that affect the serine and threonine residues that are targeted by GSK3α/β or CKIα, These mutant β-catenin proteins are refractory to phosphorylation and thus escape proteasomal degradations. Consequently, β-catenin accumulates within affected cells. Stabilized and nuclear-localized β-catenin is a hallmark of nearly all cases of colon cancer. (Clevers, H., 2006, Cell 127:469-480). Morin et al. demonstrated that mutations of β-catenin that altered phosphorylation sites rendered the cells insensitive to APC-mediated down-regulation of β-catenin and that this disrupted mechanism was critical to colorectal tumorigenesis. (Morin et al., 1997, Science 275:1787-1790).
  • Other studies also report on the detection of mutations in β-catenin in various cancer cell lines (see e.g., Chan et al., 1999, Nature Genet. 21:410-413: Blaker et al., 1999, Genes Chromosomes Cancer 25:399-402; Sagae et al., 1999, Jpn. J. Cancer Res. 90:510-515; Wang et al., 2008, Cancer Epidemiol Biomarkers Prev. 17(8):2101-8). Additionally, abnormally high amounts of β-catenin have also been found in melanoma cell lines (see e.g, Ruhinfeld et al., 1997, Science, 275:1790-1792).
  • Likewise other cancers, such as hepatocellular carcinoma (HCC), have also been associated with the Wnt/beta-catenin pathway, HCC is a complex and heterogeneous disease accounting for more than 660,000 new cases per year worldwide. Multiple reports have shown that Wnt signaling components are activated in human HCC patients. Ativated Wnt signaling and nuclear beta-catenin correlate with recurrence of disease and poor prognosis (Takigawa et al. 2008, Curr Drug Targets November; 901):1013-24). Elevated nuclear beta-catenin staining has been documented in 17-66% of HCC patients (Zulehner et al. 2010, Am J Pathol. January; 176(1):472-81; Yu et al, 2009, Hepatol. May; 50(5):948-57). Merck's internal dataset on 300 HCC patient tumors generated in collaboration with the Hong Kong University indicates Writ signaling components are activated in 50% of HCC patients. External data have shown activating beta-catenin mutations in 13-40% of HCC patients, while inactivating Axin 1 or 2 mutations were present in 10% of HCC patients (Lee et al. 2006, Frontiers in Bioscience May 1:11:1901-1915).
  • Preclinical studies provide evidence that activation of the Wnt/beta-catenin pathway is important in the generation and maintenance of HCC. Liver-targeted disruption of APC in mice activates beta-catenin signaling and leads to the formation of HCC (Colnot et al. 2004, Proc. Natl Acad Sci USA. December 7; 101(49):17216-21). Although overexpression of a beta-catenin mutant lacking the GSK-3beta phosphorylation sites alone is not sufficient for hepatocarcinogenesis (Harada et al, 2002, Cancer Res. April 1; 62(7):1971-7), overexpression of tumorigenic mutant beta-catenin has been shown to make mice susceptible to HCC induced by DEN (diethylnitrosamine), a known carcinogen (Nejak-Bowen et al. 2010, Hepatology 2010 May; 51(5):1603-13. Interestingly, 95% of HCC tumors initiated by overexpression of the human Met receptor in mice (Tre-Met transgenic mouse model) harbor beta-catenin activating mutations (Tward et al. 2007, Proc Natl Acad Sci USA. September 11; 104(37); 14771-6). This finding reflects the human disease and suggests that the Wnt pathway cooperates with Met signaling during hepatocarcinogenesis. High rates of beta-catenin activating mutations are also found in other transgenic mouse models for HCC (16% beta-catenin mutations in FGF19, 55% in c-Myc and 41% in H-Ras transgenic mice) (Nicholes et al, 2002, Am J Pathol. June; 160(6):2295-307 de la. Coste et al 1998, Proc Natl Acad Sci USA. July 21; 95(15):8847-51).
  • Preclinical studies have also shown that beta-catenin is a valid target for HCC. Beta-catenin siRNAs inhibit proliferation and viability of human HCC cell lines (Zeng et al. 2007). Similarly, treatment of human HCC cell lines with an anti-Wnt-1 antibody or TCF4/beta-catenin antagonists induce apoptosis, reduction of c-Myc, cyclin D1 and survivin expression as well as suppress tumor growth in vivo (Wei et al. 2009, Mol Cancer September 24; 8:76; Wei el al. 2010, Int J Cancer. May 15; 126(10):2426-36.2010).
  • Hepatocellular carcinoma (HCC) is a common and aggressive cancer for which effective therapies are lacking. The Wnt/beta-catenin pathway is activated in a high proportion of HCC cases (˜50%), frequently owing to mutations in beta-catenin (i.e. CTNNB1) or in the beta-catenin destruction complex (e.g. Axin1). Moreover, the Writ pathway as a target has proven to be challenging and is currently undruggable by small molecule inhibitors, making beta-catenin an attractive target for an RNAi-based therapeutic approach (Llovet et al. 2008, Hepatology October: 48: 1312-1327).
  • Alteration of gene expression, specifically CTNNB1 gene expression, through RNA interference (hereinafter “RNAi”) is one approach for meeting this need. RNAi is induced by short single-stranded RNA (“ssRNA”) or double-stranded RNA (“dsRNA”) molecules. The short dsRNA molecules, called “short interfering nucleic acids (“siNA”)” or “short interfering RNA” or “siRNA” or “RNAi inhibitors” silence the expression of messenger RNAs (“mRNAs”) that share sequence homology to the siNA. This can occur via cleavage of the mRNA mediated by an endonuclease complex containing a siNA, commonly referred to as an RNA-induced silencing complex (RISC). Cleavage of the target RNA typically takes place in the middle of the region complementary to the guide sequence of the siNA duplex (Elbashir et al., 2001, Genes Dev., 15:188). In addition, RNA interference can also involve small RNA (e.g., micro-RNA or miRNA) mediated gene silencing, presumably through cellular mechanisms that either inhibit translation or that regulate chromatin structure and thereby prevent transcription of target gene sequences (see for example Allshire, 2002, Science, 297:1818-1819; Volpe et al., 2002, Science, 297:1833-1837: Jenuwein, 2002, Science, 297:2215-2218: and Hall et al., 2002, Science, 297:2232-2237). Despite significant advances in the field of RNAi, there remains a need for agents that can inhibit CTNNB1 gene expression and that can treat disease associated with CTNNB1 expression such as cancer.
  • SUMMARY OF THE INVENTION
  • The invention provides a solution to the problem of treating diseases that respond to the modulation of the CTNNB1 gene expression using novel short interfering nucleic acid (siNA) molecules to modulate CTNNB1 expression.
  • The present invention provides compounds, compositions, and methods useful for modulating the expression of CTNNB1 genes, specifically those CTNNB1 genes associated with cancer and for treating such conditions by RNA interference (RNAi) using small nucleic acid molecules.
  • In particular, the instant invention features small nucleic acid molecules, i.e., short interfering nucleic acid (siNA) molecules including, but not limited to, short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA) and circular RNA molecules and methods used to modulate the expression of CTNNB1 genes and/or other genes involved in pathways of CTNNB1 gene expression and/or activity.
  • In one aspect, the invention provides double-stranded short interfering nucleic acid (siNA) molecules that inhibit the expression of a CTNNB1 gene in a cell or mammal, wherein the double-stranded siNAs comprise a sense and an antisense stand. The antisense strand comprises a sequence that is complementary to at least a part of an RNA associated with the expression of the CTNNB1 gene. The sense strand comprises a sequence that is complementary to the antisense strand. In various embodiments, at least one strand comprises at least a 15 nucleotide sequence selected from the group of sequences consisting of SEQ ID NOS:1-6374. In certain embodiments, the antisense strand comprises at least 15, 16, 17, 18, or 19 nucleotides having sequence complementarity to a target sequence set forth in Table 1a. In other and/or in the same embodiments, the antisense strand comprises at least a 15, 16, 17, 18, or 19 nucleotide sequence of one of the antisense sequences set forth in Table 1b. In some embodiments, the sense strand comprises at least a 15, 16, 17, 18, or 19 nucleotide sequence of a sense strand sequence as set forth in Table 1b.
  • In certain embodiments of this aspect of the invention, double-stranded short interfering nucleic acid (siNA) molecules are provided wherein the antisense stand comprises a modified sequence as set forth in Table 1c that has sequence complementarity to a target sequence of the invention. In some embodiments, the sense strand also comprises a modified sequence as set for in Table 1c.
  • In certain embodiments, the present invention provides a double-stranded short interfering nucleic acid (siNA) molecule that modulates the expression of CTNNB1, wherein the siNA comprises a sense strand and an antisense strand; each strand is independently 15 to 30 nucleotides in length; and the antisense strand comprises at least 15, 16, 17, 18, or 19 nucleotides having sequence complementary to any of:
  • (SEQ ID NO: 5)
    5′-CUGUUGGAUUGAUUCGAAA-3′;
    (SEQ ID NO: 194)
    5′-ACGACUAGUUCAGUUGCUU-3′;
    (SEQ ID NO: 196)
    5′-GGAUGAUCCUAGCUAUCGU-3′;
    or
    (SEQ ID NO: 151)
    5′-CCAGGAUGAUCCUAGCUAU-3′.
  • In some embodiments of the invention, the antisense strand of a siNA molecule comprises at least a 15, 16, 17, 18, or 19 nucleotide sequence of
  • (SEQ ID NO: 4918)
    5′-UUUCGAAUCAAUCCAACAG-3′;
    (SEQ ID NO: 5107)
    5′-AAGCAACUGAACUAGUCGU-3′;
    (SEQ ID NO: 5109)
    5′-ACGAUAGCUAGGAUCAUCC-3′;
    or
    (SEQ ID NO: 5064)
    5′-AUAGCUAGGAUCAUCCUGG-3′;
  • In some embodiments, the sense strand of a siNA molecule of the invention comprises at least a 15, 16, 17, 18, or 19 nucleotide sequence of:
  • (SEQ ID NO: 5)
    5′-CUGUUGGAUUGAUUCGAAA-3′;
    (SEQ ID NO: 194)
    5′-ACGACUAGUUCAGUUGCUU-3′;
    (SEQ ID NO: 196)
    5′-GGAUGAUCCUAGCUAUCGU-3′;
    or
    (SEQ ID NO: 151)
    5′-CCAGGAUGAUCCUAGCUAU-3′.
  • In some embodiments, a siNA molecule of the invention comprises any of:
  • (SEQ ID NO: 5)
    5′-CUGUUGGAUUGAUUCGAAA-3′
    and
    (SEQ ID NO: 4918)
    5′-UUUCGAAUCAAUCCAACAG-3′;
    or
    (SEQ ID NO: 194)
    5′-ACGACUAGUUCAGUUGCUU-3′
    and
    (SEQ ID NO: 5107)
    5′-AAGCAACUGAACUAGUCGU-3′;
    or
    (SEQ ID NO: 196)
    5′-GGAUGAUCCUAGCUAUCGU-3′
    and
    (SEQ ID NO: 5109)
    5′-ACGAUAGCUAGGAUCAUCC-3′;
    or
    (SEQ ID NO: 151)
    5′-CCAGGAUGAUCCUAGCUAU-3′
    and
    (SEQ ID NO: 5064)
    5′-AUAGCUAGGAUCAUCCUGG-3′.
  • In some embodiments, a siNA molecule of the invention comprises SEQ ID NOS: 6372 and 6374.
  • In some embodiments, a siNA molecule of the invention comprises SEQ ID NOS: 6370 and 6369.
  • In some embodiments, a siNA molecule of the invention comprises SEQ ID NOS: 2021 and 2068.
  • In some embodiments, a siNA molecule of the invention comprises SEQ ID NOS: 6372 and 6373.
  • In some embodiments, a siNA molecule of the invention comprises SEQ ID NOS: 2147 and 6368
  • In some embodiments, the invention features a composition comprising:
      • (a) a double-stranded short interfering nucleic acid (siNA) of the invention;
      • (b) a cationic lipid compound having any of compound numbers 1-46 or any combination thereof:
      • (c) cholesterol:
      • (d) DSPC; and
      • (e) PEG-DMG.
  • In some embodiments, the invention features a composition comprising:
  • (a) a double-stranded short interfering nucleic acid (siNA) of the invention;
  • (b) (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,1b-dien-1-amine;
  • (c) cholesterol;
  • (d) DSPC; and
  • (e) PEG-DMG.
  • In some embodiments, the invention features a composition comprising:
      • (a) a double-stranded short interfering, nucleic acid (siNA) having SEQ ID NOS: 6372 and 6374;
      • (b) (13 Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
      • (c) cholesterol;
      • (d) DSPC; and
      • (e) PEG-DMG.
  • In some embodiments, she invention features a composition comprising:
      • (a) a double-stranded short interfering nucleic acid (siNA) having SEQ ID NOS: 6370 and 6369;
      • (b) (13Z,6Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
      • (c) cholesterol;
      • (d) DSPC; and
      • (e) PEG-DMG.
  • In some embodiments, the invention features a composition comprising:
      • (a) a double-stranded short interfering nucleic acid (siNA) having SEQ ID NOS: 2021 and 2068;
      • (b) (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
      • (c) cholesterol;
      • (d) DSPC; and
      • (e) PEG-DMG.
  • In some embodiments, the invention features a composition comprising:
      • (a) a double-stranded short interfering nucleic acid (siNA) having SEQ ID NOS: 6372 and 6373;
      • (b) (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
      • (c) cholesterol;
      • (d) DSPC; and
      • (e) PEG-DIM.
  • In some embodiments, the invention features a composition comprising:
      • (a) a double-stranded short interfering nucleic acid (siNA) having SEQ ID NOS: 2147 and 6368;
      • (b) (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
      • (c) cholesterol;
      • (d) DSPC; and
      • (e) PEG-DMG.
  • In some embodiments, a composition of the invention comprises any Cationic Lipid having any of compound numbers 1-46 in the following molar ratios:
  • Cationic Lipid/Cholesterol/PEG-DMG 56.6/38/5.4;
  • Cationic Lipid/Cholesterol/PEG-DMG 60/38/2;
  • Cationic Lipid/Cholesterol/PEG-DMG 67.3/29/3.7;
  • Cationic Lipid/Cholesterol/PEG-DMG 49.3/47/3.7;
  • Cationic Lipid/Cholesterol/PEG-DMG 50.3/44.3/5.4;
  • Cationic Lipid/Cholesterol/PEG-C-DMA/DSPC 40/48/2/10;
  • Cationic Lipid/Cholesterol/PEG-DMG/DSPC 40/48/2/10; and
  • Cationic Lipid/Cholesterol/PEG-DMG/DSPC 58/30/2/10.
  • In some embodiments, a composition of the invention comprises (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine, cholesterol, DSPC, and PEG-DMG, having a molar ratio of 50:30:10:2 respectively.
  • In some embodiments, a composition of the invention further comprises a cryo-protectant. In some embodiments, the cryoprotectant is Sucrose, Trehalose, Raffinose, Stachyose, Verbascose, Mannitol, Glucose, Lactose, Maltose, Maltotriose-heptose, Dextran, hydroxyethyl Starch, Insulin, Sorbitol, Glycerol, Arginine, Histidine, Lysine, Praline, Dimethylsulfoxide or any combination thereof. In some embodiments, the cryoprotectant is Sucrose. In some embodiments, the cryoprotectant is Trehalose. In some embodiments, the cryoprotectant is a combination of Sucrose and Trehalose.
  • In some embodiments of the invention, all of the nucleotides of siNAs of the invention are unmodified. In other embodiments, one or more (e.g., 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) of the nucleotide positions independently in either one or both strands of an siNA molecule are modified. Modifications include nucleic acid sugar modifications, base modifications, backbone (internucleotide linkage) modifications, non-nucleotide modifications, and/or any combination thereof. In certain instances, purine and pyrimidine nucleotides are differentially modified. For example, purine and pyrimidine nucleotides can be differentially modified at the 2′-sugar position (i.e., at least one purine has a different modification from at least one pyrimidine in the same or different strand at the 2′-sugar position). In certain instances the purines are unmodified in one or both strands, while the pyrimidines in one or both strands are modified. In certain other instances, the pyrimidines are unmodified in one or both strands, while the purines in one or both strands are modified. In some instances, at least one modified nucleotide is a 2′-deoxy-2′-fluoro nucleotide, a 2′-deoxy nucleotide, or a 2′-O-alkyl nucleotide. In some instances, at least 5 or more of the pyrimidine nucleotides in one or both stands are either all 2′-deoxy-2′-fluoro or all 2′-O-methyl pyrimidine nucleotides. In some instances, at least 5 or more of the purine nucleotides in one or both stands are either all 2′-deoxy-2′-fluoro or all 2′-O-methyl purine nucleotides. In certain instances, wherein the siNA molecules comprise one or more modifications as described herein, the nucleotides at positions 1, 2, and 3 at the 5′ end of the guide (antisense) strand are unmodified.
  • In certain embodiments, the siNA molecules of the invention have 3′ overhangs of one, two, three, or tour nucleotide(s) on one or bath of the strands. In other embodiments, the siNA molecules lack overhangs (i.e., have blunt ends). Preferably, the siNA molecule has 3′ overhangs of two nucleotides on both the sense and antisense strands. The overhangs can be modified or unmodified. Examples of modified nucleotides in the overhangs include, but are not limited to, 2′-O-alkyl nucleotides, 2′-deoxy-2′-fluoro nucleotides, locked nucleic acid (LNA) nucleotides, or 2′-deoxy nucleotides. The overhang nucleotides in the antisense strand can comprise nucleotides that are complementary to nucleotides in the CTNNB1 target sequence. Likewise, the overhangs in the sense stand can comprise nucleotides that are in the CTNNB1 target sequence. In certain instances, the siNA molecules of the invention have two 3′ overhang nucleotides on the antisense stand that are 2′-O-alkyl (e.g., 2′-O-methyl) nucleotides and two 3′ overhang nucleotides on the sense stand that are 2′-deoxy nucleotides. In other instances, the siNA molecules of the invention have two 3′ overhang nucleotides that are 2′-O-alkyl 2′-O-methyl) nucleotides on both the antisense stand and on the sense stand. In certain embodiments, the 2′-O-alkyl nucleotides are 2′-O-methyl uridine nucleotides. In certain instances, the overhangs also comprise one or more phosphorothioate linkages between nucleotides of the overhang.
  • In some embodiments, the siNA molecules of the invention have caps (also referred to herein as “terminal caps.” The cap can be present at the 5′-terminus (5′-cap) or at the 3′-terminus (3′-cap) or can be present on both termini, such as at the 5′ and 3′ termini of the sense strand of the siNA.
  • In some embodiments, the siNA molecules of the invention are phosphorylated at the 5′ end of the antisense strand. The phosphate group can be a phosphate, a diphosphate or a triphosphate.
  • The siNA molecules of the invention when double stranded can be symmetric or asymmetric. Each strand of these double stranded siNAs independently can range in nucleotide length between 3 and 30 nucleotides. Generally, each strand of the siNA molecules of the invention is about 15 to 30 (i.e., about 19, 20, 21, 22, 23 or 24) nucleotides in length.
  • The siNA molecules of the invention, which are double stranded or have a duplex structure, independently comprise about 3 to about 30 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) base pairs. Generally, the duplex structure of siNAs of the invention is between 15 and 30, more generally between 18 and 25, yet more generally between 19 and 24, and most generally between 19 and 21 base pairs in length.
  • In certain embodiments, double-stranded short interfering nucleic acid (siNA) molecules are provided, wherein the molecule has a sense strand and an antisense strand and comprises formula (A):
  • Figure US20230030119A1-20230202-C00001
      • wherein, the upper strand is the sense strand and the lower strand is the antisense strand of the double-stranded nucleic acid molecule; wherein the antisense strand comprises at least a 15, 16, 17, 18, or 19 nucleotide sequence of SEQ ID NO: 4918, SEQ ID NO: 5107, SEQ ID NO: 5109, or SEQ ID NO: 5064, and the sense strand comprises a sequence having complementarity to the antisense strand;
      • each N is independently a nucleotide which is unmodified or chemically modified or a non-nucleotide;
      • each B is a terminal cap that is present or absent;
      • (N) represents overhanging nucleotides, each of which is independently unmodified or chemically modified;
      • [N] represents nucleotides that are ribonucleotides;
      • X1 and X2 are independently integers from 0 to 4;
      • X3 is an integer from 15 to 30;
      • X4 is an integer from 9 to 30; and
      • X5 is an integer from 0 to 6, provided that the sum of X4 and X5 is 15-30.
  • In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) of formula (A); wherein
      • (a) one or more pyrimidine nucleotides in NX4 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, 2′-deoxy nucleotides, ribonucleotides, or any combination thereof,
      • (b) one or more purine nucleotides in NX4 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, 2′-deoxy nucleotides, ribonucleotides, or any combination thereof;
      • (c) one or more pyrimidine nucleotides in NX3 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, 2′-deoxy nucleotides, ribonucleotides, or any combination thereof; and
      • (d) one or more purine nucleotides in NX3 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, 2′-deoxy nucleotides, ribonucleotides,
  • The present invention further provides compositions comprising the double-stranded nucleic acid molecules described herein with optionally a pharmaceutically acceptable carrier or diluent.
  • The administration of the composition can be carried out by known methods, wherein the nucleic acid is introduced into a desired target cell in vitro or in vivo.
  • Commonly used techniques for introduction of the nucleic acid molecules of the invention into cells, tissues, and organisms include the use of various carrier systems, reagents and vectors. Non-limiting examples of such carrier systems suitable for use in the present invention include conjugates, nucleic-acid-lipid particles, lipid nanoparticles (LNP), liposomes, lipoplexes, micelles, virosomes, virus like particles (VLP), nucleic acid complexes, and mixtures thereof.
  • The compositions of the invention can be in the form of an aerosol, dispersion, solution (e.g., an injectable solution), a cream, ointment, tablet, powder, suspension or the like. These compositions may be administered in any suitable way, e.g. orally, sublingually, buccally, parenterally, nasally, or topically. In some embodiments, the compositions are aerosolized and delivered via inhalation.
  • The molecules and compositions of the present invention have utility over a broad range of therapeutic applications. Accordingly another aspect of this invention relates to the use of the compounds and compositions of the invention in treating a subject. The invention thus provides a method for treating a subject, such as a human, suffering from a condition which is mediated by the action, or by the loss of action, of CTNNB1, wherein the method comprises administering to the subject an effective amount of a double-stranded short interfering nucleic acid (siNA) molecule of the invention. In certain embodiments, the condition is cancer.
  • These and other aspects of the invention will be apparent upon reference to the following detailed description and attached figures. Moreover, it is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein and that different embodiments may be combined.
  • Additionally, patents, patent applications, and other documents are cited throughout the specification to describe and more specifically set forth various aspects of this invention. Each of these references cited herein is hereby incorporated by reference in its entirety, including the drawings.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 shows a non-limiting proposed mechanistic representation of target RNA degradation involved in RNAi, Double-stranded RNA (dsRNA), which is generated by RNA-dependent. RNA polymerase (RdRP) from foreign single-stranded RNA, for example transposon, or other exogenous RNA, activates the DICER enzyme that in turn generates siNA duplexes. Alternately, synthetic or expressed siNA can be introduced directly into a cell by appropriate means. An active siNA complex forms that recognizes a target RNA, resulting in degradation of the target RNA by the RISC endonuclease complex or in the synthesis of additional RNA by RNA-dependent RNA polymerase (RdRP), which can activate DICER and result in additional siNA molecules, thereby amplifying the RNAi response,
  • FIG. 2 shows non-limiting examples of chemically modified siNA constructs of the present invention using a generalized structure of a representative siNA duplex. The specific modifications shown in the figure can be utilized alone or in combination with other modifications of the figure, in addition to other modifications and features described herein with reference to any siNA molecule of the invention. In the figure, N stands for any nucleotide or optionally a non-nucleotide as described here. The upper strand, having B—NX3—(N)X2—B-3′ is the sense (or passenger) strand of the siNA, whereas the lower strand, having B(N)X1—NX4—[N]X5-5′ is the antisense (or guide) strand of the siNA. Nucleotides (or optional non-nucleotides) of internal portions of the sense strand are designated NX3 and nucleotides (or optional non-nucleotides) of internal portions of the antisense strand are designated NX4. Nucleotides (or optional non-nucleotides) of the internal portions are generally base paired between the two strands, but can optionally lack base pairing (e.g. have mismatches or gaps) in some embodiments. Nucleotides (or optional non-nucleotides) of overhang regions are designated by parenthesis (N). Nucleotides of the 5′-terminal portion of the antisense strand are designated [N]. Terminal caps are optionally present at the 5′ and/or 3′ end of the sense strand and further optionally present at the 3′-end of the antisense strand. Generally, each strand can independently range from about 15 to about 30 nucleotides in length, but can vary depending on the presence of any overhang nucleotides. In certain embodiments, X1 and X2 are independently integers front 0 to 4; X3 is an integer from 15 to 30; X4 is an integer from 9 to 30; X5 is an integer from 0 to 6, provided that the sum of X4 and X5 is 15-30. Various modifications are shown for the nucleotides of the sense and antisense strands of the siNA constructs. The (N) overhang nucleotide positions can be chemically modified as described herein (e.g., 2′-O-methyl, 2′-deoxy-2′-fluoro, 2′-deoxy, UNA, universal bases etc.) and can be either derived from a corresponding target nucleic acid sequence or not. The constructs shown in the figure can also comprise phosphorothioate linkages as described herein. For example, phosphorothioate linkages can exist between any N, (N), and/or [N] positions. Such phosphorothioate incorporation can be utilized between purine “R” and pyrimidine “Y” positions, or for stabilization of pyrimidine linkages in general. Furthermore, although not depicted on the Figure, the constructs shown in the figure can optionally include a ribonucleotide at the 9th position from the 5′-end of the sense strand or the 11th position based on the 5′-end of the guide strand by counting 11 nucleotide positions in from the 5′-terminus of the guide strand. Similarly, the antisense strand can include a ribonucleotide at the 14th position from the 5′-end, or alternately can be selected or designed so that a 2′-O-alkyl nucleotide (e.g., a 2′-O-methyl purine) is not present at this position. Furthermore, although not shown in the Figure, the 5′-terminal position of the antisense strand can comprise a terminal phosphate group as described herein. The antisense strand generally comprises sequence complementary to any target nucleic acid sequence of the invention, such as those set forth in Table 1a herein.
  • FIG. 3 shows non-limiting examples of certain combinations of modifications applied to the representative siNA, duplex described in FIG. 2 . The table shown below the representative structure provides specific combinations of (N)X1, (N)X2, NX3, NX4, and/or [N]X5 nucleotide (and optional non-nucleotide) positions. For example, combinations of 5 or more (e.g., 5, 6, 7, 8, 9, or 10 or more) NX3 and 5 or more (e.g., 5, 6, 7, 8, 9, or 10 or more) NX4 pyrimidine “Y” and purine “R” nucleotides are specified, each of which can independently have specific (N)X1, and/or (N)X2, substitutions as shown in the figure, in addition to optional phosphorothioate substitutions. The 5′-terminal antisense strand [N] nucleotides are generally ribonucleotides, but can also be modified or unmodified depending on if they are purine “R” or pyrimidine “Y” nucleotides
  • FIG. 4A-C shows non-limiting examples of different siNA constructs of the invention. The criteria of the representative structures shown in FIGS. 2 and 3 can be applied to any of the structures shown in FIG. 4A-C.
  • The examples shown in FIG. 4A (constructs 1, 2, and 3) have 19 representative base pairs; however, different embodiments of the invention include any number of base pairs described herein. Bracketed regions represent nucleotide overhangs, for example, comprising about 1, 2, 3, or 4 nucleotides in length, preferably about 2 nucleotides. Constructs 1 and 2 can be used independently for RNAi activity. Construct 2 can comprise a polynucleotide or non-nucleotide linker, which can optionally be designed as a biodegradable linker. In one embodiment, the loop structure shown in construct 2 can comprise a biodegradable linker that results in the formation of construct 1 in vivo and/or in vitro. In another example, construct 3 can be used to generate construct 2 under the same principle wherein a linker is used to generate the active siNA construct 2 in vivo and/or in vitro, which can optionally utilize another biodegradable linker to generate the active siNA construct 1 in vivo and/or in vitro. As such, the stability and/or activity of the siNA constructs can be modulated based on the design of the siNA construct for use in vivo or in vitro and/or in vitro.
  • The examples shown in FIG. 4B represent different variations of double-stranded nucleic acid molecule of the invention, such as microRNA, that can include overhangs, bulges, loops, and stem-loops resulting from partial complementarity. Such motifs having bulges, loops, and stem-loops are generally characteristics of miRNA. The bulges, loops, and stem-loops can result from any degree of partial complementarily, such as mismatches or bulges of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more nucleotides in one or both strands of the double-stranded nucleic acid molecule of the invention.
  • The example shown in FIG. 4C represents a model double-stranded nucleic acid molecule of the invention comprising a 19 base pair duplex of two 21 nucleotide sequences having dinucleotide 3′-overhangs. The top strand (1) represents the sense strand (passenger strand), the middle strand (2) represents the antisense (guide strand), and the lower strand (3) represents a target polynucleotide sequence. The dinucleotide overhangs (NN) can comprise a sequence derived from the target polynucleotide. For example, the 3′-(NN) sequence in the guide strand can be complementary to the 5′-[NN] sequence of the target polynucleotide. In addition, the 5′-(NN) sequence of the passenger strand can comprise the same sequence as the 5′-[NN] sequence of the target polynucleotide sequence. In other embodiments, the overhangs (NN) are not derived from the target polynucleotide sequence, for example where the 3′-(NN) sequence in the guide strand are not complementary to the 5′-[NN] sequence of the target polynucleotide and the 5′-(NN) sequence of the passenger strand can comprise different sequence from the 5′-[NN] sequence of the target polynucleotide sequence. In additional embodiments, any (NN) nucleotides are chemically modified, e.g., as 2′-O-methyl, 2′-deoxy-2′-fluoro, and/or other modifications herein. Furthermore, the passenger strand can comprise a ribonucleotide position N of the passenger strand. For the representative 19 base pair 21 mer duplex shown, position N can be 9 nucleotides in from the 3′ end of the passenger strand. However, in duplexes of differing length, the position. N is determined based on the 5′-end of the guide strand by counting 11 nucleotide positions in from the 5′-terminus of the guide strand and picking the corresponding base paired nucleotide in the passenger strand. Cleavage by Agog takes place between positions 10 and 11 as indicated by the arrow. In additional embodiments, there are two ribonucleotides, NN, at positions 10 and 11 based on the 5′-end of the guide strand by counting 10 and 11 nucleotide positions in from the 5′-terminus of the guide strand and picking the corresponding base paired nucleotides in the passenger strand.
  • FIG. 5 shows non-limiting examples of different stabilization chemistries (1-10) that can be used, for example, to stabilize the 5′ and/or 3′-ends of siNA sequences of the invention, including (1) [3-3′]-inverted deoxyribose, (2) deoxyribonucleotide; (3) [5′-3′]-3′-deoxyribonucleotide; (4) [5′-3]-ribonucleotide; (5) [5′-3′]-3′-O-methyl ribonucleotide; (6) 3′-glyceryl; (7) [3′-5′]-3′-deoxyribonucleotide; (8) [3′-3′]-deoxyribonucleotide; (9) [5′-2′]-deoxyribonucleotide; and (10) [5′-3′]-dideoxyribonucleotide (when X═O). In addition to modified and unmodified backbone chemistries indicated in the figure, these chemistries can be combined with different sugar and base nucleotide modifications as described herein.
  • FIG. 6 shows a non-limiting example of a strategy used to identify chemically modified siNA constructs of the invention that are nuclease resistant while preserving the ability to mediate RNAi activity. Chemical modifications are introduced into the siNA construct based on educated design parameters (e.g. introducing 2′-modifications, base modifications; backbone modifications, terminal cap modifications etc). The modified construct is tested in an appropriate system (e.g., human serum for nuclease resistance, shown, or an animal model for PK/delivery parameters). In parallel, the siNA construct is tested for RNAi activity, for example in a cell culture system such as a luciferase reporter assay and/or against endogenous mRNA). Lead siNA constructs are then identified which possess a particular characteristic while maintaining RNAi activity, and can be further modified and assayed once again. This same approach can be used to identify siNA-conjugate molecules with improved pharmacokinetic profiles, delivery, and RNAi activity.
  • FIG. 7 shows non-limiting examples of phosphotylated siNA molecules of the invention, including linear and duplex constructs and asymmetric derivatives thereof.
  • FIG. 8 shows non-limiting examples of chemically modified terminal phosphate groups of the invention.
  • FIG. 9 shows a non-limiting example of a cholesterol linked phosphoramidite that can be used to synthesize cholesterol conjugated siNA molecules of the invention. An example is shown with the cholesterol moiety linked to the 5′-end of the sense strand of an siNA molecule.
  • FIG. 10 depicts an embodiment of 5′ and 3′ inverted abasic cap linked to a nucleic acid strand.
  • DETAILED DESCRIPTION OF THE INVENTION A. Terms and Definitions
  • The following terminology and definitions apply as used in the present application.
  • The term “abasic” as used herein refers to its meaning as is generally accepted in the art. The term generally refers to sugar moieties lacking a nucleobase or having a hydrogen atom (H) or other non-nucleobase chemical groups in place of a nucleobase at the position of the sugar moiety, see for example Adamic et al., U.S. Pat. No. 5,998,203. In one embodiment, an abasic moiety of the invention is a ribose, deoxyribose, or dideoxyribose sugar.
  • The term “acyclic nucleotide” as used herein refers to its meaning as is generally accepted in the art. The term generally refers to any nucleotide having an acyclic ribose sugar, for example where any of the ribose carbon/carbon or carbon/oxygen bonds are independently or in combination absent from the nucleotide.
  • The term “alkyl” as used herein refers to its meaning as is generally accepted in the art. The term generally refers to a saturated or unsaturated hydrocarbons, including straight-chain, branched-chain, alkenyl, alkynyl groups and cyclic groups, but excludes aromatic groups. Notwithstanding the foregoing, alkyl also refers to non-aromatic heterocyclic: groups. Preferably, the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkyl group can be substituted or unsubstituted. When substituted, the substituted group(s) is preferably, hydroxyl, halogen, cyano C1-C4 alkoxy, ═O, ═S, —NO2, SH, NH2, or NR1R2, where R1 and R2 independently are H or C1-C4 alkyl.
  • The phrase “agents that interfere with cell cycle checkpoints” refers to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents.
  • The phrase “agents that interfere with receptor tyrosine kinases (RTKs)” refers to compounds that inhibit RTKs and therefore inhibit mechanisms involved in oncogenesis and tumor progression.
  • The phrase “androgen receptor modulators” refers to compounds that interfere or inhibit the binding of androgens to the receptor, regardless of mechanism.
  • The phrase “angiogenesis inhibitors” refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • The term “aryl” as used herein refers to its meaning as is generally accepted in the art. The term generally refers to an aromatic group that has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which can be optionally substituted. The preferred substituent(s) of aryl groups are halogen, trihalomethyl, hydroxyl, SH, OH, cyano, C1-C4 alkoxy, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, NH2, and NR1, R2 groups, where R1 and R2 independently are H or C1-C4
  • The term “alkylaryl” as used herein refers to its meaning as is generally accepted in the art. The term generally refers to an alkyl group (as described above) covalently joined to an aryl group (as described above). Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms. The carbon atoms are optionally substituted. Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and examples of heterocyclic aryl groups having such heteroatoms include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted. Preferably, the alkyl group is a C1-C4 alkyl group.
  • The term “amide” as used herein refers to its meaning as is generally accepted in the art. The term generally refers to an —C(O)—NH—R, where R is either alkyl, aryl, alkylaryl or hydrogen.
  • The phrase “antisense region” as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to a nucleotide sequence of an siNA molecule having complementarity to a target nucleic acid sequence. In addition, the antisense region of an siNA molecule can optionally comprise a nucleic acid sequence having complementarily to a sense region of the siNA molecule. In one embodiment, the antisense region of the siNA molecule is referred to as the antisense strand or guide strand.
  • The phrase “asymmetric hairpin” refers to a linear siNA molecule comprising an antisense region, a loop portion that can comprise nucleotides or non-nucleotides, and a sense region that comprises fewer nucleotides than the antisense region to the extent that the sense region has enough complementary nucleotides to base pair with the antisense region and form a duplex with loop. For example, an asymmetric hairpin siNA molecule or the invention can comprise an antisense region having length sufficient to mediate RNAi in a cell or in vitro system (e.g. about 15 to about 30, or about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides) and a loop region comprising about 4 to about 12 (e.g., about 4, 5, 6, 7, 8, 9, 10, 11, or 12) nucleotides, and a sense region having about 3 to about 25 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) nucleotides that are complementary to the antisense region. The asymmetric hairpin siNA molecule can also comprise a 5′-terminal phosphate group that can be chemically modified. The loop portion of the asymmetric hairpin siNA molecule can comprise nucleotides, non-nucleotides, linker molecules, or conjugate molecules as described herein.
  • The term “biodegradable” as used herein refers to its meaning as is generally accepted in the art. The term generally refers to degradation in a biological system, for example, enzymatic degradation or chemical degradation.
  • The term “biodegradable linker” as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to a linker molecule that is designed to connect one molecule to another molecule, and which is susceptible to degradation in a biological system. The linker can be a nucleic acid or non-nucleic acid based linker. For example, a biodegradable linker can be used to attach a ligand or biologically active molecule to an siNA molecule of the invention. Alternately, biodegradable linker can be used to connect the sense and antisense strands of an siNA molecule of the invention. The biodegradable linker is designed such that its stability can be modulated for a particular purpose, such as delivery to a particular tissue or cell type. The stability of a nucleic acid-based biodegradable linker molecule can be modulated by using various chemistries, for example combinations of ribonucleotides, deoxyribonucleotides, and chemically modified nucleotides, such as 2′-O-methyl, 2′-fluoro, 2′-amino, 2′-O-amino, T-C-allyl, 2′-O-allyl, and other 2′-modified or base modified nucleotides. The biodegradable nucleic acid linker molecule can be a dirtier, trimer, tetramer or longer nucleic acid molecule, for example, an oligonucleotide of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, or can comprise a single nucleotide with a phosphorus-based linkage, for example, a phosphoramidate or phosphodiester linkage. The biodegradable nucleic acid linker molecule can also comprise nucleic acid backbone, nucleic acid sugar, or nucleic acid base modifications.
  • The phrase “biologically active molecule” as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to compounds or molecules that are capable of eliciting or modifying a biological response in a system and/or are capable of modulating the pharmacokinetics and/or pharmacodynamics of other biologically active molecules. Examples of biologically active molecules, include siNA molecules alone or in combination with other molecules including, but not limited to therapeutically active molecules such as antibodies, cholesterol, hormones, antivirals, peptides, proteins, chemotherapeutics, small molecules, vitamins, co-factors, nucleosides, nucleotides, oligonucleotides, enzymatic nucleic acids, antisense nucleic acids, triplex forming oligonucleotides, polyamines, polyamides, polyethylene glycol, other polyethers, 2-5A chimeras, siNA, dsRNA, allozymes, aptamers, decoys and analogs thereof.
  • The phrase “biological system” as used herein refers to its meaning as is generally accepted in the art. The term generally refers to material, in a purified or unpurified form, from biological sources including, but not limited to, human or animal, wherein the system comprises the components required for RNAi activity. Thus, the phrase includes, for example, a cell, tissue, subject, or organism, or extract thereof. The term also includes reconstituted material from a biological source.
  • The phrase “blunt end” as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to termini of a double-stranded siNA molecule having no overhanging nucleotides. For example, the two strands of a double-stranded siNA molecule having blunt ends align with each other with matched base-pairs without overhanging nucleotides at the termini. A siNA duplex molecule of the invention can comprise blunt ends at one or both termini of the duplex, such as termini located at the 5′-end of the antisense strand, the 5′-end of the sense strand, or both termini of the duplex.
  • The term “cap” also referred to herein as “terminal cap,” as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to a moiety, which can be a chemically modified nucleotide or non-nucleotide that can be incorporated at one or more termini of one or more nucleic acid molecules of the invention. These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and can help in delivery and/or localization within a cell. The cap can be present at the 5′-terminus (5′-cap) or at the 3′-terminal (3′-cap) or can be present on both termini of any nucleic acid molecule of the invention. A cap can be present at the 5′-end, 3-end and/or 5′ and 3′-ends of the sense strand of a nucleic acid molecule of the invention. Additionally, a cap can optionally be present at the 3′-end of the antisense strand of a nucleic acid molecule of the invention. In non-limiting examples, the 5′-cap includes, but is not limited to, LNA; glyceryl; inverted deoxy abasic residue (moiety); 4°,5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide, 4′-thio nucleotide; carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides; alpha-nucleotides; modified base nucleotide; phosphorodithioate linkage; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic 3,5-dihydroxypentyl nucleotide; 3′-3′-inverted nucleotide moiety; 3′-3′-inverted abasic moiety; 3′-2′-inverted nucleotide moiety; 3′-2′-inverted abasic moiety; 1,4-butanediol phosphate; 3′-phosphoramidate; hexylphosphate; aminohexyl phosphate; 3′-phosphate; 3′-phosphorothioate; phosphorodithioate; or bridging or non-bridging methylphosphonate moiety. Non-limiting examples of the 3′-cap include, but are not limited to, LNA; glyceryl; inverted deoxy abasic residue (moiety); 4′, 5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide; 4′-thio nucleotide; carbocyclic nucleotide; 5′-amino-alkyl phosphate; 1,3-diamino-2-propyl phosphate; 3-aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3,5-dihydroxypentyl nucleotide, 5′-5′-inverted nucleotide moiety; 5′-5′-inverted abasic moiety; 5′-phosphoramidate; 5′-phosphorothioate; 1,4-butanediol phosphate; 5′-amino; bridging and/or non-bridging 5′-phosphoramidate; phosphorothioate and/or phosphorodithioate; bridging or non bridging methylphosphonate; and 5′-mercapto moieties (for more details see Beaucage and Iyer, 1993, Tetrahedron 49, 1925; incorporated by reference herein). FIG. 5 shows some non-limiting examples of various caps.
  • The term “cell” as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term is used in its usual biological sense, and does not refer to an entire multicellular organism, e.g., specifically does not refer to a human being. The cell can be present in an organism, e.g., birds, plants and mammals, such as humans, cows, sheep, apes, monkeys, swine, dogs, and cats. The cell can be prokaryotic (e.g., bacterial cell) or eukaryotic (e.g., mammalian or plant cell). The cell can be of somatic or germ line origin, totipotent or pluripotent, dividing or non-dividing. The cell can also be derived from or can comprise a gamete or embryo, a stem cell, or a fully differentiated cell.
  • The phrase “chemical modification” as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to any modification of the chemical structure of the nucleotides that differs from nucleotides of native siRNA or RNA in general. The term “chemical modification” encompasses the addition, substitution, or modification of native siRNA or RNA at the sugar, base, or internucleotide Linkage, as described herein or as is otherwise known in the art. In certain embodiments, the term “chemical modification” can refer to certain forms of RNA that are naturally occurring in certain biological systems, for example 2′-O-methyl modifications or inosine modifications.
  • The term “CTNNB1” refers to catering (cadherin-associated protein), beta 1 which is gene that encodes CTNNB1 proteins, CTNNB1 peptides, CTNNB1 polypeptides, CTNNB1 regulatory polynucleotides CTNNB1 miRNAs and siNAs), mutant CTNNB1 genes, and splice variants of a CTNNB1 genes, as well as other genes involved in CTNNB1 pathways of gene expression and/or activity. Thus, each of the embodiments described herein with reference to the term “CTNNB1” are applicable to all of the protein, peptide, polypeptide, and/or polynucleotide molecules covered by the term “CTNNB1”, as that term is defined herein. Comprehensively, such gene targets are also referred to herein generally as “target” sequences (including the target sequences listed in Table 1a).
  • The term “complementarity” or “complementary” as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the terms generally refer to the formation or existence of hydrogen bond(s) between one nucleic acid sequence and another nucleic acid sequence by either traditional Watson-Crick or other non-traditional types of bonding as described herein. In reference to the nucleic molecules of the present invention, the binding free energy for a nucleic acid molecule with its complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., RNAi activity. Determination of binding free energies for nucleic acid molecules is well known in the art (see, e.g., Turner et al., 1987, CSII Symb. Quant. Biol. LII pp. 123-133; Frier et al., 1986, Proc. Nat. Acad. Sci. USA 83:9373-9377; Turner et al., 1987, J. Am. Chem. Soc. 109:3783-3785). Perfect complementary means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence. Partial complementarity can include various mismatches or non-based paired nucleotides (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more mismatches, non-nucleotide linkers, or non-based paired nucleotides) within the nucleic acid molecule, which can result in bulges, loops, or overhangs that result between the sense strand or sense region and the antisense strand or antisense region of the nucleic acid molecule or between the antisense strand or antisense region of the nucleic acid molecule and a corresponding target nucleic acid molecule. Such partial complementarity can be represented by a % complementarity that is determined by the number of non-base paired nucleotides, i.e., about 50%, 60%, 70%, 80%, 90% etc, depending on the total number of nucleotides involved. Such partial complementarity is permitted to the extent that the nucleic acid molecule (e.g., siNA) maintains its function, for example the ability to mediate sequence specific RNAi.
  • The terms “composition” or “formulation” as used herein refer to their generally accepted meaning in the art. These terms generally refer to a composition or formulation, such as in a pharmaceutically acceptable carrier or diluent, in a form suitable for administration, e.g., systemic or local administration, into a cell or subject, including, for example, a human. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, inhalation, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell (i.e., a cell to which the negatively charged nucleic acid is desirable for delivery). For example, compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations such as toxicity and forms that prevent the composition or formulation from exerting its effect. As used herein, pharmaceutical formulations include formulations for human and veterinary use. Non-limiting examples of agents suitable for formulation with the nucleic acid molecules of the instant invention include: Lipid Nanoparticles (see for example Semple et al., 2010, Nat Biotechnol., February; 28(2):172-6); P-glycoprotein inhibitors (such as Pluronic P85); biodegradable polymers, such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery (Einerich, D F et al, 1999, Cell Transplant, 8, 47-58); and loaded nanoparticles, such as those made of polybutylcyanoacrylate. Other non-limiting examples of delivery strategies for the nucleic acid molecules of the instant invention include material described in Boado et al., 1998, J. Pharm. Sci., 87, 1308-1315; Tyler et al., 1999, FEBS Lett., 421, 280-284; Pardridge et al., 1995, PNAS USA., 92, 5592-5596; Boado, 1995, Adv. Drug Delivery Rev., 15, 73-107; Aldrian-Herrada et al., 1998, Nucleic Acids Res., 26, 4910-4916; and Tyler et al., 1999, PNAS USA., 96, 7053-7058. A “pharmaceutically acceptable composition” or “pharmaceutically acceptable formulation” can refer to a composition or formulation that allows fir the effective distribution of the nucleic acid molecules of the instant invention to the physical location most suitable for their desired activity.
  • The phrase “cytotoxic/cytostatic agents” refer to compounds that cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mytosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors; microtubule-stabilizing agents, inhibitors of mitotic kinesins, inhibitors of histone deacetylase, inhibitors of kinases involved in mitotic progression, antimetabolites; biological response modifiers; hormonal/anti-hormonal therapeutic agents, hematopoetic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligase inhibitors.
  • The phrase “estrogen receptor modulators” refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism.
  • The term “gene” or “target gene” as used herein refers to their meaning as is generally accepted in the art. The terms generally refer a nucleic acid (e.g., DNA or RNA) sequence that comprises partial length or entire length coding sequences necessary for the production of a polypeptide. The target gene can also include the UTR or non-coding region of the nucleic acid sequence. A gene or target gene can also encode a functional RNA (fRNA) or non-coding RNA (ncRNA), such as small temporal RNA (stRNA), micro RNA (miRNA), small nuclear RNA (snRNA), short interfering RNA (siRNA), small nucleolar RNA (snRNA), ribosomal RNA (rRNA), transfer RNA (tRNA) and precursor RNAs thereof. Such non-coding RNAs can serve as target nucleic acid molecules fir siNA mediated RNA interference in modulating the activity of fRNA or ncRNA involved in functional or regulatory cellular processes. Aberrant fRNA or ncRNA activity leading to disease can therefore be modulated by siNA molecules of the invention. siNA molecules targeting fRNA and ncRNA can also be used to manipulate or alter the genotype or phenotype of a subject, organism or cell, by intervening in cellular processes such as genetic imprinting, transcription, translation, or nucleic acid processing (e.g., transamination, methylation etc.). The target gene can be a gene derived from a cell, an endogenous gene, a transgene, or exogenous genes such as genes of a pathogen, for example a virus, which is present in the cell after infection thereof. The cell containing the target gene can be derived from or contained in any organism, for example a plant, animal, protozoan, virus, bacterium, or fungus. Non-limiting examples of plants include monocots, divots, or gymnosperms. Non-limiting examples of animals include vertebrates or invertebrates. Non-limiting examples of fungi include molds or yeasts. For a review, see for example Snyder and Gerstein, 2003, Science, 300, 258-260.
  • The phrase “HMG-CoA reductase inhibitors” refers to inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds that have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
  • The phrase “homologous sequence” as used herein refers to its meaning as is generally accepted in the art. The term generally refers a nucleotide sequence that is shared by one or more polynucleotide sequences, such as genes, gene transcripts and/or non-coding polynucleotides. For example, a homologous sequence can be a nucleotide sequence that is shared by two or more genes encoding related but different proteins, such as different members of a gene family, different protein epitopes, different protein isoforms or completely divergent genes. A homologous sequence can be a nucleotide sequence that is shared by two or more non-coding polynucleotides, such as noncoding DNA or RNA, regulatory sequences, introns, and sites of transcriptional control or regulation. Homologous sequences can also include sequence regions shared by more than one polynucleotide sequence. Homology does not need to be perfect identity (100%), as partially homologous sequences are also contemplated by and within the scope of the instant invention (e.g., at least 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80% etc.). Percent homology is the number of matching nucleotides between two sequences divided by the total length being compared, multiplied by 100.
  • The phrase “improved RNAi activity” refers to an increase in RNAi activity measured in vitro and/or in vivo, where the RNAi activity is a reflection of both the ability of the siNA to mediate RNAi and the stability of the siNAs of the invention. In this invention, the product of these activities can be increased in vitro and/or in vivo compared to an all RNA siNA or an siNA containing a plurality of ribonucleotides. In some cases, the activity or stability of the siNA molecule can be decreased (i.e., less than ten-fold), but the overall activity of the siNA molecule is enhanced in vitro and/or in vivo.
  • The terms “inhibit,” “down-regulate,” or “reduce” as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, he term generally refers the reduction in the expression of the gene, or level of RNA molecules or equivalent RNA molecules encoding one or more proteins or protein subunits, or activity of one or more proteins or protein subunits, below that observed in the absence of the nucleic acid molecules (e.g., siNA) of the invention. Down-regulation can also be associated with post-transcriptional silencing, such as, RNAi mediated cleavage or by alteration in DNA methylation patterns or DNA chromatin structure. Inhibition, down-regulation or reduction with an siNA molecule can be in reference to an inactive molecule, an attenuated molecule, an siNA molecule with a scrambled sequence, or an siNA molecule with mismatches or alternatively, it cart be in reference to the system in the absence of the nucleic acid.
  • The phrase “inhibitors of cell proliferation and survival signaling pathway” refers to pharmaceutical agents that inhibit cell surface receptors and signal transduction cascades downstream of those surface receptors.
  • The term “integrin blockers” refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the αωβ3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the αωβ5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the αωβ3 integrin and the αωβ5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the αωβ6 αωβ8 α1β1 α2β1 α5β1 α6β1 and α6β4 integrins. The term also refers to antagonists of any combination of αωβ3, αωβ5, αωβ6 αωβ8 α1β1 α2β1 α5β1 α6β1 and α6β4 integrins.
  • The terms “intermittent” or “intermittently” as used herein refers to its meaning as is generally accepted in the art. The term generally refers to periodic stopping and starting at either regular or irregular intervals.
  • The terms “internucleoside linkage” or “internucleoside linker” or “internucleotide linkage” or “internucleotide linker” are used herein interchangeably and refer to any linker or linkage between two nucleoside units, as is known in the art, including, for example, but not limitation, phosphate, analogs of phosphate, phosphonate, guanidium, hydroxylamine, hydroxylhydrazinyl, amide, carbamate, alkyl, and substituted alkyl linkages. The internucleoside linkages constitute the backbone of a nucleic acid molecule.
  • The terms “mammalian” or “mammal” as used herein refers to its meaning as is generally accepted in the art. The term generally refers to any warm blooded vertebrate species, such as a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit, livestock, and the like.
  • The phrase “metered dose inhaler” or MDI refers to a unit comprising a can, a secured cap covering the can and a formulation metering valve situated in the cap, MDI systems includes a suitable channeling device. Suitable channeling devices comprise for example, a valve actuator and a cylindrical or cone-like passage through which medicament can be delivered from the filled canister via the metering valve to the nose or mouth of a patient such as a mouthpiece actuator.
  • The term “microRNA” or “miRNA” as used herein refers to its meaning as is generally accepted in the art. The term generally refers a small double-stranded RNA that regulates the expression of target messenger RNAs either by mRNA cleavage, translational repression/inhibition or heterochromatic silencing (see for example Ambros, 2004, Nature, 431, 350-355; Bartel, 2004, Cell, 116, 281-297; Cullen, 2004, Virus Research., 102, 3-9; He et al., 2004, Nat. Rev. Genet., 5, 522-531; Wing at al., 2004, Gene, 342, 25-28; and Sethupathy et al., 2006, RNA, 12:192-197).
  • The term “modulate” as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to when the expression of a gene, or level of one or more RNA molecules (coding or non-coding), or activity of one or more RNA molecules or proteins or protein subunits, is up-regulated or down-regulated, such that expression, level, or activity is greater than or less than that observed in the absence of the molecule that effects modulation. For example, the term “modulate” in some embodiments can refer to inhibition and in other embodiments can refer to potentiation or up-regulation, e.g., of gene expression.
  • The phrase “modified nucleotide” as used herein refers to its meaning as is generally accepted in the art. The term generally refers a nucleotide, which contains a modification in the chemical structure of the base, sugar and/or phosphate of the unmodified (or natural) nucleotide as is generally known in the art. Non-limiting examples of modified nucleotides are described herein and in U.S. application Ser. No. 12/064,014.
  • The phrase “NSAIDs that are selective COX-2 inhibitors” for purposes herein, refers to NSAIDs, which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays.
  • The phrase “non-base paired” refers to nucleotides that are not base paired between the sense strand or sense region and the antisense strand or antisense region of an double-stranded siNA molecule; and can include for example, but not limitation, mismatches, overhangs, single stranded loops, etc.
  • The term “non-nucleotide” refers to any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, such as for example hut not limitation abasic moieties or alkyl chains. The group or compound is “abasic” in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine and therefore lacks a nucleobase at the 1′-position.
  • The term “nucleotide” is used as is generally recognized in the art. Nucleotides generally comprise a nucleobase, a sugar, and an internucleoside linkage, e.g., a phosphate. The base can be a natural bases (standard), modified bases, or a base analog, as are well known in the art. Such bases are generally located at the 1′ position of a nucleotide sugar moiety. Additionally, the nucleotides can be unmodified or modified at the sugar, internucleoside linkage, and/or base moiety, (also referred to interchangeably as nucleotide analogs, modified nucleotides, non-natural nucleotides, non-standard nucleotides and others; see, for example, U.S. application Ser. No. 12/064,014.
  • The term “overhang” as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary double stranded nucleic acid molecules, the term generally refers to the terminal portion of a nucleotide sequence that is not base paired between the two strands of a double-stranded nucleic acid molecule (see for example, FIG. 4 ). Overhangs, when present, are typically at the 3′-end of one or both strands in a siNA duplex.
  • The term “parenteral” as used herein refers to its meaning as is generally accepted in the art. The term generally refers methods or techniques of administering a molecule, drug, agent, or compound in a manner other than through the digestive tract, and includes epicutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like.
  • The phrase “pathway target” refers to any target involved in pathways of gene expression or activity. For example, any given target can have related pathway targets that can include upstream, downstream, or modifier genes in a biologic pathway. These pathway target genes can provide additive or synergistic effects in the treatment of diseases, conditions, and traits herein.
  • The term “phosphorothioate” refers to an internucleotide phosphate linkage comprising one or more sulfur atoms in place of an oxygen atom. Hence, the term phosphorothioate refers to both phosphorothioate and phosphorodithioate internucleotide linkages.
  • “Prenyl-protein transferase inhibitor” refers to a compound that inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
  • The phrase “retinoid receptor modulators” refers to compounds that interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • The term “ribonucleotide” as used herein refers to its meaning as is generally accepted in the art. The term generally refers to a nucleotide with a hydroxyl group at the 2′ position of a β-D-ribofuranose moiety.
  • The term “RNA” as used herein refers to its generally accepted meaning in the art. Generally, the term RNA refers to a molecule comprising at least one ribofuranoside moiety. The term can include double-stranded RNA, single-stranded RNA, isolated RNA such as partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA, as well as altered RNA that differs from naturally occurring RNA by the addition, deletion, substitution and/or alteration of one or more nucleotides. Such alterations can include addition of non-nucleotide material, such as to the end(s) of the siNA or internally, for example at one or more nucleotides of the RNA. Nucleotides in the RNA molecules of the instant invention can also comprise non-standard nucleotides, such as non-naturally occurring nucleotides or chemically synthesized nucleotides or deoxynucleotides. These altered RNAs can be referred to as analogs or analogs of naturally-occurring RNA.
  • The phrase “RNA interference” or term “RNAi.” refer to the biological process of inhibiting or down regulating gene expression in a cell, as is generally known in the art, and which is mediated by short interfering nucleic acid molecules, see for example Zamore and Haley, 2005, Science, 309, 1519-1524; Vaughn and Martienssen, 2005, Science, 309, 1525-1526; Zamore et al., 2000, Cell, 101, 25-33; Bass, 2001, Nature, 411, 428-429; Elbashir et al., 2001, Nature, 411, 191-498; and Kreutzer et al., international PCT Publication No. WO 00/14895; Zernieka-Goetz et al., International PCT Publication No. WO 01/36646; Fire, International PCT Publication No. WO 99/32619; Plaetinck et al., International PCT Publication No. WO 00/01846; Mello and Fire, International PCT Publication No. WO 01/29058; Deschamps-Depaillette, International PCT Publication No. WO 99/07409; and Li et international PCT Publication No. WO 00/44914; Allshire, 2002. Science, 297, 1818-1819; Volpe et al., 2002, Science, 297, 1833-1837; Jenuwein, 2002, Science, 297, 2215-2218; and Hall et al., 2002, Science, 297, 2232-2237; Hutvagner and Zamore, 2002. Science, 297, 2056-60; McManus et al., 2002, RNA, 8, 842-850; Reinhart et al., 2002, Gene & Lev., 16, 1616-1626; and Reinhart & Bartel, 2002, Science, 297, 1831). Additionally, the term RNAi is meant to be equivalent to other terms used to describe sequence specific RNA interference, such as post transcriptional gene silencing, translational inhibition, transcriptional inhibition, or epigenetics. For example, siNA molecules of the invention can be used to epigenetically silence genes at either the post-transcriptional level or the pre-transcriptional level. In a non-limiting example, epigenetic modulation of gene expression by siNA molecules of the invention can result from siNA mediated modification of chromatin structure or methylation patterns to alter gene expression (see, for example, Verdel et al., 2004, Science, 303, 672-676; Pal-Bhadra et al., 2004, Science, 303, 669-672; Alishire, 2002, Science, 297, 1818-1819; Volpe et al., 2002, Science, 297, 1833-1837; Jenuwein, 2002, Science, 297, 2215-2218; and Hall et al., 2002, Science, 297, 2232-2237). In another non-limiting example, modulation of gene expression by siNA molecules of the invention can result from siNA mediated cleavage of RNA (either coding or non-coding RNA) via RISC, or via translational inhibition, as is known in the art or modulation can result from transcriptional inhibition (see for example Janowski et al., 2005, Nature Chemical Biology, 1, 216-222).
  • The phrase “RNAi inhibitor” refers to any molecule that can down regulate, reduce or inhibit RNA interference function or activity in a cell or organism. An RNAi inhibitor can down regulate, reduce or inhibit. RNAi (e.g., RNAi mediated cleavage of a target polynucleotide, translational inhibition, or transcriptional silencing) by interaction with or interfering with the function of any component of the RNAi pathway, including protein components such as RISC, or nucleic acid components such as miRNAs or siRNAs. A RNAi inhibitor can be an siNA molecule, an antisense molecule, an aptamer, or a small molecule that interacts with or interferes with the function of RISC, a miRNA, or an siRNA or any other component of the RNAi pathway in a cell or organism. By inhibiting RNAi (e.g., RNAi mediated cleavage of a target polynucleotide, translational inhibition, or transcriptional silencing), a RNAi inhibitor of the invention can be used to modulate (e.g., up-regulate or down regulate) the expression of a target gene.
  • The phrase “sense region” as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to a nucleotide sequence of an siNA molecule having complementarity to an antisense region of the siNA molecule. In addition, the sense region of an siNA molecule can comprise a nucleic acid sequence having homology or sequence identity with a target nucleic acid sequence. In one embodiment, the sense region of the siNA molecule is also referred to as the sense strand or passenger strand.
  • The phrases “short interfering nucleic acid”, “siNA”, “short interfering RNA”, “siRNA”, “short interfering nucleic acid molecule”, “short interfering oligonucleotide molecule”, or “chemically modified short interfering nucleic acid molecule” refer to any nucleic acid molecule capable of inhibiting or down regulating gene expression or viral replication by mediating RNA interference (“RNAi”) or gene silencing in a sequence-specific manner. These terms can refer to both individual nucleic acid molecules, a plurality of such nucleic acid molecules, or pools of such nucleic acid molecules. The siNA can be a double-stranded nucleic acid molecule comprising self-complementary sense and antisense strands, wherein the antisense strand comprises a nucleotide sequence that is complementary to a nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense strand comprises a nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. The siNA can be a polynucleotide with a duplex, asymmetric duplex, hairpin or asymmetric hairpin secondary structure, having self-complementary sense and antisense regions, wherein the antisense region comprises a nucleotide sequence that is complementary to a nucleotide sequence in a separate target nucleic acid molecule or a portion thereof and the sense region comprises a nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. The siNA can be a circular single-stranded polynucleotide having two or more loop structures and a stem comprising self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to a nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region comprises a nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof, and wherein the circular polynucleotide can be processed either in vivo or in vitro to generate an active siNA molecule capable of mediating RNAi. The siNA can also comprise a single-stranded polynucleotide having a nucleotide sequence complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof (for example, where such siNA molecule does not require the presence within the siNA molecule of a nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof), wherein the single-stranded polynucleotide can further comprise a terminal phosphate group, such as a 5′-phosphate (see for example, Martinez et al., 2002, Cell 110, 563-574 and Schwarz et al., 2002, Molecular Cell, 10, 537-568), or 5′,3′-diphosphate.
  • The term “subject” as used herein refers to its meaning as is generally accepted in the art. The term generally refers an organism to which the nucleic acid molecules of the invention can be administered. A subject can be a mammal or mammalian cells, including a human or human cells. The term also refers to an organism, which is a donor or recipient of explanted cells or the cells themselves.
  • The phrase “systemic administration” as used herein refers to its meaning as is generally accepted in the art. The term generally refers in vivo systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body.
  • The term “target” as it refers to CTNNB1 refers to any CTNNB1 target protein, peptide, or polypeptide, such as encoded by Genbank Accession Nos. shown in Table 5. The term also refers to nucleic acid sequences or target polynucleotide sequence encoding any target protein, peptide, or polypeptide, such as proteins, peptides, or polypeptides encoded by-sequences having Genbank Accession Nos, shown in Table 5. The target of interest can include target polynucleotide sequences, such as target DNA or target RNA. The term “target” is also meant to include other sequences, such as differing isoforms, mutant target genes, splice variants of target polynucleotides, target polymorphisms, and non-coding (e.g., ncRNA, miRNA, stRNA, sRNA) or other regulatory polynucleotide sequences as described herein.
  • The phrase “target site” as used herein refers to its meaning as is generally accepted in the art. The term generally refers to a sequence within a target nucleic acid molecule, (e.g., RNA) that is “targeted”, e.g., for cleavage mediated by an siNA construct, which contains sequences within its antisense region that are complementary to the target sequence.
  • The phrase “therapeutically effective amount” as used herein refers to its meaning as is generally accepted in the art. The term generally refers to the amount of the compound or composition that will elicit the biological or medical response of a cell, tissue, system, animal or human that is be sought by the researcher, veterinarian, medical doctor or other clinician. For example, if a given clinical treatment is considered effective when there is at least a 25% reduction in a measurable parameter associated with a disease or disorder, a therapeutically effective amount of a drug for the treatment of that disease or disorder is that amount necessary to effect at least a 25% reduction in that parameter.
  • The phrase “universal base” as used herein refers to its meaning as is generally accepted in the art. The term universal base generally refers to nucleotide base analogs that form base pairs with each of the natural DNA/RNA bases with little or no discrimination between them. Non-limiting examples of universal bases include C-phenyl, C-naphthyl and other aromatic derivatives, inosine, azole carboxamides, and nitroazole derivatives such as 3-nitropyrrole, 4-nitroindole, 5-nitroindole, and 6-nitroindole as known in the art (see for example, Loakes, 2001, Nucleic Acids Research, 29, 2437-2447).
  • The term “up-regulate” as used herein refers to its meaning as is generally accepted in the art. With reference to exemplary nucleic acid molecules of the invention, the term refers to an increase in the expression of a gene, or level of RNA molecules or equivalent RNA molecules encoding one or more proteins or protein subunits, or activity of one or more RNAs, proteins or protein subunits, above that observed in the absence of the nucleic acid molecules (e.g., siNA) of the invention. In certain instances, up-regulation or promotion of gene expression with an siNA molecule is above that level observed in the presence of an inactive or attenuated molecule. In other instances, up-regulation or promotion of gene expression with siNA molecules is above that level observed in the presence of, for example, an siNA molecule with scrambled sequence or with mismatches. In still other instances, up-regulation or promotion of gene expression with a nucleic acid molecule of the instant invention is greater in the presence of the nucleic acid molecule than in its absence. In some instances, up-regulation or promotion of gene expression is associated with inhibition of RNA mediated gene silencing, such as RNAi mediated cleavage or silencing of a coding or non-coding RNA target that down regulates, inhibits, or silences the expression of the gene of interest to be up-regulated. The down regulation of gene expression can, for example, be induced by a coding RNA or its encoded protein, such as through negative feedback or antagonistic effects. The down regulation of gene expression can, for example, be induced by a non-coding RNA having regulatory control over a gene of interest, for example by silencing expression of the gene via translational inhibition, chromatin structure, methylation, RISC mediated RNA cleavage, or translational inhibition. As such, inhibition or down regulation of targets that down regulate, suppress, or silence a gene of interest can be used to up-regulate expression of the gene of interest toward therapeutic use.
  • The term “vector” as used herein refers to its meaning as is generally accepted in the art. The term vector generally refers to any nucleic acid- and/or viral-based expression system or technique used to deliver one or more nucleic acid molecules.
  • B. siNA Molecules of the Invention
  • The present invention provides compositions and methods comprising siNAs targeted to CTNTNB1 that can be used to treat diseases, malignancies and/or cancers associated with CTNNB1 expression. In particular aspects and embodiments of the invention, the nucleic acid molecules of the invention comprise at least a 15 nucleotide sequence of the sequences shown in Table 1a and Table 1b. The siNAs can be provided in several forms. For example, the siNA can be isolated as one or more siNA compounds, or it may be in the form of a transcriptional cassette in a DNA plasmid. The siNA may also be chemically synthesized and can include modifications as shown, for example, but not limitation, in Table 1c and Table 6. Thus, in various embodiments, at least one strand or region of the nucleic acids of the invention comprises at least a 15 nucleotide sequence selected from the group of sequences consisting of SEQ ID NOS:1-6374. The siNAs can be administered alone or co-administered with other siNA molecules or with conventional agents that treat a CTNNB1 related disease or condition.
  • The siNA molecules of the invention can be used to mediate gene silencing, specifically CTNNB1, via interaction with RNA transcripts or alternately by interaction with particular gene sequences, wherein such interaction results in modulation of gene silencing either at the transcriptional level or post-transcriptional level such as, for example, but not limited to, RNAi or through cellular processes that modulate the chromatin structure or methylation patterns of the target and prevent transcription of the target gene, with the nucleotide sequence of the target thereby mediating silencing. More specifically, the target is any of CTNNB1 RNA, DNA, or mRNA,
  • In one aspect, the invention provides short interfering nucleic acid (siNA) molecules for inhibiting the expression of the CTNNB1 gene in a cell or mammal. The siNA can be single-stranded or double-stranded. When double-stranded, the siNA comprising a sense and an antisense stand. The antisense strand is complementary to at least a part of an mRNA formed in the expression of the CTNNB1 gene. The sense strand comprises a region that is complementary to the antisense strand. In specific embodiments, the antisense strand comprises at least a 15 nucleotide sequence of an antisense sequence listed in Table 1b. Generally, the double-stranded siNA comprises at least a 15 nucleotide sequence of the sense strand in Table 1b and at least a 15 nucleotide sequence of the antisense strand in Table 1b. One or more of the nucleotides of the siNAs of the invention are optionally modified. In further embodiments having modifications, some siNAs of the invention comprises at least one nucleotide sequence selected from the groups of sequences provide in Table 1c. In other embodiments, the siNA comprises at least two sequences selected from the group of sequences provided in Table 1c, wherein one of the at least two sequences is complementary to another of the at least two sequences and one of the at least two sequences is complementary to a sequence of a mRNA generated in the expression of the CTNNB1 gene. Examples of certain modified siNAs of the invention are in Table 1c.
  • The double stranded RNA molecules of the invention can comprise two distinct and separate strands that can be symmetric or asymmetric and are complementary, i.e., two single-stranded RNA molecules, or can comprise one single-stranded molecule in which two complementary portions, e.g., a sense region and an antisense region, are base-paired, and are covalently linked by one or more single-stranded “hairpin” areas (i.e. loops) resulting in, for example, a single-stranded short-hairpin polynucleotide or a circular single-stranded polynucleotide.
  • The linker can be polynucleotide linker or a non-nucleotide linker. In some embodiments, the linker is a non-nucleotide linker, in some embodiments, a hairpin or circular siNA molecule of the invention contains one or more loop motifs, wherein at least one of the loop portions of the siNA molecule is biodegradable. For example, a single-stranded hairpin siNA molecule of the invention is designed such that degradation of the loop portion of the siNA molecule in vivo can generate a double-stranded siNA molecule with 3′-terminal overhangs, such as 3′-terminal nucleotide overhangs comprising 1, 2, 3 or 4 nucleotides. Or alternatively, a circular siNA molecule of the invention is designed such that degradation of the loop portions of the siNA molecule in vivo can generate a double-stranded siNA molecule with 3′-terminal overhangs, such as 3′-terminal nucleotide overhangs comprising about 2 nucleotides.
  • In symmetric siNA molecules of the invention, each strand, the sense (passenger) strand and antisense (guide) strand, are independently about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides in length. Generally, each strand of the symmetric siNA molecules of the invention are about 19-24 (e.g., about 19, 20, 21, 22, 23 or 24) nucleotides in length.
  • In asymmetric siNA molecules, the antisense region or strand of the molecule is about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, or 30) nucleotides in length, wherein the sense region is about 3 to about 25 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, or 25) nucleotides in length. Generally, each strand of the asymmetric siNA molecules of the invention is about 19-24 (e.g., about 19, 20, 21, 22, 23 or 24) nucleotides in length.
  • In yet other embodiments, siNA molecules of the invention comprise single stranded hairpin siNA molecules, wherein the siNA molecules are about 25 to about 70 (e.g., about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 40, 45, 50, 55, 60, 65, or 70) nucleotides in length.
  • In still other embodiments, siNA molecules of the invention comprise single-stranded circular siNA molecules, wherein the siNA molecules are about 38 to about 70 (e.g., about 38, 40, 45, 50, 55, 60, 65, or 70) nucleotides in length.
  • In still other embodiments, siNA molecules of the invention comprise single-stranded non-circular siNA molecules, wherein the siNA molecules are independently about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides in length.
  • In various symmetric embodiments, the siNA duplexes of the invention independently comprise about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) base pairs. Generally, the duplex structure of siNAs of the invention is between 15 and 30, more generally between 18 and 25, yet more generally between 19 and 24, and most generally between 19 and 21 base pairs in length.
  • In yet other embodiments, where the duplex siNA molecules of the invention are asymmetric, the siNA molecules comprise about 3 to 25 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) base pairs. Generally, the duplex structure of siNAs of the invention is between 15 and 25, more generally between 18 and 25, yet more generally between 19 and 24, and most generally between 19 and 21 base pairs in length.
  • In still other embodiments, where the siNA molecules of the invention are hairpin or circular structures, the siNA molecules comprise about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) base pairs.
  • The sense strand and antisense strand, or the sense region and antisense region, of the siNA molecules of the invention can be complementary. Also, the antisense strand or antisense region can be complementary to a nucleotide sequence or a portion thereof of the CTNNB1 target RNA. The sense strand or sense region of the siNA can comprise a nucleotide sequence of a CTNNB1 gene or a portion thereof. In certain embodiments, the sense region or sense strand of an siNA molecule of the invention is complementary to that portion of the antisense region or antisense strand of the siNA molecule that is complementary to a CTNNB1 target polynucleotide sequence, such as for example, but not limited to, those sequences represented by GENBANK Accession Nos. shown in Table 5.
  • In some embodiments, siNA molecules of the invention have perfect complementarity between the sense strand or sense region and the antisense strand or antisense region of the siNA molecule. In other or the same embodiments, the antisense strand of the siNA molecules of the invention are perfectly complementary to a corresponding target nucleic acid molecule.
  • In yet other embodiments, siNA molecules of the invention have partial complementarity (i.e., less than 100% complementarity) between the sense strand or sense region and the antisense strand or antisense region of the siNA molecule or between the antisense strand or antisense region of the siNA molecule and a corresponding target nucleic acid molecule. Thus, in some embodiments, the double-stranded nucleic acid molecules of the invention, have between about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides in one strand that are complementary to the nucleotides of the other strand. In other embodiments, the molecules have between about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides in the sense region that are complementary to the nucleotides of the antisense region of the double-stranded nucleic acid molecule. In certain embodiments, the double-stranded nucleic acid molecules of the invention have between about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides in the antisense strand that are complementary to a nucleotide sequence of its corresponding target nucleic acid molecule.
  • In other embodiments, the siNA molecule can contain one or more nucleotide deletions, substitutions, mismatches and/or additions; provided, however, that the siNA molecule maintains its activity, for example, to mediate RNAi. In a non-limiting example, the deletion, substitution, mismatch and/or addition can result in a loop or bulge, or alternately a wobble or other alternative (non Watson-Crick) base pair. Thus, in some embodiments, for example, the double-stranded nucleic acid molecules of the invention, have 1 or more (e.g., 1, 2, 3, 4, 5, or 6) nucleotides, in one strand or region that are mismatches or non-base-paired with the other strand or region. In other embodiments, the double-stranded nucleic acid molecules of the invention, have 1 or more (e.g., 1, 2, 3, 4, 5, or 6) nucleotides in each strand or region that are mismatches or non-base-paired with the other strand or region. In a preferred embodiment, the siNA of the invention contains no more than 3 mismatches. If the antisense strand of the siNA contains mismatches to a target sequence, it is preferable that the area of mismatch not be located in the center of the region of complementarity.
  • In other embodiments, the siNA molecule can contain one or more nucleotide deletions, substitutions, mismatches and/or additions to a sequence in Table 1b provided, however, that the siNA molecule maintains its activity, for example, to mediate RNAi. In a non-limiting example, the deletion, substitution, mismatch and/or addition can result in a loop or bulge, or alternately a wobble or other alternative (non Watson-Crick) base pair.
  • The invention also comprises double-stranded nucleic acid (siNA) molecules as otherwise described hereinabove in which the first strand and second strand are complementary to each other and wherein at least one strand is hybridisable to the polynucleotide sequence of a sequence in Table 1b under conditions of high stringency, and wherein any of the nucleotides is unmodified or chemically modified.
  • Hybridization techniques are well known to the skilled artisan (see for instance, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)). Preferred stringent hybridization conditions include overnight incubation at 42° C. in a solution comprising: 50% formamide, 5×SSC (150 mM NaCl, 1.5 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5×Denhardt's solution, 10% dextran sulfate, and 20 microgram/ml denatured, sheared salmon sperm DNA; followed by washing the filters in 0.1×SSC at about 65° C.
  • In one specific embodiment, the first strand has about 15, 16, 17, 18, 19, 20 or 21 nucleotides that are complementary to the nucleotides of the other strand and at least one strand is hybridisable to a polynucleotide sequence in Table 1b. In a more preferred embodiment, the first strand has about 15, 16, 17, 18, 19, 20 or 21 nucleotides that are complementary to the nucleotides of the other strand and at least one strand is hybridisable to SEQ ID NO: 1, SEQ NO: 1049, SEQ ID NO: 43, SEQ ID NO: 1091, SEQ ID NO: 51, SEQ ID NO: 1099, SEQ ID NO: 53, or SEQ ID NO:1101; under conditions of high stringency, and wherein any of the nucleotides is unmodified or chemically modified.
  • In certain embodiments, the siNA molecules of the invention comprise overhangs of about 1 to about 4 (e.g., about 1, 2, 3 or 4) nucleotides. The nucleotides in the overhangs can be the same or different nucleotides. In some embodiments, the overhangs occur at the 3′-end at one or both strands of the double-stranded nucleic acid molecule. For example, a double-stranded nucleic acid molecule of the invention can comprise a nucleotide or non-nucleotide overhang at the 3′-end of the antisense strand/region, the 3′-end of the sense strand/region, or both the antisense strand/region and the sense strand/region of the double-stranded nucleic acid molecule.
  • In some embodiments, the nucleotides comprising the overhang portion of an siNA molecule of the invention comprise sequences based on the CTNNB1 target polynucleotide sequence in which nucleotides comprising the overhang portion of the antisense strand/region of an siNA molecule of the invention can be complementary to nucleotides in the CTNNB1 target polynucleotide sequence and/or nucleotides comprising the overhang portion of the sense strand/region of an siNA molecule of the invention can comprise the nucleotides in the CTNNB1 target polynucleotide sequence. Thus, in some embodiments, the overhang comprises a two nucleotide overhang that is complementary to a portion of the CTNNB1 target polynucleotide sequence. In other embodiments, however, the overhang comprises a two nucleotide overhang that is not complementary to a portion of the CTNNB1 target polynucleotide sequence. In certain embodiments, the overhang comprises a overhang that is not complementary to a portion of the CTNNB1 target polynucleotide sequence. In other embodiments, the overhang comprises a UU overhang at the 3′ end of the antisense strand and a TT overhang at the 3′ end of the sense strand. In other embodiments, the overhang comprises nucleotides as described in the examples, Tables, and Figures herein.
  • In any of the embodiments of the siNA molecules described herein having 3′-terminal nucleotide overhangs, the overhangs are optionally chemically modified at one or more nucleic acid sugar, base, or backbone positions. Representative, but not limiting examples of modified nucleotides in the overhang portion of a double-stranded nucleic acid (siNA) molecule of the invention include: 2′-O-alkyl (e.g., 2′-O-methyl), 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-deoxy-2′-fluoroarabino (FANA), 4′-thio, 2′-O-trifluoromethyl, 2′-O-ethyl-trifluoromethoxy, 2′4)-difluoromethoxy-ethoxy, universal base, acyclic, or 5-C-methyl nucleotides. In more preferred embodiments, the overhang nucleotides are each independently, a 2′-O-alkyl nucleotide, a 2′-O-methyl nucleotide, a 2′-dexoy-2-fluoro nucleotide, or a 2′-deoxy ribonucleotide. In some instances the overhang nucleotides are linked by a one or more phosphorothioate linkages.
  • In yet other embodiments, siNA molecules of the invention comprise duplex nucleic acid molecules with blunt ends (i.e., without nucleotide overhangs), where both ends are blunt, or alternatively, where one of the ends is blunt. In some embodiments, the siNA molecules of the invention can comprises one blunt end, for example wherein the 5′-end of the antisense strand and the 3′-end of the sense strand do not have any overhanging nucleotides. In another example, the siNA molecule comprises one blunt end, for example wherein the 3′-end of the antisense strand and the 5′-end of the sense strand do not have any overhanging nucleotides. In other embodiments, siNA molecules of the invention comprise two blunt ends, for example wherein the 3′-end of the antisense strand and the 5′-end of the sense strand as well as the 5′-end of the antisense strand and 3′-end of the sense strand do not have any overhanging nucleotides.
  • In any of the embodiments or aspects of the siNA molecules of the invention, the sense strand and/or the antisense strand can further have a cap, such as described herein or as known in the art, at the 3′-end, the 5′-end, or both of the 3′ and 5′-ends of the sense strand and/or antisense strand. Or as in the case of a hairpin siNA molecule, the cap can be at either one or both of the terminal nucleotides of the polynucleotide. In some embodiments, the cap is at one of both of the ends of the sense strand of a double-stranded siNA molecule. In other embodiments, the cap is at the 3′-end of antisense (guide) strand. In preferred embodiments, the caps are at the 3′-end of the sense strand and the 5′-end of the sense strand.
  • Representative, but non-limiting examples of such terminal caps include an inverted abasic nucleotide, an inverted deoxy abasic nucleotide, an inverted nucleotide moiety, a group shown in FIG. 5 , a glyceryl modification, an alkyl or cycloalkyl group, a heterocycle, or any other cap as is generally known in the art.
  • Any of the embodiments of the siNA molecules of the invention can have a 5′ phosphate termini. In some embodiments, the siNA molecules lack terminal phosphates.
  • Any siNA molecule or construct of the invention can comprise one or more chemical modifications. Modifications can be used to improve in vitro or in vivo characteristics such as stability, activity, toxicity, immune response (e.g., prevent stimulation of an interferon response, an inflammatory or pro-inflammatory cytokine response, or a Toll-like Receptor (TlF) response), and/or bioavailability.
  • Applicants describe herein chemically modified siNA molecules with improved RNAi activity and/or stability compared to corresponding unmodified siNA molecules. Various chemically modified siNA motifs disclosed herein provide the capacity to maintain RNAi activity that is substantially similar to unmodified or minimally modified active siRNA (see for example Elbashir et al., 2001, EMBO J., 20:6877-6888) while at the same time providing nuclease resistance and pharmacokinetic properties suitable for use in therapeutic applications.
  • In various embodiments, the siNA molecules of the invention comprise modifications wherein any (e.g., one or more or all) nucleotides present in the sense and/or antisense strand are modified nucleotides (e.g., wherein one nucleotide is modified, some nucleotides (i.e., plurality or more than one) are modified, or all nucleotides are modified nucleotides. In some embodiments, the siNA molecules of the invention are partially modified (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, or 59 nucleotides are modified) with chemical modifications. In some embodiments, an siNA molecule of the invention comprises at least about 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or 60 nucleotides that are modified nucleotides. In other embodiments, the siNA molecules of the invention are completely modified (e.g., 100% modified) with chemical modifications, i.e., the siNA molecule does not contain any, ribonucleotides. In some or embodiments, one or more of the nucleotides in the sense strand of the siNA molecules of the invention are modified. In the same or other embodiments, one or more of the nucleotides in the antisense strand of the siNA molecules of the invention are modified.
  • The chemical modification within a single siNA molecule can be the same or different. In some embodiments, at least one strand has at least one chemical modification. In other embodiments, each strand has at least one chemical modifications, which can be the same or different, such as, sugar, base, or backbone (i.e., internucleotide linkage) modifications. In other embodiments, siNA molecules of the invention contain at least 2, 3, 4, 5, or more different chemical modifications.
  • Non-limiting examples of chemical modifications that are suitable for use in the present invention, are disclosed in U.S. patent application Ser. Nos. 10/444,853; 10/981,966; 12/064,014 and in references cited therein and include sugar, base, and phosphate, non-nucleotide modifications, and/or any combination thereof.
  • In certain specific embodiments of the invention, at least one modified nucleotide is a 2′-deoxy-2-fluoro nucleotide, a 2′-deoxy nucleotide, a 2′-O-alkyl (e.g., 2′-O-methyl) nucleotide, or a locked nucleic acid (LNA) nucleotide as is generally recognized in the art.
  • In yet other embodiment of the invention, at least one nucleotide has a ribo-like, Northern or A form helix configuration (see e.g., Saenger, Principles of Nucleic Acid Structure, Springer-Verlag ed., 1984). Non-limiting examples of nucleotides having a Northern configuration include locked nucleic acid (LNA) nucleotides (e.g., 2′-O, 4′-C-methylene-(D-ribofuranosyl) nucleotides); 2′-methoxyethoxy (MOE) nucleotides; 2′-methyl-thio-ethyl nucleotides, 2′-deoxy-2′-fluoro nucleotides; 2′-deoxy-2′-chloro nucleotides; 2′-azido nucleotides; 2′-O-trifluoromethyl nucleotides; 2′-O-ethyl-trifluoromethoxy nucleotides; 2′4)-difluoromethoxy-ethoxy nucleotides; 4′-thio nucleotides and 2′-O-methyl nucleotides.
  • In various embodiments, a majority (e.g., greater than 50%) of the pyrimidine nucleotides present in the double-stranded siNA molecule comprises a sugar modification. In some of the same and/or other embodiments, a majority (e.g., greater than 50%) of the purine nucleotides present in the double-stranded siNA molecule comprises a sugar modification.
  • In some embodiments, the pyrimidine nucleotides in the antisense strand are 2′-O-methyl or 2′-deoxy-2′-fluoro pyrimidine nucleotides and the purine nucleotides present in the antisense strand are 2′-O-methyl nucleotides or 2′-deoxy nucleotides. In other embodiments, the pyrimidine nucleotides in the sense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides and the purine nucleotides present in the sense strand are 2′-O-methyl or 2′-deoxy purine nucleotides.
  • In certain embodiments of the invention, all the pyrimidine nucleotides in the complementary region on the sense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides. In certain embodiments, all of the pyrimidine nucleotides in the complementary region of the antisense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides. In certain embodiments, all the purine nucleotides in the complementary region on the sense strand are 2′-deoxy purine nucleotides. In certain embodiments, all of the purines in the complementary region on the antisense strand are 2′-O-methyl purine nucleotides, in certain embodiments, all of the pyrimidine nucleotides in the complementary regions on the sense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides; all of the pyrimidine nucleotides in the complementary region of the antisense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides; all the purine nucleotides in the complementary region on the sense strand are 2′-deoxy purine nucleotides and all of the purines in the complementary region on the antisense strand are 2′-O-methyl purine nucleotides.
  • In some embodiments, at least 5 or more of the pyrimidine nucleotides in one or both stands are 2′-deoxy-2′-fluoro pyrimidine nucleotides, in some embodiments, at least 5 or more of the pyrimidine nucleotides in one or both stands are 2′-O-methyl pyrimidine nucleotides. In some embodiments, at least 5 or more of the purine nucleotides in one or both stands are 2′-deoxy-2′-fluoro purine nucleotides In some embodiments, at least 5 or more of the purine nucleotides in one or both stands are 2′-O-methyl purine nucleotides.
  • In certain embodiments, the purines and pyrimidines are differentially modified at the 2′-sugar position (i.e., at least one purine has a different modification from at least one pyrimidine in the same or different strand at the 2′-sugar position). For example, in some instances, at least 5 or more of the pyrimidine nucleotides in one or both stands are 2′-deoxy-2′-fluoro pyrimidine nucleotides and at least 5 or more purine nucleotides in one or both strands are 2′-O-methyl purine nucleotides. In other instances at least 5 or more of the pyrimidine nucleotides in one or both stands are 2′-O-methyl pyrimidine nucleotides and at least 5 or more purine nucleotides in one or both strands are 2′-deoxy-2′-fluoro purine nucleotides.
  • Further non-limiting examples of sense and antisense strands of such siNA molecules having various modifications and modifications patterns are shown in FIGS. 2 and 3 .
  • Any of the above described modifications, or combinations thereof, including those in the references cited, can be applied to any of the siNA molecules of the invention.
  • The modified siNA molecules of the invention can comprise modifications at various locations within the siNA molecule. In some embodiments, the double-stranded siNA molecule of the invention comprises modified nucleotides at internal base paired positions within the siNA duplex. In other embodiments, a double-stranded siNA molecule of the invention comprises modified nucleotides at non-base paired or overhang regions of the siNA molecule. In yet other embodiments, a double-stranded siNA molecule of the invention comprises modified nucleotides at terminal positions of the siNA molecule. For example, such terminal regions include the 3′-position and/or 5′-position of the sense and/or antisense strand or region of the siNA molecule. Additionally, any of the modified siNA molecules of the invention can have a modification in one or both oligonucleotide strands of the siNA duplex, for example in the sense strand, the antisense strand, or both strands. Moreover, with regard to chemical modifications of the siNA molecules of the invention, each strand of the double-stranded siNA molecules of the invention can have one or more chemical modifications, such that each strand comprises a different pattern of chemical modifications.
  • In certain embodiments each strand of a double-stranded siNA molecule of the invention comprises a different pattern of chemical modifications, such as any Stab modification chemistries described herein (see Table 9) or any combination thereof, i.e., different combinations of defined Stabilization chemistry (Stab) sense and antisense strands. Further, non-limiting examples of modification schemes that could give rise to different patterns of modifications are shown in Table 9. The stabilization chemistries referred to in Table 9 as Stab, cart be combined in any combination of sense/antisense chemistries, such as Slab 7/8, Stab 7/11, Stab 8/8, Stab 18/8, Stab 18/11, Stab 12/13, Stab 7/13, Stab 18/13, Stab 7/19, Stab 8/19, Stab 18/19, Stab 7/20, Stab 8/20, Stab 18/20, Stab 7/32, Stab 8/32, or Stab 18/32 or any other combination of Stabilization chemistries.
  • In any of the siNAs of the invention, one or more (for example 1, 2, 3, 4 or 5) nucleotides at the 5′-end of the guide strand or guide region (also known as antisense strand or antisense region) of the siNA molecule are ribonucleotides.
  • In certain embodiment, the present invention provides a double-stranded short interfering nucleic acid (siNA) molecule that modulates the expression of CTNNB1, wherein the siNA comprises a sense strand and an antisense strand; each strand is independently 15 to 30 nucleotides in length; and the antisense strand comprises at least 15, 16, 17, 18, or 19 nucleotides having sequence complementary to any of:
  • (SEQ ID NO: 5)
    5′-CUGUUGGAUUGAUUCGAAA-3′;
    (SEQ ID NO: 194)
    5′-ACGACUAGUUCAGUUGCUU-3′;
    (SEQ ID NO: 196)
    5′-GGAUGAUCCUAGCUAUCGU-3′;
    or
    (SEQ ID NO: 151)
    5′-CCAGGAUGAUCCUAGCUAU-3′.
  • In some embodiments, the antisense strand of a siNA molecule of the invention comprises at least a 15, 16, 17, 18, or 19 nucleotide sequence of:
  • (SEQ ID NO: 4918)
    5′-UUUCGAAUCAAUCCAACAG-3′;
    (SEQ ID NO: 5107)
    5′-AAGCAACUGAACUAGUCGU-3′;
    (SEQ ID NO: 5109)
    5′-ACGAUAGCUAGGAUCAUCC-3′;
    or
    (SEQ ID NO: 5064)
    5′-AUAGCUAGGAUCAUCCUGG-3′;
  • In some embodiments, the sense strand of a siNA molecule of the invention comprises at least a 15, 16, 17, 18, or 19 nucleotide sequence of:
  • (SEQ ID NO: 5)
    5′-CUGUUGGAUUGAUUCGAAA-3′;
    (SEQ ID NO: 194)
    5′-ACGACUAGUUCAGUUGCUU-3′;
    (SEQ ID NO: 196)
    5′-GGAUGAUCCUAGCUAUCGU-3′;
    or
    (SEQ ID NO: 151)
    5′-CCAGGAUGAUCCUAGCUAU-3′.
  • In some embodiments, a siNA molecule of the invention comprises any of:
  • (SEQ ID NO: 5)
    5′-CUGUUGGAUUGAUUCGAAA-3′
    and
    (SEQ ID NO: 4918)
    5′-UUUCGAAUCAAUCCAACAG-3′;
    or
    (SEQ ID NO: 194)
    5′-ACGACUAGUUCAGUUGCUU-3′
    and
    (SEQ ID NO: 5107)
    5′-AAGCAACUGAACUAGUCGU-3′;
    or
    (SEQ ID NO: 196)
    5′-GGAUGAUCCUAGCUAUCGU-3′
    and
    (SEQ ID NO: 5109)
    5′-ACGAUAGCUAGGAUCAUCC-3′;
    or
    (SEQ ID NO: 151)
    5′-CCAGGAUGAUCCUAGCUAU-3′
    and
    (SEQ ID NO: 5064)
    5′-AUAGCUAGGAUCAUCCUGG-3′.
  • Any of the above described modifications, or combinations thereof, including those in the references cited, can be applied to any of these embodiments.
  • In certain embodiments, the nucleotides of the at least a 15, 16, 17, 18, or 19 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064 form a contiguous stretch of nucleotides.
  • In some embodiments, the siNA molecule can contain one or more nucleotide deletions, substitutions, mismatches and/or additions to the at least 15, 16, 17, 18, or 19 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, SEQ ID NO: 5064; provided, however, that the siNA molecule maintains its activity, for example, to mediate RNAi. In a non-limiting example, the deletion, substitution, mismatch and/or addition can result in a loop or bulge, or alternately a wobble or other alternative (non Watson-Crick) base pair.
  • In certain embodiments of the invention, double-stranded siNA molecules are provided, wherein the molecule has a sense strand and an antisense strand and comprises the following formula (A):
  • Figure US20230030119A1-20230202-C00002
      • wherein, the upper strand is the sense strand and the lower strand is the antisense strand of the double-stranded nucleic acid molecule; wherein the antisense strand comprises at least a 15, 16, 17, 18, or 19 nucleotide sequence of SEQ ID NO: 4918, SEQ ID NO: 5107, SEQ ID NO: 5109, or SEQ ID NO: 5064, and the sense strand comprises a sequence having complementarity to the antisense strand;
      • each N is independently a nucleotide which is unmodified or chemically modified or a non-nucleotide:
      • each B is a terminal cap that is present or absent;
      • (N) represents overhanging nucleotides, each of which is independently unmodified or chemically modified;
      • [N] represents nucleotides that are ribonucleotides;
      • X1 and X2 are independently integers from 0 to 4;
      • X3 is an integer from 15 to 30:
      • X4 is an integer from 9 to 30; and
      • X5 is an integer from 0 to 6, provided that the sum of X4 and X5 is 15-30.
  • In certain embodiments, the nucleotides of the at least a 15, 16, 17, 18, or 19 nucleotide sequence of SEQ ID NO: 4918, SEQ ID NO: 5107, SEQ NO: 5109, or SEQ NO: 5064 form a contiguous stretch of nucleotides.
  • In some embodiments, the siNA molecule of formula A can contain one or more nucleotide deletions, substitutions, mismatches and/or additions to the at least 15, 16, 17, 18, or 19 nucleotide sequence of SEQ ID NO: 4918, SEQ ID NO: 5107, SEQ ID NO: 5109, or SEQ ID NO: 5064; provided, however, that the siNA molecule maintains its activity, for example, to mediate RNAi. In a non-limiting example, the deletion, substitution, mismatch and/or addition can result in a loop or bulge, or alternately a wobble or other alternative (non Watson-Crick) base pair.
  • In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) of formula (A); wherein
      • (a) one or more pyrimidine nucleotides in NX4 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, T-deoxy nucleotides, ribonucleotides, or any combination thereof;
      • (b) one or more purine nucleotides in NX4 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2″-O-alkyl nucleotides, 2′-deoxy nucleotides, ribonucleotides, or any combination thereof;
      • (c) one or more pyrimidine nucleotides in NX3 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, 2′-deoxy nucleotides, ribonucleotides, or any combination thereof; and
      • (d) one or more purine nucleotides in NX3 positions are independently 2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, 2′-deoxy nucleotides, ribonucleotides, or any combination thereof.
  • In certain embodiments, the invention features a double-stranded short interfering nucleic acid (siNA) molecule of formula (A); wherein
      • (a) 1, 2, 3, 4, 5 or more pyrimidine nucleotides in NX4 positions are 2′-deoxy-2′-fluoro nucleotides;
      • (b) 1, 2, 3, 4, 5 or more purine nucleotides in NX4 positions are 2′-O-alkyl nucleotides;
      • (c) 1, 2, 3, 4, 5 or more pyrimidine nucleotides in NX3 positions are 2′-deoxy-2′-fluoro nucleotides; and
      • (d) 1, 2, 3, 4, 5 or more purine nucleotides in NX3 positions are 2′-deoxy nucleotides.
  • In certain embodiments, the invention Features a double-stranded short interfering nucleic acid (siNA) molecule of formula (A); wherein
      • (a) 1, 2, 3, 4, 5 or more pyrimidine nucleotides in NX4 positions are 2′-O-alkyl nucleotides;
      • (b) 1, 2, 3, 4, 5 or more purine nucleotides in NX4 positions are ribonucleotides;
      • (c) 1, 2, 3, 4, 5 or more pyrimidine nucleotides in NX3 positions are 2′-O-alkyl nucleotides; and
      • (d) 1, 2, 3.4, 5 or more purine nucleotides in NX3 positions are ribonucleotides.
  • In certain embodiments, the invention features a double-stranded short interfering nucleic acid (siNA) molecule of formula (A); wherein
      • (a) 1, 2, 3, 4, 5 or more pyrimidine nucleotides in NX4 positions are 2′-deoxy-2′-fluoro nucleotides;
      • (b) 1, 2, 3, 4, 5 or more purine nucleotides in NX4 positions are 2′-O-alkyl nucleotides;
      • (c) 1, 2, 3, 4, 5 or more pyrimidine nucleotides in NX3 positions are 2′-O-alkyl nucleotides; and
      • (d) 1, 2, 3, 4, 5 or more purine nucleotides in NX3 positions are 2′-deoxy-2′-fluoro nucleotides.
  • In certain embodiments, the invention features a double-stranded short interfering nucleic acid (siNA) molecule of formula (A) further comprising one or more phosphorothioate internucleotide linkages.
  • In some embodiments, siNA molecules having formula A comprise a terminal phosphate group at the 5′-end of the antisense strand or antisense region of the nucleic acid molecule.
  • In various embodiments, siNA molecules having formula A comprise X5=0, 1, 2, or 3; each X1 and X2=1 or 2; X3=18, 19, 20, 21, 22, or 23, and X4=17, 18, 19, 20, 21, 22, or 23.
  • In certain embodiments, siNA molecules having formula. A comprise X5=3. In other embodiments siNA molecules having formula A comprise X5=0.
  • In certain embodiments, siNA molecules having formula A comprise X1=2 and X2=2.
  • In various embodiments, siNA molecules having formula A comprise X5=0, X1=2, and X2=2. In other embodiments, siNA molecules having formula A comprise X5=3, X1=2, and X2=2.
  • In one specific embodiment, an siNA molecule having formula A comprises X5=3; each X1 and X2=2; X3=19, and X4=16.
  • In another specific embodiment, an siNA molecule having formula A comprises X5=0; each X1 and X2=2; X3=19, and X4=19.
  • In certain embodiments, siNA molecules having formula A comprise caps B at the 3′ and 5′ ends of the sense strand or sense region.
  • In certain embodiments, siNA molecules having formula A comprise caps (B) at the 3′-end of the antisense strand or antisense region.
  • In various embodiments, siNA molecules having formula A comprise caps (B) at the 3′ and 5′ ends of the sense strand or sense region and caps (B) at the 3′-end of the antisense strand or antisense region.
  • In yet other embodiments, siNA molecules having formula A comprise caps (B) only, at the 5′-end of the sense (upper) strand of the double-stranded nucleic acid molecule.
  • In some embodiments, siNA molecules having formula A further comprise one or more phosphorothioate internucleotide linkages between the nucleotides. In certain embodiments, siNA molecules having formula A comprise one or more phosphorothioate internucleotide linkages between the first terminal (N) and the adjacent nucleotide on the 3′ end of the sense strand, antisense strand, or both sense strand and antisense strands of the nucleic acid molecule. For example, a double-stranded nucleic acid molecule can comprise X1 and/or X2=2 having overhanging nucleotide positions with a phosphorothioate internucleotide linkage, (NsN) where “s” indicates phosphorothioate.
  • In some embodiments, one or more of the nucleotides of siNA molecules having formula A have a universal base.
  • In certain embodiments, siNA molecules having formula A have at position 14 from the 5′-end of the antisense strand a ribonucleotide when the nucleotide at that position 14 is a purine. In other embodiments, siNA molecules having formula A have at position 14 from the 5′-end of the antisense strand a ribonucleotide, a 2′-deoxy-2′-fluoro nucleotide or a 2′-O-methyl nucleotide when the nucleotide at that position 14 is a pyrimidine nucleotide.
  • In some embodiments, siNA molecules having formula. A comprises (N) nucleotides in the antisense strand (lower strand) that are complementary to nucleotides in a CTNNB1 target polynucleotide sequence, which also has complementarity to the N and [N] nucleotides of the antisense (lower) strand.
  • In certain embodiments, one or more siNA molecules of the invention are modified according to modification criteria as shown and described in U.S. Ser. No. 61/408,428 and U.S. Ser. No. 61/408,303, both of which are incorporated by reference herein.
  • Any of the above described modifications, or combinations thereof, discussed above as applicable to siNAs of the invention, including those in the references cited, can be applied to any of the embodiments to siNA molecules of the present invention.
  • C. Generation/Synthesis of siNA Molecules
  • The siNAs of the invention can be obtained using a number of techniques known to those of skill in the art. For example the siNA can be chemically synthesized or may be encoded by plasmid (e.g., transcribed as sequences that automatically fold into duplexes with hairpin loops). siNA can also be generated by cleavage of longer dsRNA dsRNA greater than about 25 nucleotides in length) by the E. coli RNase II or Dicer. These enzymes process the dsRNA into biologically active siNA (see, e.g., Yang et al., PNAS USA 99:9942-9947 (2002); Calegari et al. PNAS USA 99:14236 (2002) Byron el al. Ambion Tech Notes; 10 (11:4-6 (2009); Kawaski et al., Nucleic Acids Res., 31:981-987 (2003), Knight and Bass, Science, 293:2269-2271 (2001) and Roberston et al., J. Biol. Chem 243:82(1969),
  • 1. Chemical Synthesis
  • Preferably, siNA of the invention are chemically synthesized. Oligonucleotides (e.g., certain modified oligonucleotides or portions of oligonucleotides lacking ribonucleotides) are synthesized using protocols known in the art, for example as described in Caruthers et al., 1992, Methods in Enzymology 211, 3-19, Thompson et al., International PCT Publication No. WO 99/54459, Wincott et al., 1995, Nucleic Acids Res. 23, 2677-2684, Wincott et al., 1997, Methods Mol. Bio., 74, 59, Brennan et al., 1998, Biotechnol Bioeng., 61, 33-45, and Brennan, U.S. Pat. No. 6,001,311. The synthesis of oligonucleotides intakes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end.
  • siNA molecules without modifications are synthesized using procedures as described in Usinan et al., 1987J. Am. Chem. Soc., 109, 7845; Scaringe et al., 1990, Nucleic Acids Res., 18, 5433. These syntheses makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end that can be used for certain siNA molecules of the invention.
  • In certain embodiments, the siNA molecules of the invention are synthesized, deprotected, and analyzed according to methods described in U.S. Pat. Nos. 6,995,259, 6,686,463, 6,673,918, 6,649,751, 6,989,442, and U.S. patent application Ser. No. 10/190,359.
  • In a non-limiting synthesis example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocol with a 2.5 min coupling step for 2′-O-methylated nucleotides and a 45 second coupling step for 2′-deoxy nucleotides or 2′-deoxy-2′-fluoro nucleotides. Table 10 outlines the amounts and the contact times of the reagents used in the synthesis cycle.
  • Alternatively, the siNA molecules of the present invention can be synthesized separately and joined together post-synthetically, for example, by ligation (Moore et al., 1992, Science 256, 9923; Draper et al., International PCT Publication No. WO 93/23569; Shaharova et al., 1991, Nucleic Acids Research 19, 4247; Bellon et al., 1997, Nucleosides & Nucleotides, 16, 951; Belton et al., 1997, Bioconjugate Chem. 8, 204), or by hybridization following synthesis and/or deprotection.
  • Various siNA molecules of the invention can also be synthesized using the teachings of Scaringe et al., U.S. Pat. Nos. 5,889,136; 6,008,400; and 6,111,086.
  • 2. Vector Expression
  • Alternatively, siNA molecules of the invention that interact with and down-regulate gene encoding target CTNNB1 molecules can be expressed and delivered from transcription units (see for example Couture et al., 1996, TIG., 12, 510) inserted into DNA or RNA vectors. The recombinant vectors can be DNA plasmids or viral vectors. siNA expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus.
  • In some embodiments, pol III based constructs are used to express nucleic acid molecules of the invention. Transcription of the siNA molecule sequences can be driven from a promoter for eukaryotic RNA polymerase I (pol I), RNA polymerase II (pot II), or RNA polymerase III (pol III). (see for example, Thompson, U.S. Pat. Nos. 5,902,880 and 6,146,886). (See also, Izant and Weintraub, 1985, Science, 229, 345; McGarr: and Lindquist, 1986, Proc. Natl. Acad. Sci., USA 83, 399; Scanlon et 1991, Proc, Natl. Acad. Sci. USA, 88, 10591-5; Kashani-Sabet et al. 1992, Antisense Res. Dev., 2, 3-15; Dropulic ci al., 1992, J. Virol., 66, 1432-41; Weerasinghe et al., 1991, J. Virol., 65, 5531-4; Qjwang et at, 1992, Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen et al., 1992, Nucleic Acids Res., 20, 4581-9; Sarver et at, 1990 Science, 247, 1222-1225; Thompson et at, 1995, Nucleic Acids, Res., 23, 2259; Good et al., 1997, Gene Therapy, 4, 45. Transcripts from pol II or pol III promoters are expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type depends on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990, Proc. Natl, Acad. Sci. USA, 87, 6743-7; Ciao and Huang 1993, Nucleic Acids Res., 21, 2867-72; Lieber et al. 1993, Methods Enzymol., 217, 47-66; Zhou et al., 1990, Mol. Cell. Biol., 10, 4529-37). Several investigators have demonstrated that nucleic acid molecules expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et at, 1992, Antisense Res. Dev., 2, 3-15; Ojwang et al., 1992, Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen et al., 1992, Nucleic Acids Res., 20, 4581-9; Yu et at, 1993, Proc. Natl. Acad. Sci. U.S.A, 90, 6340-4; L'Huilher et al., 1992, EMBO J., 11, 4411-8; Lisziewiez et al., 1993, Proc. Natl. Acad. Sci. U.S.A, 90, 8000-4; Thompson et al., 1995, Nucleic Acids Res., 23, 2259; Sullenger & Cech, 1993, Science, 262, 1566). More specifically, transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA are useful in generating high concentrations of desired RNA molecules such as siNA in cells (Thompson et at, supra; Couture and Stinchcomb, 1996, supra; Noonberg et at, 1994, Nucleic Acid Res., 22, 2830; Noonberg et al., U.S. Pat. No. 5,624,803; Good et at, 1997, Gene Ther., 4, 45; Beigelman et at, International PCT Publication No. WO 96/18736. The above siNA transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (for a review see Couture and Stinchcomb, 1996, supra).
  • Vectors used to express the siNA molecules of the invention can encode one or both strands of an siNA duplex, or a single self-complementary strand that self hybridizes into an siNA duplex. The nucleic acid sequences encoding the siNA molecules of the instant invention can be operably linked in a manner that allows expression of the siNA molecule (see for example Paul et al., 2002, Nature Biotechnology, 19, 505; Miyagishi and Taira, 2002, Nature Biotechnology, 19, 497; Lee et al., 2002, Nature Biotechnology, 19, 500; and Novina et al., 2002, Nature Medicine, advance online publication doi:10.1038/nm725).
  • D. Carrier/Delivery Systems
  • The siNA molecules of the invention are added directly, or can be complexed with cationic lipids, packaged within liposomes, or as a recombinant plasmid or viral vectors which express the siNA molecules, or otherwise delivered to target cells or tissues. Methods for the delivery of nucleic acid molecules are described in Akhtar et al., 1992, Trends Cell Bio., 2, 139; Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, 1995, Maurer et al., 1999, Mol. Membr. Biol., 16, 129-140; Holland and Huang, 1999, Handb. Exp. Pharmacol., 137, 165-192; and Lee et al., 2000, ACS Symp. Ser., 752, 184-192. Beigelman et al., U.S. Pat. No. 6,395,713 and Sullivan et al., PCT WO 94/02595 further describe the general methods for delivery of nucleic acid molecules. These protocols can be utilized for the delivery of virtually any nucleic acid molecule. Nucleic acid molecules can be administered to cells by a variety of methods known to those of skill in the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as biodegradable polymers, hydrogels, cyclodextrins (see for example, Gonzalez et al., 1999, Bioconjugate Chem., 10, 1068-1074; Wang et al., International PCT Publication Nos. WO 03/47518 and WO 03/46185), poly(lactic-co-glycolic)acid (PLGA) and PLCA microspheres (see for example U.S. Pat. No. 6,447,796 and US Patent Application Publication No. US 2002130430), biodegradable nanocapsules, and bioadhesive microspheres, or by proteinaceous vectors (O'Hare and Normand, International PCT Publication No. WO 00/53722).
  • In one aspect, the present invention provides carrier systems containing the siNA molecules described herein. In some embodiments, the carrier system is a lipid-based carrier system, cationic lipid, or liposome nucleic acid complexes, a liposome, a micelle, a virosome, a lipid nanoparticle or a mixture thereof. In other embodiments, the carrier system is a polymer-based carrier system such as a cationic polymer-nucleic acid complex. In additional embodiments, the carrier system is a cyclodextrin-based carrier system such as a cyclodextrin polymer-nucleic acid complex. In further embodiments, the carrier system is a protein-based carrier system such as a cationic peptide-nucleic acid complex. Preferably, the carrier system is a lipid nanoparticle (“LNP”) formulation.
  • In certain embodiments, the siNA molecules of the invention are formulated with a lipid nanoparticle composition such as is described in U.S. patent application Ser. Nos. 11/353,630, 11/586,102, 61/189,295, 61/204,878, 61/235,476, 61/249,807, 61/298,022, 61/351,373, 61/347,640, 61/345,754, 61/322,054, 12/640,342, and 12/617,079, and PCT Applications Nos. PCT/US10/020013 and PCT/US09/053336. In certain preferred embodiments, the siNA molecules of the invention are formulated with a lipid nanoparticle composition comprising a cationic lipid/Cholesterol/PEG-C-DMA/DSPC in a 40/48/2/10 ratio or a cationic lipid/Cholesterol/PEG-DMG/DSPC in a 40/48/2/10 ratio. In more certain embodiments, the cationic lipid is DLinDMA (see Table 12), the PEG is PEG-DMG, and the N/P ratio of the formulation is 2.8. In more preferred embodiments, the cationic lipid is DLinDMA (see Tables 11 & 12).
  • In various embodiments, lipid nanoparticle formulations described in Table 11 are applied to any siNA molecule or combination of siNA molecules herein. In some embodiments, the invention features a composition comprising an siNA molecule of the invention formulated as any of formulation LNP-051; LNP-053; LNP-054; LNP-069; LNP-073; LNP-077; LNP-080; LNP-082; LNP-083; LNP-060; LIMP-061; LNP-086; LNP-097; LNP-098; LNP-099; LNP-100; LNP-101; LNP-102; LNP-103; or LNP-104 (see Table 11).
  • In certain other embodiments, the invention features a composition comprising an siNA molecule of the invention formulated with any of the cationic lipid formulations described in U.S. Patent Application Nos. 61/189,295, 61/204,878, 61/235,476, 61/249,807, and 61/298,022.
  • In other embodiments, the invention features conjugates and/or complexes of siNA molecules of the invention. Such conjugates and/or complexes can be used to facilitate delivery siNA molecules into a biological system, such as a cell. The conjugates and complexes provided by the instant invention can impart therapeutic activity by transferring therapeutic compounds across cellular membranes, altering the pharmacokinetics, and/or modulating the localization of nucleic acid molecules of the invention. Non-limiting, examples of such conjugates are described in U.S. Publication Nos. US2008/0152661 A1 and US 2004/0162260 A1 (e.g., CDM-LBA, CDM-Pip-LBA, CDM-PEG, CDM-NAG, etc) and U.S. patent application Ser. Nos. 10/427,160 10/201,394, 61/322,422, and 61/315,223; and U.S. Pat. Nos. 6,528,631; 6,335,434; 6,235,886; 6,153,737; 5,214,136; and 5,138,045.
  • In various embodiments, polyethylene glycol (PEG) can be covalently attached to siNA compounds of the present invention. The attached PEG can be any molecular weight, preferably from about 100 to about 50,000 daltons (Da).
  • In yet other embodiments, the invention features compositions or formulations comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes) and siNA molecules of the invention, such as is disclosed in for example, International PCT Publication No, WO 96/10391; Anson at al., International PCT Publication No, WO 96/10390; Holland et al., International PCT Publication No. WO 96/10392.
  • In some embodiments, the siNA molecules of the invention can also be formulated or complexed with polyethyleneimine and derivatives thereof, such as polyethyleneimine-polyethyleneglycol-N-acetylgalactosamine (PEI-PEG-GAL) or polyethyleneimine-polyethyleneglycol-tri-N-acetyl galactosamine (PEI-PEG-triGAL) derivatives. In one embodiment, the nucleic acid molecules of the invention are formulated as described in U.S. Patent Application Publication No. 20030077829.
  • In other embodiments, siNA molecules of the invention are complexed with membrane disruptive agents such as those described in U.S. Patent Application Publication No. 20010007666. In still other embodiments, the membrane disruptive agent or agents and the siNA molecule are also complexed with a cationic lipid or helper lipid molecule, such as those lipids described in U.S. Pat. No. 6,235,310.
  • In certain embodiments, siNA, molecules of the invention are complexed with delivery systems as described in U.S. Patent Application Publication Nos. 2003077829; 20050287551; 20050164220; 20050191627; 20050118594; 20050153919; 20050085486; and 20030158133; and International PCT Publication Nos. WO 00/03683 and WO 02/087541.
  • In some embodiments, a liposomal formulation of the invention comprises an siNA molecule of the invention (e.g., siNA) formulated or complexed with compounds and compositions described in U.S. Pat. Nos. 6,858,224; 6,534,484; 6,287,591; 6,835,395; 6,586,410; 6,858,225; 6,815,432; 6,586,001; 6,120,798; 6,977,223; 6,998,115; 5,981,501; 5,976,567; 5,705,385; and U.S. Patent Application Publication Nos. 2006/0019912; 2006/0019258; 2006/0008909; 2005/0255151; 2005/0079212; 2005/0008689; 2003/0077829, 2005/0064595, 2005/0175682, 2005/0118253; 2004/0071654; 2005/0244504; 2005/0265961 and 2003/0077829.
  • Alternatively, recombinant plasmids and viral vectors, as discussed above, which express siNAs of the invention can be used to deliver the molecules of the invention. Delivery of siNA molecule expressing vectors can be systemic, such as by intravenous or intra-muscular administration, by administration to target cells ex-planted from a subject followed by, reintroduction into the subject, or by any other means that would allow for introduction into the desired target cell (for a review see Couture el al., 1996, TIG., 12, 510). Such recombinant plasmids can also be administered directly or in conjunction with a suitable delivery reagents, including, for example, the Mirus Transit LT1 lipophilic reagent; lipofectin; lipofectamine; cellfectin; polycations polylysine) or liposomes lipid-based carrier system, cationic lipid, or liposome nucleic acid complexes, a micelle, a virosome, a lipid nanoparticle.
  • E. Kits
  • The present invention also provides nucleic acids in kit form. The kit may comprise a container. The kit typically contains a nucleic acid of the invention with instructions for its administration. In certain instances, the nucleic acids may have a targeting moiety attached. Methods of attaching targeting moieties (e.g. antibodies, proteins) are known to those of skill in the art. In certain instances, the nucleic acids are chemically modified. In other embodiments, the kit contains more than one siNA molecule of the invention. The kits may comprise an siNA molecule of the invention with a pharmaceutically acceptable carrier or diluent. The kits may further comprise excipients.
  • F. Therapeutic Uses/Pharmaceutical Compositions
  • The present body of knowledge in CTNNB1 research indicates the need for methods to assay CTNNB1 activity and for compounds that can regulate CTNNB1 expression for research, diagnostic, and therapeutic use. As described infra, the nucleic acid molecules of the present invention can be used in assays to diagnose disease state related of CTNNB1 levels. In addition, the nucleic acid molecules and pharmaceutical compositions can be used to treat disease states related to CTNNB1 RNA levels.
  • 1. Disease States Associated with CTNNB1
  • Particular disease states that can be associated with CTNNB1 expression modulation include various cancers including solid tumors. Non-limiting examples of such cancers include: bilary tract cancer, bladder cancer, transitional cell carcinoma, urothelial carcinoma, osteosarcoma, brain cancer, gliomas, astrocytomas, breast carcinoma, metaplastic carcinoma, cervical cancer, cervical squamous cell carcinoma, rectal cancer, colorectal carcinoma, colon cancer, hereditary nonpolyposis colorectal cancer, colorectal adenocarcinomas, gastrointestinal stromal tumors (GISTs), endometrial carcinoma, endometrial stromal sarcomas, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, ocular melanoma, uveal melanoma, gallbladder carcinomas, gallbladder adenocarcinoma, renal cell carcinoma, clear cell renal cell carcinoma, transitional cell carcinoma, urothelial carcinomas, Wilms tumor, leukemia, acute lymocylic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic (CLL), chronic myeloid (CML), chronic myelomonocytic (CMML), liver cancer, liver carcinoma, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, Lung cancer, non-small cell lung cancer (NSCLC), mesothelioma, B-cell lymphomas, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, Mantle cell lymphoma, T-ell lymphomas, non-Hodgkin lymphoma, precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphomas, multiple myeloma, nasopharyngeal carcinoma (NPC), neuroblastoma, oropharyngeal cancer, oral cavity squamous cell carcinomas, osteosarcoma, ovarian carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, pseudopapillary neoplasms, acinar cell carcinomas, Prostate cancer, prostate adenocarcinoma, skin cancer, melanoma, malignant melanoma, cutaneous melanoma, small intestine carcinomas, stomach cancer, gastric carcinoma, gastrointestinal stromal tumor (GIST), uterine cancer, and uterine sarcoma.
  • It is understood that the siNA molecules of the invention can degrade the target CTNNB1 mRNA (and thus inhibit the diseases stated above). Inhibition of a disease can be evaluated by directly measuring the progress of the disease in a subject. It can also be inferred through observing a change or reversal in a condition associated with the disease. Additionally, the siNA molecules of the invention can be used as a prophylaxis. Thus, the use ref the nucleic acid molecules and pharmaceutical compositions of the invention can be used to ameliorate, treat, prevent, and/or cure these diseases and others associated with regulation of CTNNB1 gene expression.
  • 2. Pharmaceutical Compositions
  • The siNA molecules of the instant invention provide useful reagents and methods for a variety of therapeutic, prophylactic, cosmetic, veterinary, diagnostic, target validation, genomic discovery, genetic engineering, and pharmacogenomic applications.
  • a. Formulations
  • Thus, the present invention, in one aspect, also provides for pharmaceutical compositions of the siNA molecules described, i.e., compositions in a pharmaceutically acceptable carrier or diluent. These pharmaceutical compositions include salts, esters, or salts of such esters, of the above compounds, e.g., acid addition salts, for example, salts of hydrochloric, hydrobromic, hydroiodic, acetic acid, and benzene sulfonic acid. Other salts include for example, sodium, potassium, manganese, ammonium, and calcium salts. These formulations or compositions can comprise a pharmaceutically acceptable carrier or diluent as is generally known in the art.
  • In one embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5. In another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 4918. In yet another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 194. In still another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5107. In another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 196. In another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5109. In another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 151. In yet another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5064. In still another embodiment, the invention features a pharmaceutical composition comprising an siNA molecule comprising formula (A).
  • The siNA molecules of the invention are preferably formulated as pharmaceutical compositions prior to administering to a subject, according to techniques known in the art. Pharmaceutical compositions of the present invention are characterized as being at least sterile and pyrogen-free. Methods for preparing pharmaceutical compositions of the invention are within the skill in the art for example as described in Remington's Pharmaceutical Science, 17th ed., Mack Publishing Company, Easton, Pa. (1985).
  • In some embodiments, pharmaceutical compositions of the invention (e.g. siNA and/or LNP formulations thereof) further comprise conventional pharmaceutical excipients and/or additives. Suitable pharmaceutical excipients include preservatives, flavoring agents, stabilizers, antioxidants, osmolality adjusting agents, buffers, and pH adjusting agents. Suitable additives include physiologically biocompatible buffers (e.g., trimethylamine hydrochloride), addition of chelants (such as, for example, DTPA or DTPA-bisamide) or calcium chelate complexes (as for example calcium DTPA, CaNaDTPA-bisamide), or, optionally, additions of calcium or sodium salts (for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate). In addition, antioxidants and suspending agents can be used.
  • Non-limiting examples of various types of formulations for local administration include ointments, lotions, creams, gels, foams, preparations for delivery by transdermal patches, powders, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (for example eye or nose drops), solutions/suspensions for nebulization, suppositories, pessaries, retention enemas and chewable or suckable tablets or pellets (for example for the treatment of aphthous ulcers) or liposome or microencapsulation preparations.
  • Ointments, creams and gels, can, for example, can be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents. Non limiting examples of such bases can thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol. Various thickening agents and gelling agents can be used depending on the nature of the base. Non-limiting examples of such agents include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.
  • In one embodiment lotions can be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.
  • In one embodiment powders for external application can be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops can be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents, suspending agents or preservatives.
  • Compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more such sweetening agents, flavoring agents, coloring agents or preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents; such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques. In some cases such coatings can be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate; or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions can also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents can be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid
  • Pharmaceutical compositions of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents.
  • Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
  • The nucleic acid molecules of the invention can also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
  • Nucleic acid molecules of the invention can be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • In other embodiments, the siNA and LNP compositions and formulations provided herein for use in pulmonary delivery further comprise one or more surfactants. Suitable surfactants or surfactant components for enhancing the uptake of the compositions of the invention include synthetic and natural as well as full and truncated forms of surfactant protein A, surfactant protein B, surfactant protein C, surfactant protein D and surfactant Protein E, di-saturated phosphatidylcholine (other than dipalmitoyl), dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine; phosphatidic acid, ubiquinones, lysophosphatidylethanolamine, lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, dehydroepiandrosterone, dolichols, sulfatidic acid, glycerol-3-phosphate, dihydroxyacetone phosphate, glycerol, glycero-3-phosphocholine, dihydroxyacetone, palmitate, cytidine diphosphate (CDP) diacylglycerol, CDP choline, choline, choline phosphate; as well as natural and artificial lamellar bodies which are the natural carrier vehicles for the components of surfactant, omega-3 kitty acids, polyenic acid, polyenoic acid, lecithin, palmitinic acid, non-ionic block copolymers of ethylene or propylene oxides, polyoxypropylene, monomeric and polymeric, polyoxyethylene, monomeric and polymeric, poly (vinyl amine) with dextran and/or alkanoyl side chains, Brij 35, Triton X-100 and synthetic surfactants ALEC, Exosurf, Survan and Atovaquone, among others. These surfactants can be used either as single or part of a multiple component surfactant in a formulation, or as covalently bound additions to the 5′ and/or 3′ ends of the nucleic acid component of a pharmaceutical composition herein.
  • b. Combinations
  • The siNAs and pharmaceutical formulations according to the invention can be administered to a subject alone or used in combination with or include one or more other therapeutic agents, for example, anticancer agents. Thus, combinations of the presently disclosed compounds with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), 6th edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Such anti-cancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents and agents that interfere with cell cycle checkpoints. The siNAs of the invention are also useful in combination with any therapeutic agent used in the treatment of HCC, for example, but not limitation sorafenib. The instant compounds are particularly useful when co-administered with radiation therapy.
  • In a further embodiment, therefore, the invention provides a combination comprising an siNA molecule of the invention, such as for example, but not limitation, an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064; or formula (A) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof together with one or more anti-cancer or chemotherapeutic agents.
  • In certain embodiments, the instant siNA molecules of the invention are useful in combination with known anti-cancer agents including the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors.
  • Examples of estrogen receptor modulators that can be used in combination with the compounds of the invention include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.
  • Examples of androgen receptor modulators that can be used in combination with the compounds of the invention include, hut are not limited to, finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • Examples of such retinoid receptor modulators that can be used in combination with the compounds of the invention include, but are not limited to, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
  • Examples of cytotoxic agents that can be used in combination with the compounds of the invention include, but are not limited to, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminediehloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum (II)]tetrachloride, diarizidinylspermine, arsenic trioxide, 1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN10755, and 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphortyl-daunorubicin (see WO 00/50032).
  • An example of a hypoxia activatable compound that can be used in combination with the compounds of the invention is tirapazamine.
  • Examples of proteasome inhibitors that can be used in combination with the compounds of the invention include, but are not limited to, lactacystin and bortezomib.
  • Examples of microtubule inhibitors/microtubule-stabilising agents that can be used in combination with the compounds of the invention include, but are not limited to, paclitaxel, vindesine sulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-prolyl-L-proline-t-butylamide, TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and 6,288,237) and BMS188797.
  • Some examples of topoisomerase inhibitors that can be used in combination with the compounds of the invention include, but are not limited to, are topotecan, hycaptatmine, irinotecan, rubitecan, 6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2′-dimethylamino-2′-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide, asulacrine, (5a, 5aB, 8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydro0xy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′,6,7)naplitho(2,3-d)-1,3-dioxol-6-one, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium, 6,9-bis[(2-aminoethyl)amino]benzo[g]isoguinoline-5,10-dione, 5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one, N-[1-[2(diethylamino)ethylaminol]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c] quinolin-7-one, and dimesna.
  • Examples of inhibitors of mitotic kinesins, and in particular the human mitotic kinesin KSP, that can be used in combination with the compounds of the invention include, but are not limited to, inhibitors described in PCT Publications WO 01/30768, WO 01/98278, WO 03/050,064, WO 03/050,122, WO 03019,527, WO 03/049,679, WO 03/049,678, WO04/039774, WO03/079973, WO03/099211, WO03/105855, WO03/106417, 5004/037171, WO04/058148, WO04/058700, WO04/126699, WO05/018638, WO05/019206, WO05/019205, WO05/018547, 4005/017190, US2005/0176776. In an embodiment inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKIP1, inhibitors of CENP-E, inhibitors of MCAK, inhibitors of Kif14, inhibitors of Mphosph1 and inhibitors of Rabb-KIFL.
  • Examples of “histone deacetylase inhibitors” that can be used in combination with the compounds of the invention include, but are not limited to, TSA, oxamflatin, PXD101, MG98, valproic acid and scriptaid. Further reference to other histone deacetylase inhibitors may be found m the following manuscript; Miller, T. A. et al. J. Med. Chem. 216(24):5097-5116 (2003).
  • Inhibitors of kinases involved in mitotic progression that can be used in combination with the compounds of the invention include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK) (in particular inhibitors of PLK-1), inhibitors of bub-1 and inhibitors of bub-R1.
  • Antiproliferative agents that can be used in combination with the compounds of the invention include, but are not limited to, antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2′-deoxy-2′-methylidenecytidine, 2′-fluoromethylene-2′-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimdino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamic acid, aminopterin, 5-flurouracil, alanosine, 11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-yl acetic acid ester, swaiusonine, lometrexol, dexrazoxane, methioninase, 2′-cyatio-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone.
  • Examples of monoclonal antibody targeted therapeutic agents that can be used in combination with the compounds of the invention include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody, such as, for example, Bexxar.
  • Examples of HMG-CoA reductase inhibitors that may be used that can be used in combination with the compounds of the invention include, but are not limited to, lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®; see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896) and atorvastatin (LIPITOR®; see U.S. Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952). The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, “Cholesterol Lowering, Drugs”, Chemistry & Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos. 4,782,084 and 4,885,314.
  • Examples of prenyl-protein transferase inhibitors that can be used in combination with the compounds of the invention include, but are not limited to, can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. Nos. 5,420,245, 5,523,430, 5,532,359, 5,510,510, 5,589,485, 5,602,098, European Patent Publ. 0 618 221, European Patent 0 675 112, European Patent Publ. 0 604 181, European Patent Publ. 0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/3.4535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO 98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of a prenyl-protein transferase inhibitor on angiogenesis see European J. of Cancer, Vol. 35, No. 9, pp. 1394-1401 (1999).
  • Examples of angiogenesis inhibitors that can be used in combination with the compounds of the invention include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-α, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib (PNAS, Vol, 89, p, 7384 (1992); JNCI, Vol, 69, p. 475 (1982); Arch. Opthalmol., Vol. 108, p. 573 (1990); Anat. Rec., Vol. 238, p. 68 (1994); FEBS Letters, Vol. 372, p. 83 (1995), Clin. Orthop. Vol. 313, p. 76 (1995); J. Mol. Endocrinol., Vol. 16, p. 107 (1996); Jpn. J. Pharmacol., Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol. 93, p, 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see, Nature Biotechnology, Vol. 17, pp. 963-968 (October 1999); Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).
  • Other therapeutic agents that modulate or inhibit angiogenesis may also be used in combination with the compounds of the instant invention and include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examples of such agents that modulate or inhibit the coagulation and fibrinolysis pathways that can be used in combination with the compounds of the invention include, but are not limited to, heparin (see Thromb. Haemost. 80:10-23 (1998)), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res, 101:329-354 (2001)). TAFIa inhibitors have been described in PCT Publication WO 03/013,526 and U.S. Ser. No. 60/349,925 (filed Jan. 18, 2002).
  • Agents that interfere with cell cycle checkpoints that can be used in combination with the compounds of the invention include, but are not limited to, inhibitors of ATR, ATM, the Chk1 and Chk2 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
  • Agents that interfere with receptor tyrosine kinases (RTKs) that can be used in combination with the compounds of the invention include, but are not limited to, inhibitors of c-Kit, Eph, PDGF, Flt3 and CTNNB1. Further agents include inhibitors of RTKs as described by Bunco-Jensen and Hunter, Nature, 41.1:355-365, 2001.
  • Inhibitors of cell proliferation and survival signaling pathway that can be used in combination with the compounds of the invention include, but are not limited to, inhibitors of EGER (for example gefitinib and erlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors of IGFR, inhibitors of cytokine receptors, inhibitors of CTNNB1, inhibitors of PI3K (for example LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in WO 02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US 2004-0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO 03/086403, WO 2004/041162, WO 2004/096131, WO 2004/096129, WO 2004/096135, WO 2004/096130, WO 2005/100356, WO 2005/100344), inhibitors of Raf kinase (for example BAY-43-9006), inhibitors of MEK (for example CI-1040 and PD-098059) and inhibitors of mTOR (for example Wyeth CCI-779). Such agents include small molecule inhibitor compounds and antibody antagonists.
  • Apoptosis inducing agents that can be used in combination with the compounds of the invention include, but are not limited to, activators of TNF receptor family members (including the TRAIL receptors).
  • NSAIDs that are selective COX-2 inhibitors that can be used in combination with the compounds of the invention include, but are not limited to, those NSAIDs disclosed in U.S. Pat. Nos. 5,474,995, 5,861,419, 6,001,843, 6,020,343, 5,409,944, 5,436,265, 5,536,752, 5,550,142, 5,604,260, 5,698,584, 5,710,140, WO 94/15932, U.S. Pat. Nos. 5,344,991, 5,134,142, 5,380,738, 5,393,790, 5,466,823, 5,633,272, and 5,932,598, all of which are hereby incorporated by reference.
  • Inhibitors of COX-2 that are particularly useful in combination with the compounds of the invention include: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and 5-chloro-3-(4-methylsulfonyl)-phenyl-2-(2-methyl-5-pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof.
  • Compounds that have been described as specific inhibitors of COX-2 and are therefore useful in the present invention include, but are not limited to: parecoxib, CELEBREX® and BEXTRA® or a pharmaceutically acceptable salt thereof.
  • Angiogenesis inhibitors that can be used in combination with the compounds of the invention include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)-phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalene disulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416).
  • Tyrosine kinase inhibitors that can be used in combination with the compounds of the invention include, but are not limited to, N-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one, 17-(allylamino)-17-demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one, SH268, genistein, imatirtib (ST1571), CEP2563, 4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethane sulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, ST1571A, N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD 121974.
  • Combinations with compounds other than anti-cancer compounds are also encompassed in the instant compositions and methods. For example, combinations of the instantly claimed compounds with PPAR-γ (i.e., PPAR-gamma) agonists and PPAR-δ (i.e., PPAR-delta) agonists are useful in the treatment of certain malignancies. PPAR-γ and PPAR-δ are the nuclear peroxisome proliferator-activated receptors γ and δ. The expression of PPAR-γ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc, Pharmacol, 31:909-913 (1993); J. Biol. Chem. 274:9116-9121 (1999): Invest. Ophthalmol Vis. Sci. 41:2309-2317 (2000)). More recently, PPAR-γ agonists have been shown to inhibit the angiogenic response to VEGE in vitro; both troglitazone and rosiglitazone maleate inhibit the development of retinal neovascularization in mice. (Arch. Ophthalmol. 119:709-717 (2001)). Examples of PPAR-γ agonists and PPAR-γ/α agonists that can be used in combination with the compounds of the invention include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, HT-501, MCC-555, GW2331, (GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionic acid (disclosed in U.S. Ser. No. 09/782,856), and 2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy) phenoxy)propoxy)-2-ethylchromone-2-carboxylic acid (disclosed in U.S. Ser. No. 60/235,708 and 60/244,697).
  • Another embodiment of the instant invention is the use of the presently disclosed compounds in combination with gene therapy for the treatment of cancer. For an overview of genetic strategies to treating cancer see Hall et al. (Am J Hum Genet 61:785-789 (1997)) and Kufe et al. (Cancer Medicine, 5th Ed, pp 876-889, BC Decker, Hamilton, 2000). Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134, for example), a uPA/uPAR antagonist (“Adenovirus-Mediated Delivery of a uPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice,” Gene Therapy, August 5(8):1105-13 (1998)), and interferon gamma (J Immunol 164:217-222 (2000)).
  • The compounds of the instant invention may also be administered in combination with an inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins. Such MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (vaispodar).
  • A compound of the present invention may be employed in conjunction with anti-emetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy. For the prevention or treatment of emesis, a compound of the present invention may be used in conjunction with other anti-emetic agents, especially neurokinin-1 receptor antagonists, 5H T3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, an antidopaminergic, such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol. In an embodiment, an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is administered as an adjuvant for the treatment or prevention of emesis that may result upon administration of the instant compounds.
  • Neurokinin-1 receptor antagonists of use in conjunction with the compounds of the present invention are fully described, for example, in U.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European Patent Publication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430 771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0 585 913, 0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; PCT International Patent Publication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 9708144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, and 2 302 689. The preparation of such compounds is fully described in the aforementioned patents and publications, which are incorporated herein by reference.
  • In an embodiment, the neurokinin-1 receptor antagonist for use in conjunction with the compounds of the present invention is selected from: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Pat. No. 5,719,147.
  • A compound of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids). Examples of bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ihandronate (Boniva), incadronate or cimadronate clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.
  • A compound of the instant invention may also be administered with an agent useful in the treatment of anemia. Such an anemia treatment agent is, for example, a continuous eyttropolesis receptor activator (such as epoetin alfa).
  • A compound of the instant invention may also be administered with an agent useful in the treatment of neutropenia. Such a neutropenia treatment agent is, for example, a hematopoletic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF). Examples of a G-CSF include filgrastim and PEG-filgrastim.
  • A compound of the instant invention may also be administered with an immunologic-enhancing drug, such as levamisole, isoprinosine and Zadaxin.
  • A compound of the instant invention may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors. Examples of aromatase inhibitors include but are not limited to: anastrozole, letrozole and exemestane.
  • A compound of the instant invention may also be useful for treating or preventing cancer in combination with other siNA therapeutics.
  • The compounds of the instant invention may also be administered in combination with γ-secretase inhibitors and/or inhibitors of NOTCH signaling. Such inhibitors include compounds described in WO 01/90084, WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO 03/093264, WO 03/093251, WO 03/093253, WO 2004/039800, WO 2004/039370, WO 2005/030731, WO 2005/014553, U.S. Ser. No. 10/957,251, WO 2004/089911, WO 02/081435, WO 02/081433, WO 03/018543, WO 2004/031137, WO 2004/031139, WO 2004/031138, WO 2004/101538, WO 2004/101539 and WO 02/47671 (including LY-450139).
  • A compound of the instant invention may also be useful for treating or preventing cancer in combination with PARP inhibitors.
  • A compound of the instant invention may also be useful for treating cancer in combination with the following therapeutic agents: abarelix (Plenaxis Depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumahh (Carripath®); alitretinoin (Panretin®); allopurinol (Zyloprin®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine. (Vidaza®); bendamustine hydrochloride (Treanda®); bevacuzimab (Avastir®); bexaroiene capsules (Targretin®), bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezotnib (Velcade®); brefeldin busulfan intravenous (Busulfex®); busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (Gliadel Wafer®), celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin (Platinol®); ciadribine (Leustatin®, 2-CdA®); clofarahine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®) cytarabine (Cytosar-Uφ); cytarabine liposomal (DepoCyt®); dacarbazine (MIC-Dome®); dactinomycin, actinomycin D (Cosmegen®); dalteparin sodium injection (Fragmin®); Darhepoetin alfa (Aranesp®); dasatinib (Sprycel®); daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); degarelix (Firmagon®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®); dexrazoxane hydrochloride (Totec®); didemnin B; 17-DMAG; docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate (Dromostanolone®); droniostanolone propionate (Masterorte Injection®); eculizumab injection (Soliris®); B Solution (Elliott's B Solution®); eltrombopag (Promacta®); epirubicin (Ellence®); Epoetin alfa (Epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); ethinyl estradiol; etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®); everolimus tablets (Afinitor®); exemestane (Aromasin®); ferurnoxytol (Feraherne Injection®); Filgrastim (Neupogen®); floxuridine (intraarterial) (FLTDR®); fludarabine (Fludara®); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); geldariamyein; gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelin Implant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfatnide (IFEX®); iniatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (Intron A®); iobengmane I 123 injection (AdreView®); irinotecan (Camptosar®); ixabepilone (Ixempra®); lapatinib tablets (Tykerh®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®); meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex Tabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); 8-methoxypsoralen, mitomycin C (Mutarnycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®); mitramycin; nandrolone phenpropionate (Durabolin-50®); nelarabine (Arration®); nilotinih (Tasigna®); Nofetumomab (Verluma®); ofatumumab (Arzerra®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivarice®); pamidronate (Aredia®); panitumumab (Vectibix®); pazoparib tablets (Votrientim®); pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastirn (Neulasta®); pemetrexed disodium (Alitntan; pentostatin (Nipent®); pipobroman (Vereyte®); plerixafor (Mozobiln; plicamyein, mithramycin (Mithracin®); porfimer sodium (Photofring); pralatrexate injection (Folotyn®); procarbazine (Matulane®); quinacrine (Atabrine®); rapamycin; Rasburicase (Elitek®); raloxifene hydrochloride (Evista®); Rituximab (Rituxart®); romidepsin (Istodax®); romiplostim (Nplate®); sargramostim (Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunning) maleate (Sutent®); talc (Scierosol®); tamoxifen (Nolvadex®); temozolomide (Temodar®); temsirolimus (Torisel®); teniposide, VM-26 (Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiopurire; thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®); Tositurnomab/I-131 tositumomab (Bexxar®); trans-retinoic acid; Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); triethylenemelamine; Uracil Mustard (Uracil Mustard Capsules®); vatrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); vorinostat (Zolinza®); wortmannin; and zoledronate (Zometa®).
  • The invention also provides a combination comprising an siNA molecule of the invention comprising at least a 15 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064; or formula (A) and/or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with another CTNNB1 inhibitor.
  • The combinations referred to above can conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.
  • The individual compounds of such combinations can be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.
  • Thus, the described molecules could be used in combination with one or more known compounds, treatments, or procedures to prevent or treat diseases, disorders, conditions, and traits described herein in a subject or organism as are known in the art, such as other CTNNB1 inhibitors.
  • 3. Therapeutic Applications
  • The present body of knowledge in CTNNB1 research indicates the need for methods that can regulate CTNNB1 expression for therapeutic use.
  • Thus, one aspect of the invention comprises a method of treating a subject including, but not limited to, a human suffering from a condition which is mediated by the action, or by loss of action, of CTNNB1 gene expression, which method comprises administering to said subject an effective amount of a double-stranded siNA molecule of the invention. In one embodiment of this aspect, the siNA molecules comprises at least a 15 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064; or formula (A). In another embodiment of this aspect, the condition is or is caused by cancer. Thus, in certain embodiments the molecules and compositions of the instant invention are useful in a method for treating cancer. Cancers treatable according to this aspect of the invention include bilary tract cancer, bladder cancer, transitional cell carcinoma, urothelial carcinoma, osteosarcoma, brain cancer, gliomas, astrocytomas, breast carcinoma, metaplastic carcinoma, cervical cancer, cervical squamous cell carcinoma, rectal cancer, colorectal carcinoma, colon cancer, hereditary nonpolyposis colorectal cancer, colorectal adenocarcinomas, gastrointestinal stromal tumors (GISTs), endotnetrial carcinoma, endometrial stromal sarcomas, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, ocular melanoma, uveal melanoma, gallbladder carcinomas, gallbladder adenocarcinoma, renal cell carcinoma, clear cell renal cell carcinoma, transitional cell carcinoma, urothehal carcinomas, wilms tumor, leukemia, acute lymocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic (CLL), chronic myeloid (CML), chronic myelomonocytic (CMML), liver cancer, liver carcinoma, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, lung cancer, non-small cell lung cancer (NSCLC), mesothelioma, B-cell lymphomas, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, Mantle cell lymphoma, T-cell lymphomas, non-Hodgkin lymphoma, precursor T-lymphoblastic lymphoma/leukemia, peripheral I-cell lymphomas, multiple myeloma, nasopharyngeal carcinoma (NPC), neuroblastoma, oropharyngeal cancer, oral cavity squamous cell carcinomas, osteosarcoma, ovarian carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, pseudopapillary neoplasms, acinar cell carcinomas, prostate cancer, prostate adenocarcinoma, skin cancer, melanoma, malignant melanoma, cutaneous melanoma, small intestine carcinomas, stomach cancer, gastric carcinoma, gastrointestinal stromal tumor (GIST), uterine cancer, uterine sarcoma
  • In one embodiment, the siNA molecules of the instant invention are useful in a method for treating or preventing cancer selected from: brain cancer, breast carcinoma, cervical cancer, colorectal carcinoma, renal cell carcinoma, leukemia, hepatocellular carcinoma, lung cancer, B-cell lymphomas, multiple myeloma, ovarian carcinoma, pancreatic cancer, prostate cancer, melanoma, and gastric carcinoma. In certain embodiments, the compounds of the instant invention are useful for treating breast carcinoma, colorectal carcinoma, hepatocellular carcinoma, lung cancer; and prostate cancer. In a particular embodiment, the compounds of the instant invention are useful for treating hepatocellular carcinoma.
  • In another embodiment, the siNA molecules of the instant invention are useful in a method for the prevention or modulation of the metastases of cancer cells and cancer. In particular, the siNA molecules of the instant invention are useful in a method to prevent or modulate the metastases of brain cancer, breast carcinoma, cervical cancer, colorectal carcinoma, renal cell carcinoma, leukemia, hepatocellular carcinoma, lung cancer, B-cell lymphomas, multiple myeloma, ovarian carcinoma, pancreatic cancer, prostate cancer, melanoma, and gastric carcinoma.
  • In certain embodiments, the administration of the siNA molecule is via local administration or systemic administration. In other embodiments, the invention features contacting the subject or organism with an siNA molecule of the invention via local administration to relevant tissues or cells, such as lung cells and tissues, such as via pulmonary delivery. In yet other embodiments, the invention features contacting the subject or organism with an siNA molecule of the invention via systemic administration (such as via intravenous or subcutaneous administration of siNA) to relevant tissues or cells, such as cancerous tissues or cells in a subject or organism.
  • siNA molecules of the invention are also used as reagents in ex vivo applications. For example, siNA reagents are introduced into tissue or cells that are transplanted into a subject for therapeutic effect. The cells and/or tissue can be derived from an organism or subject that later receives the explant, or can be derived from another organism or subject prior to transplantation. The siNA molecules can be used to modulate the expression of one or more genes in the cells or tissue, such that the cells or tissue obtain a desired phenotype or are able to perform a function when transplanted in vivo. In one embodiment, certain CTNNB1 target cells from a patient are extracted. These extracted cells are contacted with CTNNB1 siNAs targeting a specific nucleotide sequence within the cells under conditions suitable for uptake of the siNAs by these cells (e.g., using delivery reagents such as cationic lipids, liposomes and the like or using techniques such as electroporation to facilitate the delivery of siNAs into cells). The cells are then reintroduced back into the same patient or other patients.
  • For therapeutic applications, a pharmaceutically effective dose of the siNA molecules or pharmaceutical compositions of the invention is administered to the subject. A pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) a disease state. One skilled in the art can readily determine a therapeutically effective dose of the siNA of the invention to be administered to a given subject, by taking into account factors, such as the size and weight of the subject, the extent of the disease progression or penetration, the age, health, and sex of the subject, the route of administration, and whether the administration is regional or systemic. Generally, an amount between 0.1 μg/kg and 100 mg/kg body weight/day of active ingredients is administered dependent upon potency of the negatively charged polymer. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. The siNA molecules of the invention can be administered in a single dose or in multiple doses.
  • siNA molecules of the instant invention can be administered once monthly, once weekly, once daily (QD), or divided into multiple monthly, weekly, or daily doses, such as, for example, but not limitation, twice daily (BID), three times daily (TID), once every two weeks. Persons of ordinary skill in the art can easily estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues.
  • In addition, the administration can be continuous, i.e., every day, or intermittently. For example, intermittent administration of a compound of the instant invention may be administration one to six days per week or it may mean administration in cycles (e.g. daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week) or it may mean administration on alternate days.
  • G. Administration
  • Compositions or formulations can be administered in a variety of sways. Non-limiting examples of administration methods of the invention include oral, buccal, sublingual, parenteral (i.e., intraarticularly, intravenously, intraperitoneally, subcutaneously, or intramuscularly), local rectal administration or other local administration. In one embodiment, the composition of the invention can be administered by insufflation and inhalation. Administration can be accomplished via single or divided doses. In some embodiments, the pharmaceutical compositions are administered intravenously or intraperitoneally by a bolus injection (see, e.g., U.S. Pat. No. 5,286,634). Lipid nucleic acid particles can be administered by direct injection at the site of disease or by injection at a site distal from the site of disease (see, e.g., Culver, HUMAN GENE THERAPY, MaryAnn Liebert, Inc., Publishers, New York. pp. 70-71 (1994)). In one embodiment, the siNA molecules of the invention and formulations or compositions thereof are administered to a cell, subject, or organism as is described herein and as is generally known in the art.
  • 1. in Vivo Administration
  • In any of the methods of treatment of the invention, the siNA can be administered to the subject systemically as described herein or otherwise known in the art, either alone as a monotherapy or in combination with additional therapies described herein or as are known in the art. Systemic administration can include, for example, pulmonary (inhalation, nebulization etc.) intravenous, subcutaneous, intramuscular, catheterization, nasopharangeal, transdermal, or oral/gastrointestinal administration as is generally known in the art.
  • In any of the methods of treatment or prevention of the invention, the siNA can be administered to the subject locally or to local tissues as described herein or otherwise known in the art, either alone as a monotherapy or in combination with additional therapies as are known in the art. Local administration can include, for example, inhalation, nebulization, catheterization, implantation, direct injection, dermal/transdermal application, patches, stenting, ear/eye drops, or portal vein administration to relevant tissues, or any other local administration technique, method or procedure, as is generally known in the art.
  • In one embodiment, the siNA molecules of the invention and formulations or compositions thereof are administered to the liver as is generally known in the art (see for example Wen et al., 2004, World J Gastroenterol., 10, 244-9; Murao et al., 2002, Pharm Res., 19, 1808-14; Liu et al., 2003, gene Ther., 10, 180-7; Hong et al., 2003, J Pharm Pharmacol., 54, 51-8; Herrmann et al., 2004, Arch Virol., 149, 1611-7; and Matsuno et al., 2003, gene Ther, 10, 1559-66).
  • In one embodiment, the invention features the use of methods to deliver the siNA molecules of the instant invention to hematopoietic cells, including monocytes and lymphocytes. These methods are described in detail by Hartmann et al., 1998, J. Phamacol. Exp. Ther., 285(2), 920-928; Kronenwett et al., 1998, Blood, 91(3), 852-862; Rion and Phillips, 1997, Biochim. Biophys. Acta., 1329(2), 345-356; Ma and Wei, 1996, Leuk. Res., 20(11/12), 925-930; and Bongartz et al., 1994, Nucleic Acids Research, 22(22), 4681-8.
  • In one embodiment, the siNA molecules of the invention and formulations or compositions thereof are administered directly or topically (e.g., locally) to the dermis or follicles as is generally known in the art (see for example Brand, 2001, Curr. Opin. Mol. Ther., 3, 244-8; Regnier et al., 1998, J. Drug Target, 5, 275-89; Kanikkannan, 2002, BioDrugs, 16, 339-47; Wraight et al., 2001, Pharmacol. Ther., 90, 89-104; and Preat and Dujardin, 2001, STP PharmaSciences, 11, 57-68). In one embodiment, the siNA molecules of the invention and formulations or compositions thereof are administered directly or topically using a hydroalcoholic gel formulation comprising an alcohol (e.g., ethanol or isopropanol), water, and optionally including additional agents such isopropyl myristate and carbomer 980. In other embodiments, the siNA are formulated to be administered topically to the nasal cavity. Topical preparations can be administered by one or more applications per day to the affected area; over skin areas occlusive dressings can advantageously be used. Continuous or prolonged delivery can be achieved by an adhesive reservoir system.
  • In one embodiment, an siNA molecule of the invention is administered iontophoretically, for example to a particular organ or compartment (e.g., the eye, back of the eye, heart, liver, kidney, bladder, prostate, tumor, CNS etc.). Non-limiting examples of iontophoretic delivery are described in, for example, WO 03/043689 and WO 03/030989, which are incorporated by reference in their entireties herein.
  • In one embodiment, the siNA molecules of the invention and formulations or compositions thereof are administered to the lung as is described herein and as is generally known in the art. In another embodiment, the siNA molecules of the invention and formulations or compositions thereof are administered to lung tissues and cells as is described in U.S. Patent Publication Nos, 2006/0062758; 2006/0011289; and 2004/0077540.
  • 2. Aerosols and Delivery Devices
  • a. Aerosol Formulations
  • The compositions of the present invention, either alone or in combination with other suitable components, can be made into aerosol formulations (i.e., they can be “nebulized”) to be administered via inhalation (e.g., intranasally or intratracheally) (see, Brigham et al, Am. J. Sci., 298:278 (1989)). Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
  • In one embodiment, the siNA molecules of the invention and formulations thereof are administered via pulmonary delivery, such as by inhalation of an aerosol or spray dried formulation administered by an inhalation device or nebulizer, providing rapid local uptake of the nucleic acid molecules into relevant pulmonary tissues. Solid particulate compositions containing respirable dry particles of micronized nucleic acid compositions can be prepared by grinding dried or lyophilized nucleic acid compositions, and then passing the micronized composition through, for example, a 400 mesh screen to break up or separate out large agglomerates. A solid particulate composition comprising the siNA compositions of the invention cart optionally contain a dispersant which serves to facilitate the formation of an aerosol as well as other therapeutic compounds. A suitable dispersant is lactose, which can be blended with the nucleic acid compound in any suitable ratio, such as a 1 to 1 ratio by weight.
  • Spray compositions comprising siNA molecules or compositions of the invention can, for example, be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurized packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant. In one embodiment, aerosol compositions of the invention suitable for inhalation can be either a suspension or a solution and generally contain an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064; or formula (A), and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. The aerosol composition can optionally contain additional formulation excipients well known in the art such as surfactants. Non-limiting examples include oleic acid, lecithin or an oligolactic acid or derivative such as those described in WO94/21229 and WO98/34596 and co-solvents for example ethanol. In one embodiment a pharmaceutical aerosol formulation of the invention comprising a compound of the invention and a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof as propellant, optionally in combination with a surfactant and/or a co-solvent.
  • The aerosol formulations of the invention can be buffered by the addition of suitable buffering agents.
  • Aerosol formulations can include optional additives including preservatives if the formulation is not prepared sterile. Non-limiting examples include, methyl hydroxybenzoate, anti-oxidants, flavorings, volatile oils, buffering agents and emulsifiers and other formulation surfactants. In one embodiment, fluorocarbon or perfluorocarbon carriers are used to reduce degradation and provide safer biocompatible non-liquid particulate suspension compositions of the invention siNA and/or LNP formulations thereof). In another embodiment, a device comprising a nebulizer delivers a composition of the invention (e.g., siNA and/or LNP formulations thereof) comprising fluorochemicals that are bacteriostatic thereby decreasing the potential for microbial growth in compatible devices.
  • Capsules and cartridges comprising the composition of the invention for use in an inhaler or insufflator, of for example gelatine, can be formulated containing a powder mix for inhalation of a compound of the invention and a suitable powder base such as lactose or starch. In one embodiment, each capsule or cartridge contains an siNA molecule comprising at least a 15 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064; or formula (A), and one or more excipients. In another embodiment, the compound of the invention can be presented without excipients such as lactose
  • The aerosol compositions of the present invention can be administered into the respiratory system as a formulation including particles of respirable size, particles of a size sufficiently small to pass through the nose, mouth and larynx upon inhalation and through the bronchi and alveoli of the lungs. In general, respirable particles range from about 0.5 to 10 microns in size. In one embodiment, the particulate range can be from 1 to 5 microns. In another embodiment, the particulate range can be from 2 to 3 microns. Particles of non-respirable size which are included in the aerosol tend to deposit in the throat and be swallowed, and the quantity of non-respirable particles in the aerosol is thus minimized. For nasal administration, a particle size in the range of 10-500 um is preferred to ensure retention in the nasal cavity.
  • In some embodiments, an siNA composition of the invention is administered topically to the nose for example, for the treatment of rhinitis via pressurized aerosol formulations, aqueous formulations administered to the nose by pressurized pump or by nebulization. Suitable formulations contain water as the diluent or carrier for this purpose. In certain embodiments, the aqueous formulations for administration of the composition of the invention to the lung or nose can be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like.
  • b. Devices
  • The siNA molecules of the invention can be formulated and delivered as particles and/or aerosols as discussed above and dispensed from various aerosolization devices known by, those of skill in the art.
  • Aerosols of liquid or non-liquid particles comprising an siNA molecule or formulation of the invention can be produced by any suitable means, such as with a device comprising a nebulizer (see for example U.S. Pat. No. 4,501,729) such as ultrasonic or air jet nebulizers.
  • Solid particle aerosols comprising an siNA molecule or formulation of the invention and surfactant can be produced with any solid particulate aerosol generator. One type of solid particle aerosol generator used with the siNA molecules of the invention is an insufflator. A second type of illustrative aerosol generator comprises a metered dose inhaler (“MDI”). MDIs containing siNA molecules or formulations taught herein can be prepared by methods of the art (for example, see Byron, above and WO96/32099).
  • The siNA molecules can also be formulated as a fluid formulation for delivery from a fluid dispenser, such as those described and illustrated in WO05/044354.
  • In certain embodiments of the invention, nebulizer devices are used in applications for conscious, spontaneously breathing subjects, and for controlled ventilated subjects of all ages. The nebulizer devices can be used for targeted topical and systemic drug delivery to the lung. In one embodiment, a device comprising a nebulizer is used to deliver an siNA molecule or formulation of the invention locally to lung or pulmonary tissues. In another embodiment, a device comprising a nebulizer is used to deliver a an siNA molecule or formulation of the invention systemically.
  • H. Other Applications/Uses of siNA Molecules of the Invention
  • The siNA molecules of the invention can also be used for diagnostic applications, research applications, and/or manufacture of medicants.
  • In one aspect, the invention features a method for diagnosing a disease, trait, or condition in a subject comprising administering to the subject a composition of the invention under conditions suitable for the diagnosis of the disease, trait, or condition in the subject.
  • In one embodiment, siNA molecules of the invention are used to down regulate or inhibit the expression of CTNNB1 proteins arising from haplotype polymorphisms that are associated with a trait, disease or condition in a subject or organism. Analysis of CTNNB1 genes, or CTNNB1 protein or RNA levels can be used to identify subjects with such polymorphisms or those subjects who are at risk of developing traits, conditions, or diseases described herein. These subjects are amenable to treatment, for example, treatment with siNA molecules of the invention and any other composition useful in treating diseases related to target gene expression. As such, analysis of CTNNB1 protein or RNA levels can be used to determine treatment type and the course of therapy in treating a subject. Monitoring of CTNNB1 protein or RNA levels can be used to predict treatment outcome and to determine the efficacy of compounds and compositions that modulate the level and/or activity of certain CTNNB1 proteins associated with a trait, disorder, condition, or disease.
  • In another embodiment, the invention comprises use of a double-stranded nucleic acid according to the invention for use in the manufacture of a medicament. In an embodiment, the medicament is for use in treating a condition that is mediated by the action, or by loss of action, of CTNNB1. In one embodiment, the medicament is for use for the treatment of cancer. In an embodiment, the medicament is for use for the treatment of brain cancer, breast carcinoma, cervical cancer, colorectal carcinoma, renal cell carcinoma, leukemia, hepatocellular carcinoma, lung cancer, B-cell lymphomas, multiple myeloma, ovarian carcinoma, pancreatic cancer, prostate cancer, melanoma, and gastric carcinoma. In a particular embodiment, the compounds of the instant invention are useful for treating hepatocellular carcinoma.
  • In certain embodiments, siNAs wherein at least one strand comprises at least a 15 nucleotide sequence of SEQ ID NO: 5, SEQ ID NO: 4918, SEQ ID NO: 194, SEQ ID NO: 5107, SEQ ID NO: 196, SEQ ID NO: 5109, SEQ ID NO: 151, or SEQ ID NO: 5064; or formula (A),are for use in a method for treating a cancer, such as, for example but not limitation, brain cancer, breast carcinoma, cervical cancer, colorectal carcinoma, renal cell carcinoma, leukemia, hepatocellular carcinoma, lung cancer, B-cell lymphomas, multiple myeloma, ovarian carcinoma, pancreatic cancer, prostate cancer, melanoma, and gastric carcinoma.
  • I. Examples
  • The invention will now be illustrated with the following non-limiting examples. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results.
  • Example 1: Design, Synthesis, and Identification of siNAs Active Against CTNNB1
  • CTNNB1 siNA Synthesis
  • A series of siNA molecules were designed, synthesized and evaluated for efficacy against CTNNB1 gene expression. Certain CTNNB1 sequences were designed and selected by methods set forth in U.S. Application No. 60/182,604. Other sequences were designed and selected using a proprietary algorithm. The primary criteria for design of certain of the CTNNB1 sequences for human siNAs were (i) homology between two species (human and rhesus monkey) and (ii) high efficacy scores as determined by a proprietary algorithm. The effects of the siNAs on CTNNB1 RNA levels. The target sequences of the siNAs that were selected are set forth in Table 1a (target sequences). The sense and antisense strands of the siNA, sequences corresponding to the target sequences in Table 1a are set forth in Table 1b. Various chemically modified siNAs that were synthesized are set forth in Table 1c.
  • TABLE 1a
    CTNNB1 Target Sequences,
    noting human target sites.
    Target Site SEQ ID
    Target Sequence (human) NO: 1
    UCGAGCUCAGAGGGUACGA  535    1
    GAGGCUCUUGUGCGUACUG 1601    2
    GCCCAGAAUGCAGUUCGCC 1709    3
    CGAGCUCAGAGGGUACGAG  536    4
    CUGUUGGAUUGAUUCGAAA 1797    5
    GUCUGCUAUUGUACGUACC  853    6
    AAUUCUUGGCUAUUACGAC 1143    7
    GGAUGUUCACAACCGAAUU 2014    8
    ACAGUAUGCAAUGACUCGA  520    9
    AGCUUCCAGACACGCUAUC  814   10
    UGUCUGCUAUUGUACGUAC  852   11
    ACUGUUGGAUUGAUUCGAA 1796   12
    CAGGAUACCCAGCGCCGUA 1901   13
    GACACGCUAUCAUGCGUUC  822   14
    UACUGUUGGAUUGAUUCGA 1795   15
    UUCUUGGCUAUUACGACAG 1145   16
    ACACGCUAUCAUGCGUUCU  823   17
    CAGACACGCUAUCAUGCGU  820   18
    UGUUGGAUUGAUUCGAAAU 1798   19
    CAGAUCCAAGUCAACGUCU 1380   20
    AGGCUCUUGUGCGUACUGU 1602   21
    GCGUACUGUCCUUCGGGCU 1612   22
    ACUAAUGUCCAGCGUUUGG  626   23
    CACAUCCUAGCUCGGGAUG 2000   24
    GUUGCUGAGAGGGCUCGAG 2665   25
    CAUCUGACCAGCCGACACC 1676   26
    UGCGUACUGUCCUUCGGGC 1611   27
    ACAAGAUUACAAGAAACGG 2269   28
    GUUGUAAACUUGAUUAACU  674   29
    UAAACUUGAUUAACUAUCA  678   30
    AUAUAAUGAGGACCUAUAC 1245   31
    AAACUUGAUUAACUAUCAA  679   32
    GAAAUAGUUGAAGGUUGUA 1970   33
    AUAAUGAGGACCUAUACUU 1247   34
    UUAAAUUCUUGGCUAUUAC 1140   35
    UGUAAACUUGAUUAACUAU  676   36
    GUAAACUUGAUUAACUAUC  677   37
    UUGUAAACUUGAUUAACUA  675   38
    GCUUUAGUAAAUAUAAUGA 1235   39
    UGGCCACCACCCUGGUGCU 2488   40
    CUUUAGUAAAUAUAAUGAG 1236   41
    UUUAGUAAAUAUAAUGAGG 1237   42
    GUAAAUCGUCCUUUAGGUA 2555   43
    ACCUCACUUGCAAUAAUUA 1545   44
    UACCAUUCCAUUGUUUGUG 2050   45
    UCCAAAGAGUAGCUGCAGG 2097   46
    UAUCCAGUUGAUGGGCUGC 2510   47
    CAUGCAGAAUACAAAUGAU  871   48
    CCAAAGAGUAGCUGCAGGG 2098   49
    CACCAUCCCACUGGCCUCU 1767   50
    ACCAUGCAGAAUACAAAUG  869   51
    AAGACAUCACUGAGCCUGC 1641   52
    AAUCAGCUGGCCUGGUUUG 2582   53
    AACCUCACUUGCAAUAAUU 1544   54
    ACCUCAUGGAUGGGCUGCC 2550   55
    ACCAUUCCAUUGUUUGUGC 2051   56
    CCAUGCAGAAUACAAAUGA  870   57
    CUUCGUCAUCUGACCAGCC 1670   58
    CUGUGAACUUGCUCAGGAC 2122   59
    AGACAUCACUGAGCCUGCC 1642   60
    GAGCCAAUGGCUUGGAAUG 2324   61
    ACUGAGCCUGCCAUCUGUG 1649   62
    AUUGAAGCUGAGGGAGCCA 2159   63
    GUUAUGGUCCAUCAGCUUU  785   64
    AAUGUGGUCACCUGUGCAG 1511   65
    AGCUGGCCUGGUUUGAUAC 2586   66
    UGGCUGAACCAUCACAGAU  642   67
    CACCCACCAUCCCACUGGC 1763   68
    CAAUGGCUUGGAAUGAGAC 2328   69
    UGGACCACAAGCAGAGUGC 1280   70
    CCAUUCCAUUGUUUGUGCA 2052   71
    CAGGACCUCAUGGAUGGGC 2546   72
    GUGAACUUGCUCAGGACAA 2124   73
    CCAGGACCUCAUGGAUGGG 2545   74
    GGCUGAACCAUCACAGAUG  643   75
    GGUGCUGACUAUCCAGUUG 2501   76
    AUGGCUUGGAAUGAGACUG 2330   77
    GGGAAGACAUCACUGAGCC 1638   78
    UGGUGACAGGGAAGACAUC 1630   79
    UGCUCAUCCCACUAAUGUC  616   80
    CUAUCCAGUUGAUGGGCUG 2509   81
    GGACCUCAUGGAUGGGCUG 2548   82
    CCCACUGGCCUCUGAUAAA 1773   83
    UCCGAAUGUCUGAGGACAA 2247   84
    UGGCUUGGAAUGAGACUGC 2331   85
    UUCAGAUGAUAUAAAUGUG 1498   86
    CCACAAGAUUACAAGAAAC 2267   87
    CUCACUUGCAAUAAUUAUA 1547   88
    CACUUGCAAUAAUUAUAAG 1549   89
    GUACCAUGCAGAAUACAAA  867   90
    UCAACGUCUUGUUCAGAAC 1390   91
    AUCCCAUCUACACAGUUUG  593   92
    UACUCAAGCUGAUUUGAUG  274   93
    ACCAGGUGGUGGUUAAUAA  759   94
    GCUGCAACUAAACAGGAAG 1439   95
    UGGAUUGAUUCGAAAUCUU 1801   96
    CAGAUGAUAUAAAUGUGGU 1500   97
    AUGGUGUCUGCUAUUGUAC  848   98
    CACAAGAUUACAAGAAACG 2268   99
    CAAAUGAUGUAGAAACAGC  882  100
    GCCACAAGAUUACAAGAAA 2266  101
    UACAAAUGAUGUAGAAACA  880  102
    UCGAAAUCUUGCCCUUUGU 1810  103
    GAUUAACUAUCAAGAUGAU  685  104
    CCAGUGGAUUCUGUGUUGU 1007  105
    AAAGGCUACUGUUGGAUUG 1789  106
    ACAAGUAGCUGAUAUUGAU  499  107
    GAUGGAACAUGAGAUGGGU 2470  108
    UCAAGAUGAUGCAGAACUU  674  109
    CAAGCUGAUUUGAUGGAGU  278  110
    UGGACUCUCAGGAAUCUUU 1415  111
    UAAAUACCAUUCCAUUGUU 2046  112
    AUUACAUCAAGAAGGAGCU 1057  113
    UCAGGAAUCUUUCAGAUGC 1422  114
    UGAUUAACUAUCAAGAUGA  684  115
    ACUUCACUCUAGGAAUGAA 2197  116
    AACAUGCAGUUGUAAACUU  666  117
    AAGCUGAUUUGAUGGAGUU  279  118
    UCUGGGUUCAGAUGAUAUA 1492  119
    UUACUUCACUCUAGGAAUG 2195  120
    AGGAAUCUUUCAGAUGCUG 1424  121
    GCUGAAACAUGCAGUUGUA  661  122
    GUUGCUUGUUCGUGCACAU 1882  123
    GGAAGAAAUAGUUGAAGGU 1966  124
    AGGACAAGCCACAAGAUUA 2259  125
    CAUGCGUUCUCCUCAGAUG  832  126
    GAUGAUCCCAGCUACCGUU 2346  127
    AGCCUGCCAUCUGUGCUCU 1653  128
    UGGAUAUCGCCAGGAUGAU 2389  129
    UCUUCGUCAUCUGACCAGC 1669  130
    UGUGAACUUGCUCAGGACA 2123  131
    CCUGUGCAGCUGGAAUUCU 1521  132
    UGAACUUGCUCAGGACAAG 2125  133
    UGCUGACUAUCCAGUUGAU 2503  134
    GAUGAUAUAAAUGUGGUCA 1502  135
    GUGCUGACUAUCCAGUUGA 2502  136
    UGACUAUCCAGUUGAUGGG 2506  137
    AACUUGCUCAGGACAAGGA 2127  138
    CUGACUAUCCAGUUGAUGG 2505  139
    GCUCAUCCCACUAAUGUCC  617  140
    GCUGACUAUCCAGUUGAUG 2504  141
    AUGAUAUAAAUGUGGUCAC 1503  142
    CUCAUCCCACUAAUGUCCA  618  143
    GCUUUAUUCUCCCAUUGAA 2074  144
    CUGGUGCUGACUAUCCAGU 2499  145
    AACUGUCUUUGGACUCUCA 1406  146
    AGGGCAUGCAGAUCCCAUC  582  147
    GAUAUAAAUGUGGUCACCU 1505  148
    UUCAGAUGCUGCAACUAAA 1432  149
    AAGAAAUAGUUGAAGGUUG 1968  150
    CCAGGAUGAUCCUAGCUAU 2398  151
    UGGCCAUCUUUAAGUCUGG  954  152
    AGCUGAUAUUGAUGGACAG  505  153
    UCGGGAUGUUCACAACCGA 2011  154
    UGUAGAAGCUGGUGGAAUG 1339  155
    UAAAUAUAAUGAGGACCUA 1242  156
    CUGAGACAUUAGAUGAGGG  567  157
    AGUAAAUAUAAUGAGGACC 1240  158
    UGGAUACCUCCCAAGUCCU  438  159
    AGGAUGCCUUGGGUAUGGA 2445  160
    AUUGUACGUACCAUGCAGA  860  161
    UUUGGACUCUCAGGAAUCU 1413  162
    UUGGAUUGAUUCGAAAUCU 1800  163
    UCAGAGGACUAAAUACCAU 2037  164
    CCAGGAUGCCUUGGGUAUG 2443  165
    AUGGAACAUGAGAUGGGUG 2471  166
    GGCUACUGUUGGAUUGAUU 1792  167
    AGGACCUCAUGGAUGGGCU 2547  168
    UCUGUGCUCUUCGUCAUCU 1662  169
    UGAUGGAGUUGGACAUGGC  288  170
    AUGAGGGCAUGCAGAUCCC  579  171
    ACUAUCCAGUUGAUGGGCU 2508  172
    UGAGGGCAUGCAGAUCCCA  580  173
    UUGGAUAUCGCCAGGAUGA 2388  174
    GCCCAGGACCUCAUGGAUG 2543  175
    AACUUGCCACACGUGCAAU  708  176
    CCCAAGUCCUGUAUGAGUG  447  177
    CACAGAUGCUGAAACAUGC  654  178
    CUGGGACCUUGCAUAACCU  912  179
    AGUGGAUUCUGUGUUGUUU 1009  180
    AAUGCAAGCUUUAGGACUU 1354  181
    AGAAAUAGUUGAAGGUUGU 1969  182
    UCCGCAUGGAAGAAAUAGU 1959  183
    GCUAUGUUCCCUGAGACAU  557  184
    UCUGAGUGGUAAAGGCAAU  403  185
    UGCAAGCUUUAGGACUUCA 1356  186
    UGGACAGUAUGCAAUGACU  517  187
    UUAGUAAAUAUAAUGAGGA 1238  188
    CUCAGAUGGUGUCUGCUAU  843  189
    AGAACAAGUAGCUGAUAUU  496  190
    CUUGGAUAUCGCCAGGAUG 2387  191
    CAUCUGUGCUCUUCGUCAU 1660  192
    CCCUGGUGCUGACUAUCCA 2497  193
    ACGACUAGUUCAGUUGCUU 1870  194
    UCUUGGACUUGAUAUUGGU 2353  195
    GGAUGAUCCUAGCUAUCGU 2401  196
    AAUACAAAUGAUGUAGAAA  878  197
    GAACCAUCACAGAUGCUGA  647  198
    UUCACAUCCUAGCUCGGGA 1998  199
    UGCAGAUCCCAUCUACACA  588  200
    GGACUAAAUACCAUUCCAU 2042  201
    CUGCUAUUGUACGUACCAU  855  202
    CAGAGGACUAAAUACCAUU 2038  203
    GAUAAAGGCUACUGUUGGA 1786  204
    AGAUGAUAUAAAUGUGGUC 1501  205
    AAAUCAUGCACCUUUGCGU 1834  206
    ACGACAGACUGCCUUCAAA 1157  207
    UAGUAAAUAUAAUGAGGAC 1239  208
    UAAUGAGGACCUAUACUUA 1248  209
    UGCUGAAACAUGCAGUUGU  660  210
    AUUUGAUGGAGUUGGACAU  285  211
    CUGCCAAGUGGGUGGUAUA 1582  212
    UGGACUACCAGUUGUGGUU 1735  213
    UUAAUAAGGCUGCAGUUAU  771  214
    ACAUCAAGAAGGAGCUAAA 1060  215
    GGAUAUCGCCAGGAUGAUC 2390  216
    CUGACAGAGUUACUUCACU 2186  217
    GUGACAGGGAAGACAUCAC 1632  218
    UCAUCCCACUAAUGUCCAG  619  219
    CUGCCAUCUGUGCUCUUCG 1656  220
    AUAUAAAUGUGGUCACCUG 1506  221
    CCACCCUGGUGCUGACUAU 2494  222
    UGCUCUUCGUCAUCUGACC 1666  223
    ACAGGGAAGACAUCACUGA 1635  224
    AGUUGGACAUGGCCAUGGA  294  225
    UUGGCUGAACCAUCACAGA  641  226
    UAGAUGAGGGCAUGCAGAU  576  227
    AGAUGAGGGCAUGCAGAUC  577  228
    AUCUGUGCUCUUCGUCAUC 1661  229
    GAACUUGCCACACGUGCAA  707  230
    CCAUCUGUGCUCUUCGUCA 1659  231
    AUGGCAACCAAGAAAGCAA 1185  232
    GAAACAUGCAGUUGUAAAC  664  233
    UGGUUAAGCUCUUACACCC 1749  234
    AGCUUUAGUAAAUAUAAUG 1234  235
    CUAUCAAGAUGAUGCAGAA  691  236
    AAGUCAACGUCUUGUUCAG 1387  237
    GAUCCAAGUCAACGUCUUG 1382  238
    CUAUCAUGCGUUCUCCUCA  828  239
    AAUAUAAUGAGGACCUAUA 1244  240
    GUGCUAUCUGUCUGCUCUA 1304  241
    UAAUUAUAAGAACAAGAUG  812  242
    AUACAAAUGAUGUAGAAAC 1558  243
    AUACAAAUGAUGUAGAAAC  879  244
    CUGUCUGCUCUAGUAAUAA 1311  245
    UGCUAUUGUACGUACCAUG  856  246
    UGCUGAAGGUGCUAUCUGU 1296  247
    UCUUUAAGUCUGGAGGCAU  960  248
    AUACCAUUCCAUUGUUUGU 2049  249
    AGGCUACUGUUGGAUUGAU 1791  250
    CAGUUAUGGUCCAUCAGCU  783  251
    ACAAGAUGAUGGUCUGCCA 1569  252
    GACAUAUGCAGCUGCUGUU 2224  253
    CCAUCAUCGUGAGGGCUUA  934  254
    GACAGAUCCAAGUCAACGU 1378  255
    GAGACAUUAGAUGAGGGCA  569  256
    UUCGCCUUCACUAUGGACU 1722  257
    UGUUCAGCUUCUGGGUUCA 1473  258
    AUCUUGGACUUGAUAUUGG 2352  259
    CGUGCAAUCCCUGAACUGA  719  260
    AGGUGGUGGUUAAUAAGGC  762  261
    UCUACACAGUUUGAUGCUG  599  262
    AGAUGGCCCAGAAUGCAGU 1704  263
    CAAGAUUACAAGAAACGGC 2270  264
    CUGAAACAUGCAGUUGUAA  662  265
    CUCCUUCUCUGAGUGGUAA  396  266
    AGCAAGCUCAUCAUACUGG 1199  267
    AUUAUAAGAACAAGAUGAU 1560  268
    UCUGUCUGCUCUAGUAAUA 1310  269
    AAGCUUUAGUAAAUAUAAU 1233  270
    GCCGGCUAUUGUAGAAGCU 1330  271
    UGUCUGCUCUAGUAAUAAG 1312  272
    AAUAAUUAUAAGAACAAGA 1556  273
    UAUGGCCAGGAUGCCUUGG 2438  274
    UGUCCCGCAAAUCAUGCAC 1829  275
    CUUGUUCAGAACUGUCUUU 1397  276
    GCUGUGAUACGAUGCUUCA 3181  277
    GCGCCGUACGUCCAUGGGU 1912  278
    AGAUGGUGUCUGCUAUUGU  846  279
    AGAACUGUCUUUGGACUCU 1404  280
    CAUGCAGAUCCCAUCUACA  586  281
    CUCCUUGGGACUCUUGUUC 1469  282
    GGUGCCACUACCACAGCUC  380  283
    AGCUGGUGGAAUGCAAGCU 1345  284
    CCAUUCCACGACUAGUUCA 1863  285
    CAGCGUUUGGCUGAACCAU  635  286
    AUCUUUAAGUCUGGAGGCA  959  287
    UGGCCAGGAUGCCUUGGGU 2440  288
    GAAUACAAAUGAUGUAGAA  877  289
    UGGAUGGGCUGCCUCCAGG 2556  290
    CGUACGUCCAUGGGUGGGA 1916  291
    GGUGUCUGCUAUUGUACGU  850  292
    GGUGCUAUCUGUCUGCUCU 1303  293
    CCUUCACUAUGGACUACCA 1726  294
    GACUCUUGUUCAGCUUCUG 1477  295
    AUCUACACAGUUUGAUGCU  598  296
    GUUUGUGCAGCUGCUUUAU 2062  297
    CAAGAAACGGCUUUCAGUU 2278  298
    GUUCAGUUGCUUGUUCGUG 1877  299
    UCAGAUGAUAUAAAUGUGG 1499  300
    AAUGUUAAAUUCUUGGCUA 1136  301
    UGGGUUCAGAUGAUAUAAA 1494  302
    AAUAGUUGAAGGUUGUACC 1972  303
    CAUGCAGUUGUAAACUUGA  668  304
    AAUCUGAAUAAAGUGUAAC 2945  305
    CACCACCCUGGUGCUGACU 2492  306
    GAGUUGGACAUGGCCAUGG  293  307
    AUACCCAGCGCCGUACGUC 1905  308
    GAGGGCUUACUGGCCAUCU  944  309
    GAGGGCAUGCAGAUCCCAU  581  310
    GAAGGGAUGGAAGGUCUCC 1454  311
    GUCUGAGGACAAGCCACAA 2254  312
    UCAUGCACCUUUGCGUGAG 1837  313
    GGAAUCUUUCAGAUGCUGC 1425  314
    UCACCUGACAGAUCCAAGU 1372  315
    CUGAAGGUGCUAUCUGUCU 1298  316
    GUCAUCUGACCAGCCGACA 1674  317
    CAUUCCACGACUAGUUCAG 1864  318
    UGAUCCUAGCUAUCGUUCU 2404  319
    GAGCCCUUCACAUCCUAGC 1992  320
    GAUGAGGGCAUGCAGAUCC  578  321
    AUGGGUAGGGUAAAUCAGU 3081  322
    GUGCAAUCCCUGAACUGAC  720  323
    AUUCCAUUGUUUGUGCAGC 2054  324
    CAUUCUGGUGCCACUACCA  374  325
    UACCAUGCAGAAUACAAAU  868  326
    AUGCAGUUCGCCUUCACUA 1716  327
    UUACUGGCCAUCUUUAAGU  950  328
    GCUUCUGGGUUCAGAUGAU 1489  329
    CAGGAAGGGAUGGAAGGUC 1451  330
    GCUUAUGGCAACCAAGAAA 1181  331
    UGACAGGGAAGACAUCACU 1633  332
    AUCGCCAGGAUGAUCCUAG 2395  333
    AGUAAUAAGCCGGCUAUUG 1322  334
    AAUGAUGUAGAAACAGCUC  884  335
    UCUGAGGACAAGCCACAAG 2255  336
    GGUCUCCUUGGGACUCUUG 1466  337
    UGUUCAGAACUGUCUUUGG 1399  338
    CUGGUGCCACUACCACAGC  378  339
    GUCCAUGGGUGGGACACAG 1921  340
    GUGCGUUUAGCUGGUGGGC 1085  341
    ACGUACCAUGCAGAAUACA  865  342
    GAUGUUCACAACCGAAUUG 2015  343
    AGAAAGCAAGCUCAUCAUA 1195  344
    GUUCAGCUUCUGGGUUCAG 1484  345
    GCAGGGUGCCAUUCCACGA 1855  346
    UAGAAGCUGGUGGAAUGCA 1341  347
    CAUGGAAGAAAUAGUUGAA 1963  348
    UGAUAUUGGUGCCCAGGGA 2362  349
    GGCAUGCAGAUCCCAUCUA  584  350
    CGUACUGUCCUUCGGGCUG 1613  351
    UUACGACAGACUGCCUUCA 1155  352
    UAGUCACUGGCAGCAACAG  334  353
    GCCAUUACAACUCUCCACA 1031  354
    GCCUUCACUAUGGACUACC 1725  355
    GUUCACAACCGAAUUGUUA 2018  356
    GGGACCUUGCAUAACCUUU  915  357
    AAGCCACAAGAUUACAAGA 2264  358
    GCAGCAACAGUCUUACCUG  343  359
    UAUUACAUCAAGAAGGAGC 1056  360
    UAAUAAGGCUGCAGUUAUG  772  361
    GGUGGUGGUUAAUAAGGCU  763  362
    UAAUGUCCAGCGUUUGGCU  628  363
    CUUCUCUGAGUGGUAAAGG  399  364
    ACCAGCCGACACCAAGAAG 1682  365
    AUACCUCCCAAGUCCUGUA  441  366
    UCACUAUGGACUACCAGUU 1729  367
    AGGAUACCCAGCGCCGUAC 1902  368
    AGGGAAGACAUCACUGAGC 1637  369
    GAUAUCGCCAGGAUGAUCC 2391  370
    AAGUAGCUGAUAUUGAUGG  501  371
    CAAGCUUUAGGACUUCACC 1358  372
    CCCUUUGUCCCGCAAAUCA 1821  373
    UUAGAUGAGGGCAUGCAGA  575  374
    CAAUGACUCGAGCUCAGAG  528  375
    GUGGAUAUGGCCAGGAUGC 2433  376
    GUUCAGAUGAUAUAAAUGU 1497  377
    UCAGGACAAGGAAGCUGCA 2134  378
    UUGAAGCUGAGGGAGCCAC 2160  379
    UGGAGUUGGACAUGGCCAU  291  380
    AGAUGCUGAAACAUGCAGU  657  381
    UGAUGGUCUGCCAAGUGGG 1575  382
    ACAUGCAGUUGUAAACUUG  667  383
    CAGAGUUACUUCACUCUAG 2190  384
    GACUCGAGCUCAGAGGGUA  532  385
    CUGGCCAUCUUUAAGUCUG  953  386
    UACGAUGCUUCAAGAGAAA 3188  387
    UGACCAGCUCUCUCUUCAG 2301  388
    CUCUCUUCAGAACAGAGCC 2310  389
    GCUUUCAGUUGAGCUGACC 2287  390
    GGGUGGGACACAGCAGCAA 1927  391
    UGCCACACGUGCAAUCCCU  712  392
    UCUGUGAACUUGCUCAGGA 2121  393
    UGAGUAAUGGUGUAGAACA 2898  394
    GUUGGAUUGAUUCGAAAUC 1799  395
    UACAACUCUCCACAACCUU 1036  396
    CAAGUCCUGUAUGAGUGGG  449  397
    AGGAAGGGAUGGAAGGUCU 1452  398
    AGCUCAUCAUACUGGCUAG 1203  399
    GCAAGCUUUAGGACUUCAC 1357  400
    AUGUGGUCACCUGUGCAGC 1512  401
    ACUCAAGCUGAUUUGAUGG  275  402
    GACAUGGCCAUGGAACCAG  299  403
    GUAAAUAUAAUGAGGACCU 1241  404
    CGCAUGGAAGAAAUAGUUG 1961  405
    GAUGCUGCAACUAAACAGG 1436  406
    UGAUGGAACAUGAGAUGGG 2469  407
    CCAGGUGGUGGUUAAUAAG  760  408
    UGAGGACAAGCCACAAGAU 2257  409
    ACUGGCCAUCUUUAAGUCU  952  410
    AACGGCUUUCAGUUGAGCU 2283  411
    CUACUGUUGGAUUGAUUCG 1794  412
    GUUGUGGUUAAGCUCUUAC 1745  413
    AUACUGGCUAGUGGUGGAC 1211  414
    GACCUCAUGGAUGGGCUGC 2549  415
    UAGCUCGGGAUGUUCACAA 2007  416
    GAACAUGAGAUGGGUGGCC 2474  417
    CAGAAUGCAGUUCGCCUUC 1712  418
    ACGUCCAUGGGUGGGACAC 1919  419
    UGGUUCACCAGUGGAUUCU 1000  420
    AUAUCGCCAGGAUGAUCCU 2392  421
    AACAGGAAGGGAUGGAAGG 1449  422
    GUUGAGCUGACCAGCUCUC 2294  423
    AAAUGUUAAAUUCUUGGCU 1135  424
    GGCUAUUGUAGAAGCUGGU 1333  425
    CAGUUGUGGUUAAGCUCUU 1743  426
    CUACACAGUUUGAUGCUGC  600  427
    UGGAGGCAUUCCUGCCCUG  970  428
    GGACAGUUUACCAGUUGCC 3137  429
    UCCAUUCUGGUGCCACUAC  372  430
    UACACCCACCAUCCCACUG 1761  431
    CUGAGCCUGCCAUCUGUGC 1650  432
    GAGGCAUUCCUGCCCUGGU  972  433
    CUUGGCUAUUACGACAGAC 1147  434
    CCCUGAGACAUUAGAUGAG  565  435
    AUGCAAUGACUCGAGCUCA  525  436
    UAGAGGCUCUUGUGCGUAC 1599  437
    UUCACUCUAGGAAUGAAGG 2199  438
    GACAAGCCACAAGAUUACA 2261  439
    CAGAACUUGCCACACGUGC  705  440
    GACCUUGCAUAACCUUUCC  916  441
    CACUACCACAGCUCCUUCU  385  442
    CUAUUUGGGAUAUGUAUGG 3076  443
    UCUUGUUCAGAACUGUCUU 1396  444
    GAUGCCUUGGGUAUGGACC 2447  445
    UUGUAGAAGCUGGUGGAAU 1338  446
    AGGUGUGGCGACAUAUGCA 2215  447
    GCAAUCCCUGAACUGACAA  722  448
    UGCUCUAGUAAUAAGCCGG 1316  449
    CCGACACCAAGAAGCAGAG 1687  450
    AGAUGAUGCAGAACUUGCC  697  451
    UUGAUGGGCUGCCAGAUCU 2517  452
    AGCCGACACCAAGAAGCAG 1685  453
    UAUGGGUAGGGUAAAUCAG 3090  454
    CUCAUCAUACUGGCUAGUG 1205  455
    UAUUACGACAGACUGCCUU 1153  456
    CAAUCCCUGAACUGACAAA  723  457
    UCUCCUUGGGACUCUUGUU 1468  458
    GAGAUGGGUGGCCACCACC 2480  459
    CAGGGUGCCAUUCCACGAC 1856  460
    AGUUACUUCACUCUAGGAA 2193  461
    UUGGACUUGAUAUUGGUGC 2355  462
    CCCUUCACAUCCUAGCUCG 1995  463
    AGACACGCUAUCAUGCGUU  821  464
    AAUGCAGUUCGCCUUCACU 1715  465
    CUUAUGGCAACCAAGAAAG 1182  466
    CUCCCAAGUCCUGUAUGAG  445  467
    CUUACACCCACCAUCCCAC 1759  468
    UGGAAGGUCUCCUUGGGAC 1461  469
    AGCCCUUCACAUCCUAGCU 1993  470
    GAUGGGCUGCCUCCAGGUG 2558  471
    AGCUUCUGGGUUCAGAUGA 1488  472
    GAGCCUGCCAUCUGUGCUC 1652  473
    UUAAGUCUGGAGGCAUUCC  963  474
    ACCUGUGCAGCUGGAAUUC 1520  475
    UCCCGCAAAUCAUGCACCU 1828  476
    AAGGUGUGGCGACAUAUGC 2214  477
    AGCUAUUGAAGCUGAGGGA 2155  478
    GUUAGUCACUGGCAGCAAC  332  479
    UUCAGUUGCUUGUUCGUGC 1878  480
    GAUGAUGGUCUGCCAAGUG 1573  481
    CUAAACAGGAAGGGAUGGA 1446  482
    CCACGACUAGUUCAGUUGC 1868  483
    ACUAGUUCAGUUGCUUGUU 1873  484
    GUUCACCAGUGGAUUCUGU 1002  485
    GUGGUAAAGGCAAUCCUGA  408  486
    UUGAUGGAGUUGGACAUGG  287  487
    ACUUGCUCAGGACAAGGAA 2128  488
    CCAGUUGAUGGGCUGCCAG 2513  489
    GAAAGCAAGCUCAUCAUAC 1196  490
    ACAUUAGAUGAGGGCAUGC  572  491
    UCCCACUAAUGUCCAGCGU  622  492
    GGCAACCAAGAAAGCAAGC 1187  493
    AAAUAGUUGAAGGUUGUAC 1971  494
    GGAUAUGUAUGGGUAGGGU 3083  495
    UAAUCUGAAUAAAGUGUAA 2944  496
    UGCACAUCAGGAUACCCAG 1894  497
    GUAAUAAGCCGGCUAUUGU 1323  498
    AAGCUCAUCAUACUGGCUA 1202  499
    ACGUGCAAUCCCUGAACUG  718  500
    AGUUGUGGUUAAGCUCUUA 1744  501
    AGGACCAGGUGGUGGUUAA  756  502
    GCUCUAGUAAUAAGCCGGC 1317  503
    GAUUUGAUGGAGUUGGACA  284  504
    UGAUGUAGAAACAGCUCGU  886  505
    CUGGUGGAUAUGGCCAGGA 2430  506
    CAUCAUACUGGCUAGUGGU 1207  507
    GAUCCCAUCUACACAGUUU  592  508
    CACGCUAUCAUGCGUUCUC  824  509
    GACAGUAUGCAAUGACUCG  519  510
    AAGUUGUUGUAACCUGCUG 3166  511
    GCUAUUACGACAGACUGCC 1151  512
    GCCUCCAGGUGACAGCAAU 2566  513
    UCCUGUAUGAGUGGGAACA  453  514
    AUGCAGAUCCCAUCUACAC  587  515
    UUUCCCAUCAUCGUGAGGG  930  516
    CCAAGUGGGUGGUAUAGAG 1585  517
    GGACCUUGCAUAACCUUUC  915  518
    UCCCAAGUCCUGUAUGAGU  446  519
    CACGACUAGUUCAGUUGCU 1869  520
    CCGCAUGGAAGAAAUAGUU 1960  521
    GGCCCAGAAUGCAGUUCGC 1708  522
    CCAUGGAACCAGACAGAAA  303  523
    GAAACGGCUUUCAGUUGAG 2281  524
    GGGAUAUGUAUGGGUAGGG 3082  525
    UUGGGACUCUUGUUCAGCU 1473  526
    UAUGUUCCCUGAGACAUUA  559  527
    GGACUCUCAGGAAUCUUUC 1416  528
    AAGCUGCAGAAGCUAUUGA 2145  529
    GCCCUUCACAUCCUAGCUC 1994  530
    AGAGAUGGCCCAGAAUGCA 1702  531
    GCAAUCCUGAGGAAGAGGA  417  532
    CAGGAUGCCUUGGGUAUGG 2444  533
    CUGCUAUGUUCCCUGAGAC  555  534
    UUCACAACCGAAUUGUUAU 2019  535
    AAAGCAAGCUCAUCAUACU 1197  536
    AGGCAAUCCUGAGGAAGAG  415  537
    UGUUUGUGCAGCUGCUUUA 2061  538
    GGAAUGCAAGCUUUAGGAC 1352  539
    CCGGCUAUUGUAGAAGCUG 1331  540
    AAUAAGCCGGCUAUUGUAG 1325  541
    UCAGCUUCUGGGUUCAGAU 1486  542
    CCUGUAUGAGUGGGAACAG  454  543
    CACUCAAGAACAAGUAGCU  490  544
    CCUUCACAUCCUAGCUCGG 1996  545
    AUGCACCUUUGCGUGAGCA 1839  546
    UGUUCGUGCACAUCAGGAU 1888  547
    UCAGUUGCUUGUUCGUGCA 1879  548
    CCCGCAAAUCAUGCACCUU 1829  549
    GCUGAUUUGAUGGAGUUGG  281  550
    AUAGAGGCUCUUGUGCGUA 1598  551
    CAGGACAAGGAAGCUGCAG 2135  552
    AGCUCUUACACCCACCAUC 1755  553
    CAUCACAGAUGCUGAAACA  651  554
    CUAUUGUAGAAGCUGGUGG 1335  555
    AUGCCCAGGACCUCAUGGA 2541  556
    UGACUCGAGCUCAGAGGGU  531  557
    AGUUUGAUGCUGCUCAUCC  606  558
    UCCUUCGGGCUGGUGACAG 1620  559
    AUGAAGGUGUGGCGACAUA 2211  560
    AGUUGAGCUGACCAGCUCU 2293  561
    CUGUAUGAGUGGGAACAGG  455  562
    CUCAGAGGGUACGAGCUGC  540  563
    GGCAAUCCUGAGGAAGAGG  416  564
    CAUACUGGCUAGUGGUGGA 1210  565
    ACAAGCCACAAGAUUACAA 2262  566
    GCUCUUGUGCGUACUGUCC 1604  567
    AUGUGGAUACCUCCCAAGU  435  568
    UUGUUUGUGCAGCUGCUUU 2060  569
    ACAUAUGCAGCUGCUGUUU 2225  570
    UCAGUCCUUCACUCAAGAA  481  571
    ACCUUGCAUAACCUUUCCC  917  572
    GGCGACAUAUGCAGCUGCU 2221  573
    UGGUGUCUGCUAUUGUACG  849  574
    GUUCCCUGAGACAUUAGAU  562  575
    AUAAAGGCUACUGUUGGAU 1787  576
    GUGCCAUUCCACGACUAGU 1860  577
    UGGGUGGUAUAGAGGCUCU 1590  578
    GGCCAUCUUUAAGUCUGGA  955  579
    UAUUGGUGCCCAGGGAGAA 2365  580
    CUCGAGCUCAGAGGGUACG  534  581
    AGAACUUGCCACACGUGCA  706  582
    UACCAGUUGUGGUUAAGCU 1740  583
    CGUUUGGCUGAACCAUCAC  638  584
    GCUAUUGUAGAAGCUGGUG 1334  585
    GGAGGCAUUCCUGCCCUGG  971  586
    ACCACCCUGGUGCUGACUA 2493  587
    AAUCUUGCCCUUUGUCCCG 1814  588
    CGUUUAGCUGGUGGGCUGC 1088  589
    CAGUUGAGCUGACCAGCUC 2292  590
    UGAUAUAAAUGUGGUCACC 1504  591
    CUGAGUGGUAAAGGCAAUC  404  592
    AAGGUGCUAUCUGUCUGCU 1301  593
    UCCUAGCUCGGGAUGUUCA 2004  594
    UCAAGCUGAUUUGAUGGAG  277  595
    CCAGCUCUCUCUUCAGAAC 2304  596
    ACAUGGCCAUGGAACCAGA  300  597
    UACCCAGCGCCGUACGUCC 1906  598
    AUAGUUGAAGGUUGUACCG 1973  599
    AGCUUUAGGACUUCACCUG 1360  600
    ACAUCCAAAGAGUAGCUGC 2094  601
    UUGCAUAACCUUUCCCAUC  920  602
    UGGCCCAGAAUGCAGUUCG 1707  603
    AUUCGAAAUCUUGCCCUUU 1808  604
    AUAAGCCGGCUAUUGUAGA 1324  605
    CGACAGACUGCCUUCAAAU 1158  606
    UGCAGUUAUGGUCCAUCAG  781  607
    GUUUGAUGCUGCUCAUCCC  607  608
    CUAAUGUCCAGCGUUUGGC  627  609
    CAAGUAGCUGAUAUUGAUG  500  610
    UCUGACAGAGUUACUUCAC 2185  611
    GGUGGUAUAGAGGCUCUUG 1592  612
    GACCAGGUGGUGGUUAAUA  758  613
    CCUCAUGGAUGGGCUGCCU 2551  614
    UGUCUUUGGACUCUCAGGA 1409  615
    GAACAAGUAGCUGAUAUUG  497  616
    GUGCCACUACCACAGCUCC  381  617
    GCACCUUUGCGUGAGCAGG 1841  618
    GACUUCACCUGACAGAUCC 1368  619
    AAAUACCAUUCCAUUGUUU 2047  620
    CUCAAGAACAAGUAGCUGA  492  621
    UCCUCUGUGAACUUGCUCA 2118  622
    UCUGGAGGCAUUCCUGCCC  968  623
    AAGUCUGGAGGCAUUCCUG  965  624
    UUGAAGGUUGUACCGGAGC 1977  625
    ACAUCCUAGCUCGGGAUGU 2001  626
    ACCAAGAAAGCAAGCUCAU 1191  627
    UUUGGCUGAACCAUCACAG  640  628
    CACACGUGCAAUCCCUGAA  715  629
    GCUCAUCAUACUGGCUAGU 1204  630
    GGGUAGGGUAAAUCAGUAA 3093  631
    UUCACCUGACAGAUCCAAG 1371  632
    UGGUAAAGGCAAUCCUGAG  409  633
    GAUCCUAGCUAUCGUUCUU 2405  634
    UUCGUCAUCUGACCAGCCG 1671  635
    AAUCUUUCAGAUGCUGCAA 1427  636
    UGCAGUUCGCCUUCACUAU 1717  637
    AGGAUGAUCCUAGCUAUCG 2400  638
    CAGCUCUCUCUUCAGAACA 2305  639
    GGUGGGACACAGCAGCAAU 1928  640
    CAGGAUGAUCCUAGCUAUC 2399  641
    AGGAAGAGGAUGUGGAUAC  426  642
    AUCUGUCUGCUCUAGUAAU 1309  643
    UAACCUUUCCCAUCAUCGU  925  644
    CUGCUUUAUUCUCCCAUUG 2072  645
    AAUUGUAAUCUGAAUAAAG 2939  646
    UCUUGUUCAGCUUCUGGGU 1480  647
    GUUCGUGCACAUCAGGAUA 1889  648
    AUGAUGCAGAACUUGCCAC  699  649
    GCUGAUAUUGAUGGACAGU  506  650
    GGUUAAGCUCUUACACCCA 1750  651
    GCCCUUUGUCCCGCAAAUC 1820  652
    UCAGAGGGUACGAGCUGCU  541  653
    AAACAUGCAGUUGUAAACU  665  654
    CUUGCCCUUUGUCCCGCAA 1817  655
    UUACAAGAAACGGCUUUCA 2275  656
    CACUCUGGUGGAUAUGGCC 2426  657
    CAUCUUUAAGUCUGGAGGC  958  658
    UGCCAUCUGUGCUCUUCGU 1657  659
    UCUUGGCUAUUACGACAGA 1146  660
    AUUUGGGAUAUGUAUGGGU 3078  661
    CAGUGGAUUCUGUGUUGUU 1008  662
    CCUUCGGGCUGGUGACAGG 1621  663
    GGACACAGCAGCAAUUUGU 1932  664
    CCAGCGCCGUACGUCCAUG 1909  665
    AAGAAACGGCUUUCAGUUG 2279  666
    AUUAGAUGAGGGCAUGCAG  574  667
    ACCAGCUCUCUCUUCAGAA 2303  668
    AGUUAUGGUCCAUCAGCUU  784  669
    GACUAUCCAGUUGAUGGGC 2507  670
    AUGCUUGGUUCACCAGUGG  995  671
    CUAGCUCGGGAUGUUCACA 2006  672
    CUCUUACACCCACCAUCCC 1757  673
    CUUGCUCAGGACAAGGAAG 2129  674
    AGAUUACAAGAAACGGCUU 2272  675
    ACCACAGCUCCUUCUCUGA  389  676
    AGAUGCUGCAACUAAACAG 1435  677
    UUAAGCUCUUACACCCACC 1752  678
    AAUAAGGCUGCAGUUAUGG  773  679
    UUGGGAUAUGUAUGGGUAG 3080  680
    GUAACCUGCUGUGAUACGA 3174  681
    UGGUCUGCCAAGUGGGUGG 1578  682
    CCUUCUCUGAGUGGUAAAG  398  683
    GAAGCUAUUGAAGCUGAGG 2153  684
    AUGCAGAACUUGCCACACG  702  685
    GUAGCUGAUAUUGAUGGAC  503  686
    CUCAAGCUGAUUUGAUGGA  278  687
    GCAUGGAAGAAAUAGUUGA 1962  688
    CUGGUGGAAUGCAAGCUUU 1347  689
    CCCAGGACCUCAUGGAUGG 2544  690
    UUUGGGAUAUGUAUGGGUA 3079  691
    CAAAGUUGUUGUAACCUGC 3164  692
    CCGAAUUGUUAUCAGAGGA 2026  693
    UAAUUGUAAUCUGAAUAAA 2938  694
    AUUGUAAUCUGAAUAAAGU 2940  695
    CGAAUUGUUAUCAGAGGAC 2027  696
    CCAAGUCCUGUAUGAGUGG  448  697
    AAGCCGGCUAUUGUAGAAG 1328  698
    AUCCUAGCUAUCGUUCUUU 2406  699
    AUAACCUUUCCCAUCAUCG  924  700
    GCCAAGUGGGUGGUAUAGA 1584  701
    CGACUAGUUCAGUUGCUUG 1871  702
    UUGGUUCACCAGUGGAUUC  999  703
    GUUCAGAACUGUCUUUGGA 1400  704
    UGCUGUGAUACGAUGCUUC 3180  705
    UCCAGGUGACAGCAAUCAG 2569  706
    UAUGGUCCAUCAGCUUUCU  787  707
    UGCCAUUCCACGACUAGUU 1861  708
    AACCAAGAAAGCAAGCUCA 1190  709
    AUAAUUAUAAGAACAAGAU 1557  710
    GUUAAGCUCUUACACCCAC 1751  711
    UUGAGUAAUGGUGUAGAAC 2897  712
    GUGUGGCGACAUAUGCAGC 2217  713
    GACCAGCUCUCUCUUCAGA 2302  714
    UUGUACCGGAGCCCUUCAC 1984  715
    AUGGCCAUGGAACCAGACA  302  716
    UGGUGGAUAUGGCCAGGAU 2431  717
    CCUCUGACAGAGUUACUUC 2183  718
    AUGAUCCUAGCUAUCGUUC 2403  719
    AUGGUCCAUCAGCUUUCUA 788  720
    GGACUCUUGUUCAGCUUCU 1476  721
    GCUAUCAUGCGUUCUCCUC  827  722
    GCUGACCAGCUCUCUCUUC 2299  723
    UCGUGCACAUCAGGAUACC 1891  724
    UACUUCACUCUAGGAAUGA 2196  725
    UGAAACAUGCAGUUGUAAA  663  726
    UAUGCCAUUACAACUCUCC 1028  727
    UGUUAUCAGAGGACUAAAU 2032  728
    GAUGGAAGGUCUCCUUGGG 1459  729
    CAUCCAAAGAGUAGCUGCA 2095  730
    GCCGACACCAAGAAGCAGA 1686  731
    CUUUGGACUCUCAGGAAUC 1412  732
    GGAACAUGAGAUGGGUGGC 2473  733
    UGGCAGUGCGUUUAGCUGG 1080  734
    GGAAGCUGCAGAAGCUAUU 2143  735
    CUCUAGGAAUGAAGGUGUG 2203  736
    GUACGAGCUGCUAUGUUCC 548  737
    UCCACGACUAGUUCAGUUG 1867  738
    CCUCAGAUGGUGUCUGCUA  842  739
    CUCUGUGAACUUGCUCAGG 2120  740
    GCAGUUAUGGUCCAUCAGC  782  741
    UCUUACACCCACCAUCCCA 1758  742
    CGCCAGGAUGAUCCUAGCU 2396  743
    CACCUGACAGAUCCAAGUC 1373  744
    UCACCUGUGCAGCUGGAAU 1518  745
    GGAUGGGCUGCCUCCAGGU 2557  746
    UACCGGAGCCCUUCACAUC 1987  747
    UGAGACAUUAGAUGAGGGC  568  748
    CACUCUAGGAAUGAAGGUG 2201  749
    UUGAUGCUGCUCAUCCCAC  609  750
    UUCUCUGAGUGGUAAAGGC  400  751
    UGUUAGUCACUGGCAGCAA  331  752
    GAAGAAAUAGUUGAAGGUU 1967  753
    CUUCACUCUAGGAAUGAAG 2198  754
    CUGGGUUCAGAUGAUAUAA 1493  755
    GGACAAGCCACAAGAUUAC 2260  756
    ACCCUGGUGCUGACUAUCC 2496  757
    UUGAUAUUGGUGCCCAGGG 2361  758
    ACCUCCCAAGUCCUGUAUG  443  759
    GUAUGCAAUGACUCGAGCU  523  760
    CCAGUUGUGGUUAAGCUCU 1742  761
    AUGACUCGAGCUCAGAGGG  530  762
    UUGUUGUAACCUGCUGUGA 3168  763
    CCAAGUCAACGUCUUGUUC 1385  764
    AUCAGAGGACUAAAUACCA 2036  765
    UGUAUGGGUAGGGUAAAUC 3088  766
    CGUGAGCAGGGUGCCAUUC 1850  767
    UGAUGGGCUGCCAGAUCUG 2518  768
    CUUGUUCGUGCACAUCAGG 1886  769
    CCAUCACAGAUGCUGAAAC  650  770
    ACAGUUUACCAGUUGCCUU 3139  771
    ACCGAAUUGUUAUCAGAGG 2025  772
    GCAGUGCGUUUAGCUGGUG 1082  773
    AACAUGAGAUGGGUGGCCA 2475  774
    CCUGACAGAUCCAAGUCAA 1375  775
    GGGAUGUUCACAACCGAAU 2013  776
    GGAUUGAUUCGAAAUCUUG 1802  777
    GAAGCUGCAGAAGCUAUUG 2144  778
    AAUGACUCGAGCUCAGAGG  529  779
    UUGUUCAGCUUCUGGGUUC 1482  780
    CCUCACUUGCAAUAAUUAU 1546  781
    CAGAUGGUGUCUGCUAUUG  845  782
    CUUCACUCAAGAACAAGUA  487  783
    AUCACAGAUGCUGAAACAU  652  784
    AGUUCGCCUUCACUAUGGA 1720  785
    UACUGGCCAUCUUUAAGUC  951  786
    CAAGCUUUAGUAAAUAUAA 1232  787
    AGCCACAAGAUUACAAGAA 2265  788
    AAGCAGAGAUGGCCCAGAA 1698  789
    GAUGCAGAACUUGCCACAC  701  790
    AUCUUUCAGAUGCUGCAAC 1428  791
    UGGGACACAGCAGCAAUUU 1930  792
    ACAGAUCCAAGUCAACGUC 1379  793
    ACAGCAGCAAUUUGUGGAG 1936  794
    UGCAACUAAACAGGAAGGG 1441  795
    GCUCAGGACAAGGAAGCUG 2132  796
    GACUAAAUACCAUUCCAUU 2043  797
    UUUGAUGCUGCUCAUCCCA  608  798
    UGGCAGCAACAGUCUUACC  341  799
    AAGAAAGCAAGCUCAUCAU 1194  800
    UGAUCUUGGACUUGAUAUU 2350  801
    CUGAAUAAAGUGUAACAAU 2948  802
    ACUAAAUACCAUUCCAUUG 2044  803
    AUCCCACUAAUGUCCAGCG  621  804
    CCACUACCACAGCUCCUUC  384  805
    CAUCAGGAUACCCAGCGCC 1898  806
    UCACAGAUGCUGAAACAUG  653  807
    UUUGCGUGAGCAGGGUGCC 1846  808
    GCUGAUCUUGGACUUGAUA 2348  809
    GGCUAUUACGACAGACUGC 1150  810
    GGACAUGGCCAUGGAACCA  298  811
    AACAAGAUGAUGGUCUGCC 1568  812
    UUACAUCAAGAAGGAGCUA 1058  813
    AAUCAUGCACCUUUGCGUG 1835  814
    GCAAAUCAUGCACCUUUGC 1832  815
    GAGUGGUAAAGGCAAUCCU  406  816
    UCGCCUUCACUAUGGACUA 1723  817
    AUCCAUUCUGGUGCCACUA  371  818
    AUCAGGAUACCCAGCGCCG 1899  819
    AGUAUGCAAUGACUCGAGC  522  820
    CGGCUUUCAGUUGAGCUGA 2285  821
    GCUGCAGUUAUGGUCCAUC  779  822
    AUUGAGUAAUGGUGUAGAA 2896  823
    GUAAUCUGAAUAAAGUGUA 2943  824
    UUGAUGGACAGUAUGCAAU  513  825
    GAUAUGUAUGGGUAGGGUA 3084  826
    GAACAAGAUGAUGGUCUGC 1567  827
    UUAUCAGAGGACUAAAUAC 2034  828
    UUCACCAGUGGAUUCUGUG 1003  829
    AAGGUUGUACCGGAGCCCU 1980  830
    GUAGAAGCUGGUGGAAUGC 1340  831
    AUGCUGCAACUAAACAGGA 1437  832
    UCACUCUGGUGGAUAUGGC 2425  833
    CUGAUUUGAUGGAGUUGGA  282  834
    UCAUCAUACUGGCUAGUGG 1206  835
    GCUUGUUCGUGCACAUCAG 1885  836
    UCUGCUCUAGUAAUAAGCC 1314  837
    UAUCUGUCUGCUCUAGUAA 1308  838
    GCAAGCUCAUCAUACUGGC 1200  839
    AGAGGGUACGAGCUGCUAU  543  840
    UGUGCGUACUGUCCUUCGG 1609  841
    GGAAGGGAUGGAAGGUCUC 1453  842
    AUGCGUUCUCCUCAGAUGG  833  843
    GACAGAGUUACUUCACUCU 2188  844
    UUGGCUAUUACGACAGACU 1148  845
    GGACUACCAGUUGUGGUUA 1736  846
    UUCAGAACUGUCUUUGGAC 1401  847
    AUCUGACCAGCCGACACCA 1677  848
    ACACAGCAGCAAUUUGUGG 1934  849
    UACCACAGCUCCUUCUCUG  388  850
    CGUCCAUGGGUGGGACACA 1920  851
    UGUGGUUAAGCUCUUACAC 1747  852
    UUGUACGUACCAUGCAGAA  861  853
    GAUACCCAGCGCCGUACGU 1904  854
    UCAUGCGUUCUCCUCAGAU  831  855
    GCACAUCAGGAUACCCAGC 1895  856
    GAUUACAAGAAACGGCUUU 2273  857
    ACUACCAGUUGUGGUUAAG 1738  858
    GUCUUGUUCAGAACUGUCU 1395  859
    UCAUCUGACCAGCCGACAC 1675  860
    CUUUGCGUGAGCAGGGUGC 1845  861
    CUGUCUUUGGACUCUCAGG 1408  862
    UACAUCAAGAAGGAGCUAA 1059  863
    AGAUCCAAGUCAACGUCUU 1381  864
    CAAGUCAACGUCUUGUUCA 1386  865
    UCCUUGGGACUCUUGUUCA 1470  866
    GGUGGAAUGCAAGCUUUAG 1349  867
    CUGCAACUAAACAGGAAGG 1440  868
    UUAGGACUUCACCUGACAG 1364  869
    AGUAGCUGAUAUUGAUGGA  502  870
    UAUAAUGAGGACCUAUACU 1246  871
    CCUGCUGUGAUACGAUGCU 3178  872
    AUGGGUGGCCACCACCCUG 2483  873
    GACUCUCAGGAAUCUUUCA 1417  874
    GUGCACAUCAGGAUACCCA 1893  875
    UUCCAGACACGCUAUCAUG  817  876
    UUGCCACACGUGCAAUCCC  711  877
    UCAGAUGCUGCAACUAAAC 1433  878
    CUUUAGGACUUCACCUGAC 1362  879
    CAUGCACCUUUGCGUGAGC 1838  880
    ACAACUCUCCACAACCUUU 1037  881
    UGGGACUCUUGUUCAGCUU 1474  882
    GCUUGGUUCACCAGUGGAU  997  883
    UUCCCAUCAUCGUGAGGGC  931  884
    GUCUGCUCUAGUAAUAAGC 1313  885
    CAGCUUCUGGGUUCAGAUG 1487  886
    CGUCAUCUGACCAGCCGAC 1673  887
    UGUUCCCUGAGACAUUAGA  561  888
    GCAACCAAGAAAGCAAGCU 1188  889
    GGAGUUGGACAUGGCCAUG  292  890
    GUCCGCAUGGAAGAAAUAG 1958  891
    CUGAUCUUGGACUUGAUAU 2349  892
    AUGGAAGGUCUCCUUGGGA 1460  893
    GAUGGUCUGCCAAGUGGGU 1576  894
    ACUAUCAAGAUGAUGCAGA  690  895
    ACAGAUGCUGAAACAUGCA  655  896
    UUCAGUUGAGCUGACCAGC 2290  897
    AGAGGCUCUUGUGCGUACU 1600  898
    GGUGGAUAUGGCCAGGAUG 2432  899
    CUUGCCACACGUGCAAUCC  710  900
    GAAUGCAGUUCGCCUUCAC 1714  901
    CCUAGCUCGGGAUGUUCAC 2005  902
    UUCACUAUGGACUACCAGU 1728  903
    GAUGGGUGGCCACCACCCU 2482  904
    UGGUUAAUAAGGCUGCAGU  768  905
    AUCAAGAUGAUGCAGAACU  693  906
    CUGCUGUGAUACGAUGCUU 3179  907
    AUGCCUUGGGUAUGGACCC 2448  908
    UGUGAUACGAUGCUUCAAG 3183  909
    GAGUGCUGAAGGUGCUAUC 1293  910
    GAGGGUACGAGCUGCUAUG  544  911
    UUAAUUGUAAUCUGAAUAA 2937  912
    CACCAAGAAGCAGAGAUGG 1691  913
    GAAUGCAAGCUUUAGGACU 1353  914
    ACCUUUGCGUGAGCAGGGU 1843  915
    AGGUGCUAUCUGUCUGCUC 1302  916
    UUGCUCAGGACAAGGAAGC 2130  917
    GCUGAGGGAGCCACAGCUC 2165  918
    CUACCACAGCUCCUUCUCU  387  919
    UGGAACAUGAGAUGGGUGG 2472  920
    GCUAUUGUACGUACCAUGC  857  921
    UCUUGCCCUUUGUCCCGCA 1816  922
    UUAUAAGAACAAGAUGAUG 1561  923
    GGAAGCUUCCAGACACGCU  811  924
    UAAGCCGGCUAUUGUAGAA 1327  925
    GGACCAGGUGGUGGUUAAU  757  926
    CUGAUAUUGAUGGACAGUA  507  927
    UGGGUAGGGUAAAUCAGUA 3092  928
    ACUUGAUAUUGGUGCCCAG 2359  929
    UAAGCUCUUACACCCACCA 1753  930
    CUACUCAAGCUGAUUUGAU  273  931
    GGUGCCAUUCCACGACUAG 1859  932
    UUGGACAUGGCCAUGGAAC  296  933
    CUGCUCAUCCCACUAAUGU  615  934
    CAUGGCCAUGGAACCAGAC  301  935
    UAUGGCAACCAAGAAAGCA 1184  936
    ACCAGUGGAUUCUGUGUUG 1006  937
    ACAGAGUUACUUCACUCUA 2189  938
    UAGGACUUCACCUGACAGA 1365  939
    GCCAGGAUGCCUUGGGUAU 2442  940
    AAUGAGGACCUAUACUUAC 1249  941
    AUUCUUGGCUAUUACGACA 1144  942
    CUUUAUUCUCCCAUUGAAA 2075  943
    UAGCUGAUAUUGAUGGACA  504  944
    GAACUGUCUUUGGACUCUC 1405  945
    UUAGUCACUGGCAGCAACA  333  946
    CCAUUACAACUCUCCACAA 1032  947
    GUGGUUAAGCUCUUACACC 1748  948
    UGAUUUGAUGGAGUUGGAC  283  949
    GCAGAGAUGGCCCAGAAUG 1700  950
    ACUAAACAGGAAGGGAUGG 1445  951
    ACAAAUGUUAAAUUCUUGG 1133  952
    GCAAUGACUCGAGCUCAGA  527  953
    CUCGGGAUGUUCACAACCG 2010  954
    GUGUCUGCUAUUGUACGUA  851  955
    UGUGGAUACCUCCCAAGUC  436  956
    GGAUGCCUUGGGUAUGGAC 2446  957
    AAAUUCUUGGCUAUUACGA 1142  958
    UACGAGCUGCUAUGUUCCC  549  959
    CAGUGCGUUUAGCUGGUGG 1083  960
    CAAGAUGAUGCAGAACUUG  695  961
    AUGAUGUAGAAACAGCUCG  885  962
    UGCAGCUGCUUUAUUCUCC 2067  963
    CCACAGCUCCUUCUCUGAG  390  964
    CAGUUCGCCUUCACUAUGG 1719  965
    AAGCUUCCAGACACGCUAU  813  966
    UUUCAGUUGAGCUGACCAG 2289  967
    UCUGGUGCCACUACCACAG  377  968
    CGCUAUCAUGCGUUCUCCU  826  969
    GACAGGGAAGACAUCACUG 1634  970
    AUCAUACUGGCUAGUGGUG 1208  971
    GCUGGUGACAGGGAAGACA 1628  972
    AUCCUAGCUCGGGAUGUUC 2003  973
    GUCCUGUAUGAGUGGGAAC  452  974
    UGGGAUAUGUAUGGGUAGG 3081  975
    CUUGGACUUGAUAUUGGUG 2354  976
    CCUUUGUCCCGCAAAUCAU 1822  977
    UGAAGGUGCUAUCUGUCUG 1299  978
    CCUUCACUCAAGAACAAGU  486  979
    GAAGGUCUCCUUGGGACUC 1463  980
    AGAAACGGCUUUCAGUUGA 2280  981
    ACCCAGCGCCGUACGUCCA 1907  982
    CAUAACCUUUCCCAUCAUC  823  983
    GAAGGUUGUACCGGAGCCC 1979  984
    GUCCCGCAAAUCAUGCACC 1827  985
    CAAGCUCAUCAUACUGGCU 1201  986
    CGCCGUACGUCCAUGGGUG 1913  987
    AGAGUUACUUCACUCUAGG 2191  988
    GUUGGACAUGGCCAUGGAA  295  989
    UGGCUAUUACGACAGACUG 1149  990
    ACUCGAGCUCAGAGGGUAC  533  991
    ACAGUUUGAUGCUGCUCAU  604  992
    GGUGGUUAAUAAGGCUGCA  766  993
    CUUUGUCCCGCAAAUCAUG 1823  994
    AAUACCAUUCCAUUGUUUG 2045  995
    CCACACGUGCAAUCCCUGA  714  996
    AUGGCCAGGAUGCCUUGGG 2439  997
    GGAUACCCAGCGCCGUACG 1903  998
    UCGCCAGGAUGAUCCUAGC 2395  999
    UGGUCCAUCAGCUUUCUAA  789 1000
    AUAUGUAUGGGUAGGGUAA 3085 1001
    CCCAGAAUGCAGUUCGCCU 1710 1002
    UAUUGUAGAAGCUGGUGGA 1336 1003
    GUAUGGGUAGGGUAAAUCA 3089 1004
    GAUCUUGGACUUGAUAUUG 2351 1005
    ACACGUGCAAUCCCUGAAC  716 1006
    AGCGCCGUACGUCCAUGGG 1911 1007
    UGUACCGGAGCCCUUCACA 1985 1008
    GUUGAUGGGCUGCCAGAUC 2516 1009
    ACACCCACCAUCCCACUGG 1762 1010
    UACGACAGACUGCCUUCAA 1156 1011
    UUGUUCGUGCACAUCAGGA 1887 1012
    CAAAUCAUGCACCUUUGCG 1833 1013
    GUCUGGAGGCAUUCCUGCC  967 1014
    CACUAUGGACUACCAGUUG 1730 1015
    UAUCAUGCGUUCUCCUCAG  829 1016
    GUAGAAACAGCUCGUUGUA  890 1017
    CUCCUCUGACAGAGUUACU 2181 1018
    UGCUCAGGACAAGGAAGCU 2131 1019
    CAAGUGGGUGGUAUAGAGG 1586 1020
    UGGUGGUUAAUAAGGCUGC  765 1021
    ACUUCACCUGACAGAUCCA 1369 1022
    CGCCUUCACUAUGGACUAC 1724 1023
    UGCGUUCUCCUCAGAUGGU  834 1024
    GUUGUACCGGAGCCCUUCA 1983 1025
    CGACACCAAGAAGCAGAGA 1688 1026
    UCACCAGUGGAUUCUGUGU 1004 1027
    GGUGACAGGGAAGACAUCA 1631 1028
    UCUAGUAAUAAGCCGGCUA 1319 1029
    GUGGUUAAUAAGGCUGCAG  767 1030
    UCCUCAGAUGGUGUCUGCU  841 1031
    AUGGACAGUAUGCAAUGAC  516 1032
    UGCGUGAGCAGGGUGCCAU 1848 1033
    ACUCUAGGAAUGAAGGUGU 2202 1034
    GACAUUAGAUGAGGGCAUG  571 1035
    CUGGUGACAGGGAAGACAU 1629 1036
    UGAUUCGAAAUCUUGCCCU 1806 1037
    GCUCUUACACCCACCAUCC 1756 1038
    GUCCUUCGGGCUGGUGACA 1619 1039
    GUGCGUACUGUCCUUCGGG 1610 1040
    UGGUGCUGACUAUCCAGUU 2500 1041
    GCUAUUGAAGCUGAGGGAG 2156 1042
    CAACCAAGAAAGCAAGCUC 1189 1043
    GUGCAGCUGCUUUAUUCUC 2066 1044
    CUAUCUGUCUGCUCUAGUA 1307 1045
    AAACAGGAAGGGAUGGAAG 1448 1046
    ACUGGCUAGUGGUGGACCC 1213 1047
    CCUCUGUGAACUUGCUCAG 2119 1048
    UGUAGAAACAGCUCGUUGU  889 1049
    CUGACAGAUCCAAGUCAAC 1376 1050
    GGAAGAGGAUGAGGAUACC  427 1051
    ACCAUCACAGAUGCUGAAA  649 1052
    CCGUACGUCCAUGGGUGGG 1915 1053
    CAUUCCAUUGUUUGUGCAG 2053 1054
    CUCCAGGUGACAGCAAUCA 2568 1055
    CUACCAGUUGUGGUUAAGC 1739 1056
    UUGUGGUUAAGCUCUUACA 1746 1057
    UAGUAAUAAGCCGGCUAUU 1321 1058
    CAGUCCUUCACUCAAGAAC  482 1059
    AGCUGAUUUGAUGGAGUUG  280 1060
    AGGUCUCCUUGGGACUCUU 1465 1061
    ACUAUGGACUACCAGUUGU 1731 1062
    CAGCAGCAAUUUGUGGAGG 1937 1063
    CGUGCACAUCAGGAUACCC 1892 1064
    CGUUCUCCUCAGAUGGUGU  836 1065
    CAGUAUGCAAUGACUCGAG  521 1066
    GGUAUAGAGGCUCUUGUGC 1595 1067
    AUCCAGUUGAUGGGCUGCC 2511 1068
    UGCCAAGUGGGUGGUAUAG 1583 1069
    ACAUCAGGAUACCCAGCGC 1897 1070
    GCCAUCUUUAAGUCUGGAG  926 1071
    AACCUUUCCCAUCAUCGUG  926 1072
    CUAGUUCAGUUGCUUGUUC 1874 1073
    UUCACUCAAGAACAAGUAG  488 1074
    AAGAAGCAGAGAUGGCCCA 1695 1075
    UCCUCUGACAGAGUUACUU 2182 1076
    AAUUGUUAUCAGAGGACUA 2029 1077
    UCUCAGUCCUUCACUCAAG  479 1078
    UCCAGACACGCUAUCAUGC  818 1079
    CACUAAUGUCCAGCGUUUG  625 1080
    UUGUAACCUGCUGUGAUAC 3172 1081
    CUUCUGGGUUCAGAUGAUA 1490 1082
    GCCGUACGUCCAUGGGUGG 1914 1083
    UAGUUGAAGGUUGUACCGG 1974 1084
    GAGGACAAGCCACAAGAUU 2258 1085
    GGGAGCCACAGCUCCUCUG 2170 1086
    CUUCACCUGACAGAUCCAA 1370 1087
    UCUUUCAGAUGCUGCAACU 1429 1088
    UGUAACCUGCUGUGAUACG 3173 1089
    CCUCCCAAGUCCUGUAUGA  444 1090
    GGCAGUGCGUUUAGCUGGU 1081 1091
    CUCUAGUAAUAAGCCGGCU 1318 1092
    GCUGUUAGUCACUGGCAGC  329 1093
    GUCAACGUCUUGUUCAGAA 1389 1094
    GAAGAGGAUGUGGAUACCU  428 1095
    UAACCUGCUGUGAUACGAU 3175 1096
    GUUAUUUGGAACCUUGUUU 3117 1097
    UCACAACCGAAUUGUUAUC 2020 1098
    CGGGCUGGUGACAGGGAAG 1625 1099
    ACAACCGAAUUGUUAUCAG 2022 1100
    CCACUAAUGUCCAGCGUUU  624 1101
    CACUGAGCCUGCCAUCUGU 1648 1102
    GGUCCAUCAGCUUUCUAAA  790 1103
    AUCCCAAAGUUGUUGUAAC 3160 1104
    UGAGGACCUAUACUUACGA 1251 1105
    UGUCUGAGGACAAGCCACA 2253 1106
    AGUUGAUGGGCUGCCAGAU 2515 1107
    UGACCAGCCGACACCAAGA 1680 1108
    AGGGAGCCACAGCUCCUCU 2169 1109
    AAAGUUGUUGUAACCUGCU 3165 1110
    CUGCAGUUAUGGUCCAUCA  780 1111
    UGAAGGUUGUACCGGAGCC 1978 1112
    UUCCCUGAGACAUUAGAUG  563 1113
    CUUCGGGCUGGUGACAGGG 1622 1114
    UUGAGCUGACCAGCUCUCU 2295 1115
    GAACUUGCUCAGGACAAGG 2126 1116
    CCAGCCGACACCAAGAAGC 1683 1117
    AGGGUGCCAUUCCACGACU 1857 1118
    UUGUGCAGCUGCUUUAUUC 2064 1119
    UCACUCAAGAACAAGUAGC  489 1120
    GCUGGUGGAAUGCAAGCUU 1346 1121
    GCAACUAAACAGGAAGGGA 1442 1122
    AGGUUGUACCGGAGCCCUU 1981 1123
    AGGCUGCAGUUAUGGUCCA  777 1124
    GCAGAUCCCAUCUACACAG  589 1125
    CUAGGAAUGAAGGUGUGGC 2205 1126
    AGCUCCUUCUCUGAGUGGU  394 1127
    UUACAACUCUCCACAACCU 1035 1128
    GGUAAAGGCAAUCCUGAGG  410 1129
    GUUCGCCUUCACUAUGGAC 1721 1230
    CAAAUGUUAAAUUCUUGGC 1134 1231
    CUGUGAUACGAUGCUUCAA 3182 1232
    ACAAAUGAUGUAGAAACAG  881 1133
    GGUACGAGCUGCUAUGUUC  547 1134
    GAAUUGUUAUCAGAGGACU 2028 1135
    CAACCGAAUUGUUAUCAGA 2023 1136
    GUGAUACGAUGCUUCAAGA 3184 1137
    AAAGGCAAUCCUGAGGAAG  413 1138
    CAGCUCCUCUGACAGAGUU 2178 1139
    AUGGUCUGCCAAGUGGGUG 1577 1140
    GCUACUGUUGGAUUGAUUC 1793 1141
    UGCAAUGACUCGAGCUCAG  526 1142
    GACUUGAUAUUGGUGCCCA 2358 1143
    CAGAACUGUCUUUGGACUC 1403 1144
    UAGUUCAGUUGCUUGUUCG 1875 1145
    ACAGACUGCCUUCAAAUUU 1160 1146
    GGGUGGUAUAGAGGCUCUU 1591 1147
    AUGGACUACCAGUUGUGGU 1734 1148
    AUUGUUAUCAGAGGACUAA 2030 1149
    UAAGGCUGCAGUUAUGGUC  775 1150
    AAAUCUUGCCCUUUGUCCC 1813 1151
    AGCAGCAAUUUGUGGAGGG 1938 1152
    AGAGGACUAAAUACCAUUC 2039 1153
    GCUGAAGGUGCUAUCUGUC 1297 1154
    UGUAUGAGUGGGAACAGGG  456 1155
    CAGAUCCCAUCUACACAGU  590 1156
    GACAGACAGCAAUUUGUG 1933 1157
    GGGCAUGCAGAUCCCAUCU  583 1158
    CAUGCCCAGGACCUCAUGG 2540 1159
    GAAGCUGAGGGAGCCACAG 2162 1160
    CUGUUAGUCACUGGCAGCA  330 1161
    CUUGUUCAGCUUCUGGGUU 1481 1162
    AAGCUGGUGGAAUGCAAGC 1344 1163
    GAGGAUGUGGAUACCUCCC  431 1164
    AUAAAUGUGGUCACCUGUG 1508 1165
    UACGUCCAUGGGUGGGACA 1918 1166
    GAUGGAGUUGGACAUGGCC  289 1167
    UGUCCAGCGUUUGGCUGAA  631 1168
    GAGCAGGGUGCCAUUCCAC 1853 1169
    AAAUAUAAUGAGGACCUAU 1243 1170
    UACUGGCUAGUGGUGGACC 1212 1171
    UGCUUGGUUCACCAGUGGA  996 1172
    CUGAGGACAAGCCACAAGA 2256 1173
    CUUGUGCGUACUGUCCUUC 1607 1174
    UGUUAUUUGGAACCUUGUU 3116 1175
    UAGCUUAUGGCAACCAAGA 1179 1176
    UGAUACGAUGCUUCAAGAG 3185 1177
    UGGUAUAGAGGCUCUUGGU 1594 1178
    GAUGUAGAAACAGCUCGUU  887 1179
    CCUUUCCCAUCAUCGUGAG  928 1180
    GCGUUCUCCUCAGAUGGUG  835 1181
    UCAGGAUACCCAGCGCCGU 1900 1182
    ACGGCUUUCAGUUGAGCUG 2284 1183
    GUUGAAGGUUGUACCGGAG 1976 1184
    UAUCGCCAGGAUGAUCCUA 2393 1185
    GUGCUGAAGGUGCUAUCUG 1295 1186
    GUCUUUGGACUCUCAGGAA 1410 1187
    GGGAUGGAAGGUCUCCUUG 1457 1188
    UGAGCUGACCAGCUCUCUC 2296 1189
    CUUUCCCAUCAUCGUGAGG  929 1190
    AAGCUUUAGGACUUCACCU 1359 1191
    UGGAAUGCAAGCUUUAGGA 1351 1192
    CUGGAGGCAUUCCUGCCCU  969 1193
    AGUUCAGUUGCUUGUUCGU 1876 1194
    GAGCUGCUAUGUUCCCUGA  552 1195
    GGCCAGGAUGCCUUGGGUA 2441 1196
    GAUGAUCCUAGCUAUCGUU 2402 1197
    GAUUGAUUCGAAAUCUUGC 1803 1198
    CAGAGAUGGCCCAGAAUGC 1701 1199
    CAGCGCCGUACGUCCAUGG 1910 1200
    AUGUAGAAACAGCUCGUUG  888 1201
    AGUGCUGAAGGUGCUAUCU 1294 1202
    GACUACCAGUUGUGGUUAA 1737 1203
    ACAGGAAGGGAUGGAAGGU 1450 1204
    CAGGUGGUGGUUAAUAAGG  761 1205
    AAGGCUGCAGUUAUGGUCC  776 1206
    UAAAUGUGGUCACCUGUGC 1509 1207
    UAAAGGCUACUGUUGGAUU 1788 1208
    GAUGGACAGUAUGCAAUGA  515 1209
    UUCUGGGUUCAGAUGAUAU 1491 1210
    GUACUGUCCUUCGGGCUGG 1614 1211
    CUUGGUUCACCAGUGGAUU  998 1212
    UAUUGAAGCUGAGGGAGCC 2158 1213
    GUUGUUGUAACCUGCUGUG 3168 1214
    AGCAGGGUGCCAUUCCACG 1854 1215
    GUCCUCUGUGAACUUGCUC 2117 1216
    UCUGACCAGCCGACACCAA 1678 1217
    GCCAUGGAACCAGACAGAA  305 1218
    AAGCUAUUGAAGCUGAGGG 2154 1219
    GAUUCGAAAUCUUGCCCUU 1807 1220
    AGUUGCUUGUUCGUGCACA 1881 1221
    AAGAACAAGAUGAUGGUCU 1565 1222
    AGUGGUAAAGGCAAUCCUG  407 1223
    CAGAUGCUGCAACUAAACA 1434 1224
    CCUGAGACAUUAGAUGAGG  566 1225
    UCCCAAAGUUGUUGUAACC 3161 1226
    CUGACCAGCCGACACCAAG 1679 1227
    AUCCAAAGAGUAGCUGCAG 2096 1228
    AUGUCCAGCGUUUGGCUGA  630 1229
    UCUUGUGCGUACUGUCCUU 1606 1230
    AGGAUGUGGAUACCUCCCA  432 1231
    GGCUGCAGUUAUGGUCCAU  778 1232
    UCACAUCCUAGCUCGGGAU 1999 1233
    ACCAAGAAGCAGAGAUGGC 1692 1234
    GCCACCACCCUGGUGCUGA 2490 1235
    CCCACUAAUGUCCAGCGUU  623 1236
    ACUGGCAGCAACAGUCUUA  339 1237
    AUCUGAAUAAAGUGUAACA 2946 1238
    GCCUGCCAUCUGUGCUCUU 1654 1239
    CAUUACAACUCUCCACAAC 1033 1240
    CUCCUCAGAUGGUGUCUGC  840 1241
    CAGUUGCUUGUUCGUGCAC 1880 1242
    AUCCUGAGGAAGAGGAUGU  420 1243
    CACCAGUGGAUUCUGUGUU 1005 1244
    CAAGAAAGCAAGCUCAUCA 1193 1245
    CUUGCAUAACCUUUCCCAU  919 1246
    CUUCACUAUGGACUACCAG 1727 1247
    UUGCUUGUUCGUGCACAUC 1883 1248
    UAUUGUACGUACCAUGCAG  859 1249
    GAAAUCUUGCCCUUUGUCC 1812 1250
    CUCUUGUGCGUACUGUCCU 1605 1251
    CACAACCGAAUUGUUAUCA 2021 1252
    GCUCCUCUGACAGAGUUAC 2180 1253
    AGCGUUUGGCUGAACCAUC  636 1254
    AAACGGCUUUCAGUUGAGC 2282 1255
    UUUGUCCCGCAAAUCAUGC 1824 1256
    UCUAGGAAUGAAGGUGUGG 2204 1257
    AAGUCCUGUAUGAGUGGGA  450 1258
    GGUUCACCAGUGGAUUCUG 1001 1259
    GGUCUGCCAAGUGGGUGGU 1579 1260
    AGCUCCUCUGACAGAGUUA 2179 1261
    UUCUGGUGCCACUACCACA  376 1262
    UGCUAUGUUCCCUGAGACA  556 1263
    AUUGAUUCGAAAUCUUGCC 1804 1264
    CUCAUGGAUGGGCUGCCUC 2552 1265
    GCUGCUUUAUUCUCCCAUU 2071 1266
    AUCAUGCACCUUUGCGUGA 1836 1267
    GUCACUGGCAGCAACAGUC  336 1268
    UGAGUGGGAACAGGGAUUU  460 1269
    AAUUAUAAGAACAAGAUGA 1559 1270
    UGGACAGUUUACCAGUUGC 3136 1271
    AUGAGGACCUAUACUUACG 1250 1272
    GGAAGGUCUCCUUGGGACU 1462 1273
    UGGAAGAAAUAGUUGAAGG 1954 1274
    GGUGUUAUUUGGAACCUUG 3114 1275
    GUGCUCUUCGUCAUCUGAC 1665 1276
    GGCCAUGGAACCAGACAGA  304 1277
    CGGCUGUUAGUCACUGGCA  327 1278
    UUCCACGACUAGUUCAGUU 1866 1279
    AGCAGAGAUGGCCCAGAAU 1699 1280
    GCCAGGAUGAUCCUAGCUA 2397 1281
    GCCAUCUGUGCUCUUCGUC 1658 1282
    UAGAAACAGCUCGUUGUAC  891 1283
    AGAUGAUGGUCUGCCAAGU 1572 1284
    ACCUUUCCCAUCAUCGUGA  927 1285
    AUGGAGUUGGACAUGGCCA  290 1286
    CUGUGCUCUUCGUCAUCUG 1663 1287
    UAUAAGAACAAGAUGAUGG 1562 1288
    UCUGAAUAAAGUGUAACAA 2947 1289
    CCAGAAUGCAGUUCGCCUU 1711 1290
    AGAACAAGAUGAUGGUCUG 1566 1291
    AUCUUGCCCUUUGUCCCGC 1815 1292
    GCGUUUAGCUGGUGGGCUG 1087 1293
    GGGUUCAGAUGAUAUAAAU 1495 1294
    UUUAGGACUUCACCUGACA 1363 1295
    CACAGCUCCUUCUCUGAGU  391 1296
    AACGUCUUGUUCAGAACUG 1392 1297
    CACAGCAGCAAUUUGUGGA 1935 1298
    GACUAGUUCAGUUGCUUGU 1872 1299
    GACAGACUGCCUUCAAAUU 1159 1300
    CUCUCUCUUCAGAACAGAG 2308 1301
    GUCCAGCGUUUGGCUGAAC  632 1302
    UAAGAACAAGAUGAUGGUC 1564 1303
    UCCAAGUCAACGUCUUGUU 1384 1304
    ACACCAAGAAGCAGAGAUG 1690 1305
    CUCAGGAAUCUUUCAGAUG 1421 1306
    UAAAUUCUUGGCUAUUACG 1141 1307
    CUAUGGACUACCAGUUGUG 1732 1308
    CCAGCGUUUGGCUGAACCA  634 1309
    UCCCAUCAUCGUGAGGGCU  932 1310
    AGGACUUCACCUGACAGAU 1366 1311
    UUGUGCGUACUGUCCUUCG 1608 1312
    CCAUGGGUGGGACACAGCA 1923 1313
    GGAUGGAAGGUCUCCUUGG 1458 1314
    CCCAGCGCCGUACGUCCAU 1908 1315
    GCUCAGAGGGUACGAGCUG  539 1316
    AUGUUCACAACCGAAUUGU 2016 1317
    UGCUUGUUCGUGCACAUCA 1884 1318
    AUGUUCCCUGAGACAUUAG  560 1319
    GUAAAGGCAAUCCUGAGGA  411 1320
    CACUGGCAGCAACAGUCUU  338 1321
    AUCAUGCGUUCUCCUCAGA  830 1322
    UAUGUAUGGGUAGGGUAAA 3086 1323
    GUGUUAUUUGGAACCUUGU 3115 1324
    ACAGCUCCUCUGACAGAGU 2177 1325
    UAUGGACUACCAGUUGUGG 1733 1326
    AUUCUGGUGCCACUACCAC  375 1327
    UGCCUCCAGGUGACAGCAA 2565 1328
    UACCUCCCAAGUCCUGUAU  442 1329
    CCAGACACGCUAUCAUGCG  819 1330
    UGAUGCAGAACUUGCCACA  700 1331
    GUUUAGCUGGUGGGCUGCA 1089 1332
    GUCUGCCAAGUGGGUGGUA 1580 1333
    GGUUGUACCGGAGCCCUUC 1982 1334
    GUACCGGAGCCCUUCACAU 1986 1335
    CAAUCCUGAGGAAGAGGAU  418 1336
    GCUAUCUGUCUGCUCUAGU 1306 1337
    UGACAGAUCCAAGUCAACG 1377 1338
    CAUGAUGGAACAUGAGAUG 2467 1339
    UUGGACUCUCAGGAAUCUU 1414 1340
    CUCUUCGUCAUCUGACCAG 1668 1341
    UUGCCCUUUGUCCCGCAAA 1818 1342
    GAAGCAGAGAUGGCCCAGA 1697 1343
    CCUUGCAUAACCUUUCCCA  918 1344
    CAGUUUGAUGCUGCUCAUC  605 1345
    ACCUGACAGAUCCAAGUCA 1374 1346
    CUUUCAGAUGCUGCAACUA 1430 1347
    GAUACGAUGCUUCAAGAGA 3186 1348
    AUGCAAGCUUUAGGACUUC 1355 1349
    GGAUGUGGAUACCUCCCAA  433 1350
    AGAAUGCAGUUCGCCUUCA 1713 1351
    CGAAAUCUUGCCCUUUGUC 1811 1352
    ACUCAAGAACAAGUAGCUG  491 1353
    GAAUGAAGGUGUGGCGACA 2209 1354
    UGCACCUUUGCGUGAGCAG 1840 1355
    ACGAGCUGCUAUGUUCCCU  550 1356
    AAGAGGAUGUGGAUACCUC  429 1357
    GAUAUGGCCAGGAUGCCUU 2436 1358
    UAUAGAGGCUCUUGUGCGU 1597 1359
    GGUUCAGAUGAUAUAAAUG 1496 1360
    AGGGAUGGAAGGUCUCCUU 1456 1361
    UAUCCCAAAGUUGUUGUAA 3159 1362
    UCUCUCUUCAGAACAGAGC 2309 1363
    CUGACCAGCUCUCUCUUCA 2300 1364
    ACCUGCUGUGAUACGAUGC 3177 1365
    AUGGCAGUGCGUUUAGCUG 1079 1366
    AUCCAAGUCAACGUCUUGU 1383 1367
    GCUGCCUCCAGGUGACAGC 2563 1368
    AGUGCGUUUAGCUGGUGGG 1084 1369
    AGCCGGCUAUUGUAGAAGC 1329 1370
    CAUUAGAUGAGGGCAUGCA  573 1371
    GAAGGUGUGGCGACAUAUG 2213 1372
    AAGUGGGUGGUAUAGAGGC 1587 1373
    CUGAGGGAGCCACAGCUCC 2166 1374
    GCGUUUGGCUGAACCAUCA  637 1375
    UCCUUCUCUGAGUGGUAAA  397 1376
    GCAGUUCGCCUUCACUAUG 1718 1377
    GGACUUGAUAUUGGUGCCC 2357 1378
    GUUUGGCUGAACCAUCACA  639 1379
    GCAUGCAGAUCCCAUCUAC  585 1380
    GAUGGGCUGCCAGAUCUGG 2519 1381
    GGACUUCACCUGACAGAUC 1367 1382
    CAACGUCUUGUUCAGAACU 1391 1383
    GAUAUUGAUGGACAGUAUG  509 1384
    UGGCCAUGGAACCAGACAG  303 1385
    CAAGAACAAGUAGCUGAUA  494 1386
    GGCUGUUAGUCACUGGCAG  328 1387
    CAUUGUUUGUGCAGCUGCU 2058 1388
    UAAACAGGAAGGGAUGGAA 1447 1389
    AUAAGAACAAGAUGAUGGU 1563 1390
    GUGGAAUGCAAGCUUUAGG 1350 1391
    GGAAUGAAGGUGUGGCGAC 2208 1392
    GACACCAAGAAGCAGAGAU 1689 1393
    ACUGUCUUUGGACUCUCAG 1407 1394
    GGACAAGGAAGCUGCAGAA 2137 1395
    UCUGCUAUUGUACGUACCA  854 1396
    AGCUGCUUUAUUCUCCCAU 2070 1397
    AGGGUACGAGCUGCUAUGU  545 1398
    GAAGACAUCACUGAGCCUG 1640 1399
    CGGGAUGUUCACAACCGAA 2012 1400
    CAGCCGACACCAAGAAGCA 1684 1401
    UGUUCACAACCGAAUUGUU 2017 1402
    GCUCUCUCUUCAGAACAGA 2307 1403
    UCAGAUGGUGUCUGCUAUU  844 1404
    UGAGUGGUAAAGGCAAUCC  405 1405
    UGGUGCCACUACCACAGCU  379 1406
    UUGUCCCGCAAAUCAUGCA 1825 1407
    CACCCUGGUGCUGACUAUC 2495 1408
    AAUGUCCAGCGUUUGGCUG  629 1409
    GGGCUGCCUCCAGGUGACA 2561 1410
    GAGUUACUUCACUCUAGGA 2192 1411
    UUCGAAAUCUUGCCCUUUG 1809 1412
    GUAUAGAGGCUCUUGUGCG 1596 1413
    AGCUGACCAGCUCUCUCUU 2298 1414
    CUAUUGUACGUACCAUGCA  858 1415
    UAUGCAAUGACUCGAGCUC  524 1416
    UGCCCAGGACCUCAUGGAU 2542 1417
    AACAAGUAGCUGAUAUUGA  597 1418
    AAGGCAAUCCUGAGGAAGA  414 1419
    CAAGAUGAUGGUCUGCCAA 1570 1420
    UGCCAUUACAACUCUCCAC 1030 1421
    AUGUAUGGGUAGGGUAAAU 3087 1422
    UGUGCUCUUCGUCAUCUGA 1664 1423
    AAGGCUACUGUUGGAUUGA 1790 1424
    UACUGUCCUUCGGGCUGGU 1615 1425
    AUAAGGCUGCAGUUAUGGU  774 1426
    UCGUCAUCUGACCAGCCGA 1672 1427
    GUUGUAACCUGCUGUGAUA 3171 1428
    AAGAUUACAAGAAACGGCU 2271 1429
    UUAUGGCAACCAAGAAAGC 1183 1430
    UCCAGUUGAUGGGCUGCCA 2512 1431
    GGGACACAGCAGCAAUUUG 1931 1432
    AUGAUGGAACAUGAGAUGG 2468 1433
    UAUUUGGGAUAUGUAUGGG 3077 1434
    CAGCUGCUUUAUUCUCCCA 2069 1435
    GCUACUCAAGCUGAUUUGA  272 1436
    UCCCUGAGACAUUAGAUGA  564 1437
    GUGGAUACCUCCCAAGUCC  437 1438
    UAGGAAUGAAGGUGUGGCG 2206 1439
    UGACAGAGUUACUUCACUC 2187 1440
    AGCGGCUGUUAGUCACUGG  325 1441
    AUGGUUCAGAAUUAAACUU 3222 1442
    AACCGAAUUGUUAUCAGAG 2024 1443
    GGGUGCCAUUCCACGACUA 1858 1444
    AUGAUGGUCUGCCAAGUGG 1574 1445
    CACAUCAGGAUACCCAGCG 1896 1446
    AGGAAUGAAGGUGUGGCGA 2207 1447
    GAAGGUGCUAUCUGUCUGC 1300 1448
    CCAAGAAAGCAAGCUCAUC 1192 1449
    CGAGCUGCUAUGUUCCCUG  551 1450
    CCUGGUGCUGACUAUCCAG 2498 1451
    UGCUAUCUGUCUGCUCUAG 1305 1452
    AUUGUAGAAGCUGGUGGAA 1337 1453
  • TABLE 1b
    Various c-CTNNB1 siNA sense and antisene sequences
    corresponding to the identified target sequences in Table 1a.
    Target Site
    (human) SEQ ID NO: Sense Sequence Antisense Sequence SEQ ID NO:
     535    1 UCGAGCUCAGAGGGUACGA UCGUACCCUCUGAGCUCGA 4914
    1601    2 GAGGCUCUUGUGCGUACUG CAGUACGCACAAGAGCCUC 4915
    1709    3 GCCCAGAAUGCAGUUCGCC GGCGAACUGCAUUCUGGGC 4916
     536    4 CGAGCUCAGAGGGUACGAG CUCGUACCCUCUGAGCUCG 4917
    1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAG 4918
     853    6 GUCUGCUAUUGUACGUACC GGUACGUACAAUAGCAGAC 4919
    1143    7 AAUUCUUGGCUAUUACGAC GUCGUAAUAGCCAAGAAUU 4920
    2014    8 GGAUGUUCACAACCGAAUU AAUUCGGUUGUGAACAUCC 4921
     520    9 ACAGUAUGCAAUGACUCGA UCGAGUCAUUGCAUACUGU 4922
     815   10 AGCUUCCAGACACGCUAUC GAUAGCGUGUCUGGAAGCU 4923
     852   11 UGUCUGCUAUUGUACGUAC GUACGUACAAUAGCAGACA 4924
    1796   12 ACUGUUGGAUUGAUUCGAA UUCGAAUCAAUCCAACAGU 4925
    1901   13 CAGGAUACCCAGCGCCGUA UACGGCGCUGGGUAUCCUG 4926
     822   14 GACACGCUAUCAUGCGUUC GAACGCAUGAUAGCGUGUC 4927
    1795   15 UACUGUUGGAUUGAUUCGA UCGAAUCAAUCCAACAGUA 4928
    1145   16 UUCUUGGCUAUUACGACAG CUGUCGUAAUAGCCAAGAA 4929
     823   17 ACACGCUAUCAUGCGUUCU AGAACGCAUGAUAGCGUGU 4930
     820   18 CAGACACGCUAUCAUGCGU ACGCAUGAUAGCGUGUCUG 4931
    1798   19 UGUUGGAUUGAUUCGAAAU AUUUCGAAUCAAUCCAACA 4932
    1380   20 CAGAUCCAAGUCAACGUCU AGACGUUGACUUGGAUCUG 4933
    1602   21 AGGCUCUUGUGCGUACUGU ACAGUACGCACAAGAGCCU 4934
    1612   22 GCGUACUGUCCUUCGGGCU AGCCCGAAGGACAGUACGC 4935
     626   23 ACUAAUGUCCAGCGUUUGG CCAAACGCUGGACAUUAGU 4936
    2000   24 CACAUCCUAGCUCGGGAUG CAUCCCGAGCUAGGAUGUG 4937
    2665   25 GUUGCUGAGAGGGCUCGAG CUCGAGCCCUCUCAGCAAC 4938
    1676   26 CAUCUGACCAGCCGACACC GGUGUCGGCUGGUCAGAUG 4939
    1611   27 UGCGUACUGUCCUUCGGGC GCCCGAAGGACAGUACGCA 4940
    2269   28 ACAAGAUUACAAGAAACGG CCGUUUCUUGUAAUCUUGU 4941
     674   29 GUUGUAAACUUGAUUAACU AGUUAAUCAAGUUUACAAC 4942
     678   30 UAAACUUGAUUAACUAUCA UGAUAGUUAAUCAAGUUUA 4943
    1245   31 AUAUAAUGAGGACCUAUAC GUAUAGGUCCUCAUUAUAU 4944
     679   32 AAACUUGAUUAACUAUCAA UUGAUAGUUAAUCAAGUUU 4945
    1970   33 GAAAUAGUUGAAGGUUGUA UACAACCUUCAACUAUUUC 4946
    1247   34 AUAAUGAGGACCUAUACUU AAGUAUAGGUCCUCAUUAU 4947
    1140   35 UUAAAUUCUUGGCUAUUAC GUAAUAGCCAAGAAUUUAA 4948
     676   36 UGUAAACUUGAUUAACUAU AUAGUUAAUCAAGUUUACA 4949
     677   37 GUAAACUUGAUUAACUAUC GAUAGUUAAUCAAGUUUAC 4950
     675   38 UUGUAAACUUGAUUAACUA UAGUUAAUCAAGUUUACAA 4951
    1235   39 GCUUUAGUAAAUAUAAUGA UCAUUAUAUUUACUAAAGC 4952
    2488   40 UGGCCACCACCCUGGUGCU AGCACCAGGGUGGUGGCCA 4953
    1236   41 CUUUAGUAAAUAUAAUGAG CUCAUUAUAUUUACUAAAG 4954
    1237   42 UUUAGUAAAUAUAAUGAGG CCUCAUUAUAUUUACUAAA 4955
    2555   43 GUAAAUCGUCCUUUAGGUA UACCUAAAGGACGAUUUAC 4956
    1545   44 ACCUCACUUGCAAUAAUUA UAAUUAUUGCAAGUGAGGU 4957
    2050   45 UACCAUUCCAUUGUUUGUG CACAAACAAUGGAAUGGUA 4958
    2097   46 UCCAAAGAGUAGCUGCAGG CCUGCAGCUACUCUUUGGA 4959
    2510   47 UAUCCAGUUGAUGGGCUGC GCAGCCCAUCAACUGGAUA 4960
     871   48 CAUGCAGAAUACAAAUGAU AUCAUUUGUAUUCUGCAUG 4961
    2098   49 CCAAAGAGUAGCUGCAGGG CCCUGCAGCUACUCUUUGG 4962
    1767   50 CACCAUCCCACUGGCCUCU AGAGGCCAGUGGGAUGGUG 4963
     869   51 ACCAUGCAGAAUACAAAUG CAUUUGUAUUCUGCAUGGU 4964
    1641   52 AAGACAUCACUGAGCCUGC GCAGGCUCAGUGAUGUCUU 4965
    2582   53 AAUCAGCUGGCCUGGUUUG CAAACCAGGCCAGCUGAUU 4966
    1544   54 AACCUCACUUGCAAUAAUU AAUUAUUGCAAGUGAGGUU 4967
    2550   55 ACCUCAUGGAUGGGCUGCC GGCAGCCCAUCCAUGAGGU 4968
    2051   56 ACCAUUCCAUUGUUUGUGC GCACAAACAAUGGAAUGGU 4969
     870   57 CCAUGCAGAAUACAAAUGA UCAUUUGUAUUCUGCAUGG 4970
    1670   58 CUUCGUCAUCUGACCAGCC GGCUGGUCAGAUGACGAAG 4971
    2122   59 CUGUGAACUUGCUCAGGAC GUCCUGAGCAAGUUCACAG 4972
    1642   60 AGACAUCACUGAGCCUGCC GGCAGGCUCAGUGAUGUCU 4973
    2324   61 GAGCCAAUGGCUUGGAAUG CAUUCCAAGCCAUUGGCUC 4974
    1649   62 ACUGAGCCUGCCAUCUGUG CACAGAUGGCAGGCUCAGU 4975
    2159   63 AUUGAAGCUGAGGGAGCCA UGGCUCCCUCAGCUUCAAU 4976
     785   64 GUUAUGGUCCAUCAGCUUU AAAGCUGAUGGACCAUAAC 4977
    1511   65 AAUGUGGUCACCUGUGCAG CUGCACAGGUGACCACAUU 4978
    2586   66 AGCUGGCCUGGUUUGAUAC GUAUCAAACCAGGCCAGCU 4979
     642   67 UGGCUGAACCAUCACAGAU AUCUGUGAUGGUUCAGCCA 4980
    1763   68 CACCCACCAUCCCACUGGC GCCAGUGGGAUGGUGGGUG 4981
    2328   69 CAAUGGCUUGGAAUGAGAC GUCUCAUUCCAAGCCAUUG 4982
    1280   70 UGGACCACAAGCAGAGUGC GCACUCUGCUUGUGGUCCA 4983
    2052   71 CCAUUCCAUUGUUUGUGCA UGCACAAACAAUGGAAUGG 4984
    2546   72 CAGGACCUCAUGGAUGGGC GCCCAUCCAUGAGGUCCUG 4985
    2124   73 GUGAACUUGCUCAGGACAA UUGUCCUGAGCAAGUUCAC 4986
    2545   74 CCAGGACCUCAUGGAUGGG CCCAUCCAUGAGGUCCUGG 4987
     643   75 GGCUGAACCAUCACAGAUG CAUCUGUGAUGGUUCAGCC 4988
    2501   76 GGUGCUGACUAUCCAGUUG CAACUGGAUAGUCAGCACC 4989
    2330   77 AUGGCUUGGAAUGAGACUG CAGUCUCAUUCCAAGCCAU 4990
    1638   78 GGGAAGACAUCACUGAGCC GGCUCAGUGAUGUCUUCCC 4991
    1630   79 UGGUGACAGGGAAGACAUC GAUGUCUUCCCUGUCACCA 4992
     616   80 UGCUCAUCCCACUAAUGUC GACAUUAGUGGGAUGAGCA 4993
    2509   81 CUAUCCAGUUGAUGGGCUG CAGCCCAUCAACUGGAUAG 4994
    2548   82 GGACCUCAUGGAUGGGCUG CAGCCCAUCCAUGAGGUCC 4995
    1773   83 CCCACUGGCCUCUGAUAAA UUUAUCAGAGGCCAGUGGG 4996
    2247   84 UCCGAAUGUCUGAGGACAA UUGUCCUCAGACAUUCGGA 4997
    2331   85 UGGCUUGGAAUGAGACUGC GCAGUCUCAUUCCAAGCCA 4998
    1498   86 UUCAGAUGAUAUAAAUGUG CACAUUUAUAUCAUCUGAA 4999
    2267   87 CCACAAGAUUACAAGAAAC GUUUCUUGUAAUCUUGUGG 5000
    1547   88 CUCACUUGCAAUAAUUAUA UAUUAAUUAUUGCAAGUGAG 5001
    1549   89 CACUUGCAAUAAUUAUAAG CUUAUAAUUAUUGCAAGUG 5002
     867   90 GUACCAUGCAGAAUACAAA UUUGUAUUCUGCAUGGUAC 5003
    1390   91 UCAACGUCUUGUUCAGAAC GUUCUGAACAAGACGUUGA 5004
    593   92 AUCCCAUCUACACAGUUUG CAAACUGUGUAGAUGGGAU 5005
     274   93 UACUCAAGCUGAUUUGAUG CAUCAAAUCAGCUUGAGUA 5006
     759   94 ACCAGGUGGUGGUUAAUAA UUAUUAACCACCACCUGGU 5007
    1439   95 GCUGCAACUAAACAGGAAG CUUCCUGUUUAGUUGCAGC 5008
    1801   96 UGGAUUGAUUCGAAAUCUU AAGAUUUCGAAUCAAUCCA 5009
    1500   97 CAGAUGAUAUAAAUGUGGU ACCACAUUUAUAUCAUCUG 5010
     848   98 AUGGUGUCUGCUAUUGUAC GUACAAUAGCAGACACCAU 5011
    2268   99 CACAAGAUUACAAGAAACG CGUUUCUUGUAAUCUUGUG 5012
     882  100 CAAAUGAUGUAGAAACAGC GCUGUUUCUACAUCAUUUG 5013
    2266  101 GCCACAAGAUUACAAGAAA UUUCUUGUAAUCUUGUGGC 5014
     880  102 UACAAAUGAUGUAGAAACA UGUUUCUACAUCAUUUGUA 5015
    1810  103 UCGAAAUCUUGCCCUUUGU ACAAAGGGCAAGAUUUCGA 5016
     685  104 GAUUAACUAUCAAGAUGAU AUCAUCUUGAUAGUUAAUC 5017
    1007  105 CCAGUGGAUUCUGUGUUGU ACAACACAGAAUCCACUGG 5018
    1789  106 AAAGGCUACUGUUGGAUUG CAAUCCAACAGUAGCCUUU 5019
     499  107 ACAAGUAGCUGAUAUUGAU AUCAAUAUCAGCUACUUGU 5020
    2470  108 GAUGGAACAUGAGAUGGGU ACCCAUCUCAUGUUCCAUC 5021
     694  109 UCAAGAUGAUGCAGAACUU AAGUUCUGCAUCAUCUUGA 5022
     278  110 CAAGCUGAUUUGAUGGAGU ACUCCAUCAAAUCAGCUUG 5023
    1415  111 UGGACUCUCAGGAAUCUUU AAAGAUUCCUGAGAGUCCA 5024
    2046  112 UAAAUACCAUUCCAUUGUU AACAAUGGAAUGGUAUUUA 5025
    1057  113 AUUACAUCAAGAAGGAGCU AGCUCCUUCUUGAUGUAAU 5026
    1422  114 UCAGGAAUCUUUCAGAUGC GCAUCUGAAAGAUUCCUGA 5027
     684  115 UGAUUAACUAUCAAGAUGA UCAUCUUGAUAGUUAAUCA 5028
    2197  116 ACUUCACUCUAGGAAUGAA UUCAUUCCUAGAGUGAAGU 5029
     666  117 AACAUGCAGUUGUAAACUU AAGUUUACAACUGCAUGUU 5030
     279  118 AAGCUGAUUUGAUGGAGUU AACUCCAUCAAAUCAGCUU 5031
    1492  119 UCUGGGUUCAGAUGAUAUA UAUAUCAUCUGAACCCAGA 5032
    2195  120 UUACUUCACUCUAGGAAUG CAUUCCUAGAGUGAAGUAA 5033
    1424  121 AGGAAUCUUUCAGAUGCUG CAGCAUCUGAAAGAUUCCU 5034
     661  122 GCUGAAACAUGCAGUUGUA UACAACUGCAUGUUUCAGC 5035
    1882  123 GUUGCUUGUUCGUGCACAU AUGUGCACGAACAAGCAAC 5036
    1966  124 GGAAGAAAUAGUUGAAGGU ACCUUCAACUAUUUCUUCC 5037
    2259  125 AGGACAAGCCACAAGAUUA UAAUCUUGUGGCUUGUCCU 5038
     832  126 CAUGCGUUCUCCUCAGAUG CAUCUGAGGAGAACGCAUG 5039
    2346  127 GAUGAUCCCAGCUACCGUU AACGGUAGCUGGGAUCAUC 5040
    1653  128 AGCCUGCCAUCUGUGCUCU AGAGCACAGAUGGCAGGCU 5041
    2389  129 UGGAUAUCGCCAGGAUGAU AUCAUCCUGGCGAUAUCCA 5042
    1669  130 UCUUCGUCAUCUGACCAGC GCUGGUCAGAUGACGAAGA 5043
    2123  131 UGUGAACUUGCUCAGGACA UGUCCUGAGCAAGUUCACA 5044
    1521  132 CCUGUGCAGCUGGAAUUCU AGAAUUCCAGCUGCACAGG 5045
    2125  133 UGAACUUGCUCAGGACAAG CUUGUCCUGAGCAAGUUCA 5046
    2503  134 UGCUGACUAUCCAGUUGAU AUCAACUGGAUAGUCAGCA 5047
    1502  135 GAUGAUAUAAAUGUGGUCA UGACCACAUUUAUAUCAUC 5048
    2502  136 GUGCUGACUAUCCAGUUGA UCAACUGGAUAGUCAGCAC 5049
    2506  137 UGACUAUCCAGUUGAUGGG CCCAUCAACUGGAUAGUCA 5050
    2127  138 AACUUGCUCAGGACAAGGA UCCUUGUCCUGAGCAAGUU 5051
    2505  139 CUGACUAUCCAGUUGAUGG CCAUCAACUGGAUAGUCAG 5052
     617  140 GCUCAUCCCACUAAUGUCC GGACAUUAGUGGGAUGAGC 5053
    2504  141 GCUGACUAUCCAGUUGAUG CAUCAACUGGAUAGUCAGC 5054
    1503  142 AUGAUAUAAAUGUGGUCAC GUGACCACAUUUAUAUCAU 5055
     618  143 CUCAUCCCACUAAUGUCCA UGGACAUUAGUGGGAUGAG 5056
    2074  144 GCUUUAUUCUCCCAUUGAA UUCAAUGGGAGAAUAAAGC 5057
    2499  145 CUGGUGCUGACUAUCCAGU ACUGGAUAGUCAGCACCAG 5058
    1406  146 AACUGUCUUUGGACUCUCA UGAGAGUCCAAAGACAGUU 5059
     582  147 AGGGCAUGCAGAUCCCAUC GAUGGGAUCUGCAUGCCCU 5060
    1505  148 GAUAUAAAUGUGGUCACCU AGGUGACCACAUUUAUAUC 5061
    1432  149 UUCAGAUGCUGCAACUAAA UUUAGUUGCAGCAUCUGAA 5062
    1968  150 AAGAAAUAGUUGAAGGUUG CAACCUUCAACUAUUUCUU 5063
    2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGG 5064
     954  152 UGGCCAUCUUUAAGUCUGG CCAGACUUAAAGAUGGCCA 5065
    505 153 AGCUGAUAUUGAUGGACAG CUGUCCAUCAAUAUCAGCU 5066
    2011 154 UCGGGAUGUUCACAACCGA UCGGUUGUGAACAUCCCGA 5067
    1339 155 UGUAGAAGCUGGUGGAAUG CAUUCCACCAGCUUCUACA 5068
    1242 156 UAAAUAUAAUGAGGACCUA UAGGUCCUCAUUAUAUUUA 5069
    567 157 CUGAGACAUUAGAUGAGGG CCCUCAUCUAAUGUCUCAG 5070
    1240 158 AGUAAAUAUAAUGAGGACC GGUCCUCAUUAUAUUUACU 5071
    438 159 UGGAUACCUCCCAAGUCCU AGGACUUGGGAGGUAUCCA 5072
    2445 160 AGGAUGCCUUGGGUAUGGA UCCAUACCCAAGGCAUCCU 5073
    860 161 AUUGUACGUACCAUGCAGA UCUGCAUGGUACGUACAAU 5074
    1413 162 UUUGGACUCUCAGGAAUCU AGAUUCCUGAGAGUCCAAA 5075
    1800 163 UUGGAUUGAUUCGAAAUCU AGAUUUCGAAUCAAUCCAA 5076
    2037 164 UCAGAGGACUAAAUACCAU AUGGUAUUUAGUCCUCUGA 5077
    2443 165 CCAGGAUGCCUUGGGUAUG CAUACCCAAGGCAUCCUGG 5078
    2471 166 AUGGAACAUGAGAUGGGUG CACCCAUCUCAUGUUCCAU 5079
    1792 167 GGCUACUGUUGGAUUGAUU AAUCAAUCCAACAGUAGCC 5080
    2547 168 AGGACCUCAUGGAUGGGCU AGCCCAUCCAUGAGGUCCU 5081
    1662 169 UCUGUGCUCUUCGUCAUCU AGAUGACGAAGAGCACAGA 5082
    288 170 UGAUGGAGUUGGACAUGGC GCCAUGUCCAACUCCAUCA 5083
    579 171 AUGAGGGCAUGCAGAUCCC GGGAUCUGCAUGCCCUCAU 5084
    2508 172 ACUAUCCAGUUGAUGGGCU AGCCCAUCAACUGGAUAGU 5085
    580 173 UGAGGGCAUGCAGAUCCCA UGGGAUCUGCAUGCCCUCA 5086
    2388 174 UUGGAUAUCGCCAGGAUGA UCAUCCUGGCGAUAUCCAA 5087
    2543 175 GCCCAGGACCUCAUGGAUG CAUCCAUGAGGUCCUGGGC 5088
    708 176 AACUUGCCACACGUGCAAU AUUGCACGUGUGGCAAGUU 5089
    447 177 CCCAAGUCCUGUAUGAGUG CACUCAUACAGGACUUGGG 5090
    654 178 CACAGAUGCUGAAACAUGC GCAUGUUUCAGCAUCUGUG 5091
    912 179 CUGGGACCUUGCAUAACCU AGGUUAUGCAAGGUCCCAG 5092
    1009 180 AGUGGAUUCUGUGUUGUUU AAACAACACAGAAUCCACU 5093
    1354 181 AAUGCAAGCUUUAGGACUU AAGUCCUAAAGCUUGCAUU 5094
    1969 182 AGAAAUAGUUGAAGGUUGU ACAACCUUCAACUAUUUCU 5095
    1959 183 UCCGCAUGGAAGAAAUAGU ACUAUUUCUUCCAUGCGGA 5096
    557 184 GCUAUGUUCCCUGAGACAU AUGUCUCAGGGAACAUAGC 5097
    403 185 UCUGAGUGGUAAAGGCAAU AUUGCCUUUACCACUCAGA 5098
    1356 186 UGCAAGCUUUAGGACUUCA UGAAGUCCUAAAGCUUGCA 5099
    517 187 UGGACAGUAUGCAAUGACU AGUCAUUGCAUACUGUCCA 5100
    1238 188 UUAGUAAAUAUAAUGAGGA UCCUCAUUAUAUUUACUAA 5101
    843 189 CUCAGAUGGUGUCUGCUAU AUAGCAGACACCAUCUGAG 5102
    496 190 AGAACAAGUAGCUGAUAUU AAUAUCAGCUACUUGUUCU 5103
    2387 191 CUUGGAUAUCGCCAGGAUG CAUCCUGGCGAUAUCCAAG 5104
    1660 192 CAUCUGUGCUCUUCGUCAU AUGACGAAGAGCACAGAUG 5105
    2497 193 CCCUGGUGCUGACUAUCCA UGGAUAGUCAGCACCAGGG 5106
    1870 194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGU 5107
    2353 195 UCUUGGACUUGAUAUUGGU ACCAAUAUCAAGUCCAAGA 5108
    2401 196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCC 5109
    878 197 AAUACAAAUGAUGUAGAAA UUUCUACAUCAUUUGUAUU 5110
    647 198 GAACCAUCACAGAUGCUGA UCAGCAUCUGUGAUGGUUC 5111
    1998 199 UUCACAUCCUAGCUCGGGA UCCCGAGCUAGGAUGUGAA 5112
    588 200 UGCAGAUCCCAUCUACACA UGUGUAGAUGGGAUCUGCA 5113
    2042  201 GGACUAAAUACCAUUCCAU AUGGAAUGGUAUUUAGUCC 5114
     855  202 CUGCUAUUGUACGUACCAU AUGGUACGUACAAUAGCAG 5115
    2038  203 CAGAGGACUAAAUACCAUU AAUGGUAUUUAGUCCUCUG 5116
    1786  204 GAUAAAGGCUACUGUUGGA UCCAACAGUAGCCUUUAUC 5117
    1501  205 AGAUGAUAUAAAUGUGGUC GACCACAUUUAUAUCAUCU 5118
    1834  206 AAAUCAUGCACCUUUGCGU ACGCAAAGGUGCAUGAUUU 5119
    1157  207 ACGACAGACUGCCUUCAAA UUUGAAGGCAGUCUGUCGU 5120
    1239  208 UAGUAAAUAUAAUGAGGAC GUCCUCAUUAUAUUUACUA 5121
    1248  209 UAAUGAGGACCUAUACUUA UAAGUAUAGGUCCUCAUUA 5122
     660  210 UGCUGAAACAUGCAGUUGU ACAACUGCAUGUUUCAGCA 5123
     285  211 AUUUGAUGGAGUUGGACAU AUGUCCAACUCCAUCAAAU 5124
    1582  212 CUGCCAAGUGGGUGGUAUA UAUACCACCCACUUGGCAG 5125
    1735  213 UGGACUACCAGUUGUGGUU AACCACAACUGGUAGUCCA 5126
     771  214 UUAAUAAGGCUGCAGUUAU AUAACUGCAGCCUUAUUAA 5127
    1060  215 ACAUCAAGAAGGAGCUAAA UUUAGCUCCUUCUUGAUGU 5128
    2390  216 GGAUAUCGCCAGGAUGAUC GAUCAUCCUGGCGAUAUCC 5129
    2186  217 CUGACAGAGUUACUUCACU AGUGAAGUAACUCUGUCAG 5130
    1632  218 GUGACAGGGAAGACAUCAC GUGAUGUCUUCCCUGUCAC 5131
     619  219 UCAUCCCACUAAUGUCCAG CUGGACAUUAGUGGGAUGA 5132
    1656  220 CUGCCAUCUGUGCUCUUCG CGAAGAGCACAGAUGGCAG 5133
    1506  221 AUAUAAAUGUGGUCACCUG CAGGUGACCACAUUUAUAU 5134
    2494  222 CCACCCUGGUGCUGACUAU AUAGUCAGCACCAGGGUGG 5135
    1666  223 UGCUCUUCGUCAUCUGACC GGUCAGAUGACGAAGAGCA 5136
    1635  224 ACAGGGAAGACAUCACUGA UCAGUGAUGUCUUCCCUGU 5137
     294  225 AGUUGGACAUGGCCAUGGA UCCAUGGCCAUGUCCAACU 5138
     641  226 UUGGCUGAACCAUCACAGA UCUGUGAUGGUUCAGCCAA 5139
     576  227 UAGAUGAGGGCAUGCAGAU AUCUGCAUGCCCUCAUCUA 5140
     577  228 AGAUGAGGGCAUGCAGAUC GAUCUGCAUGCCCUCAUCU 5141
    1661  229 AUCUGUGCUCUUCGUCAUC GAUGACGAAGAGCACAGAU 5142
     707  230 GAACUUGCCACACGUGCAA UUGCACGUGUGGCAAGUUC 5143
    1657  231 CCAUCUGUGCUCUUCGUCA UGACGAAGAGCACAGAUGG 5144
    1185  232 AUGGCAACCAAGAAAGCAA UUGCUUUCUUGGUUGCCAU 5145
     664  233 GAAACAUGCAGUUGUAAAC GUUUACAACUGCAUGUUUC 5146
    1749  234 UGGUUAAGCUCUUACACCC GGGUGUAAGAGCUUAACCA 5147
    1234  235 AGCUUUAGUAAAUAUAAUG CAUUAUAUUUACUAAAGCU 5148
     691  236 CUAUCAAGAUGAUGCAGAA UUCUGCAUCAUCUUGAUAG 5149
    1387  237 AAGUCAACGUCUUGUUCAG CUGAACAAGACGUUGACUU 5150
    1382  238 GAUCCAAGUCAACGUCUUG CAAGACGUUGACUUGGAUC 5151
     828  239 CUAUCAUGCGUUCUCCUCA UGAGGAGAACGCAUGAUAG 5152
    1244  240 AAUAUAAUGAGGACCUAUA UAUAGGUCCUCAUUAUAUU 5153
    1304  241 GUGCUAUCUGUCUGCUCUA UAGAGCAGACAGAUAGCAC 5154
     812  242 GAAGCUUCCAGACACGCUA UAGCGUGUCUGGAAGCUUC 5155
    1558  243 UAAUUAUAAGAACAAGAUG CAUCUUGUUCUUAUAAUUA 5156
     879  244 AUACAAAUGAUGUAGAAAC GUUUCUACAUCAUUUGUAU 5157
    1311  245 CUGUCUGCUCUAGUAAUAA UUAUUACUAGAGCAGACAG 5158
     856  246 UGCUAUUGUACGUACCAUG CAUGGUACGUACAAUAGCA 5159
    1296  247 UGCUGAAGGUGCUAUCUGU ACAGAUAGCACCUUCAGCA 5160
     960  248 UCUUUAAGUCUGGAGGCAU AUGCCUCCAGACUUAAAGA 5161
    2049  249 AUACCAUUCCAUUGUUUGU ACAAACAAUGGAAUGGUAU 5162
    1791  250 AGGCUACUGUUGGAUUGAU AUCAAUCCAACAGUAGCCU 5163
     783  251 CAGUUAUGGUCCAUCAGCU AGCUGAUGGACCAUAACUG 5164
    1569  252 ACAAGAUGAUGGUCUGCCA UGGCAGACCAUCAUCUUGU 5165
    2224  253 GACAUAUGCAGCUGCUGUU AACAGCAGCUGCAUAUGUC 5166
     934  254 CCAUCAUCGUGAGGGCUUA UAAGCCCUCACGAUGAUGG 5167
    1378  255 GACAGAUCCAAGUCAACGU ACGUUGACUUGGAUCUGUC 5168
     569  256 GAGACAUUAGAUGAGGGCA UGCCCUCAUCUAAUGUCUC 5169
    1722  257 UUCGCCUUCACUAUGGACU AGUCCAUAGUGAAGGCGAA 5170
    1483  258 UGUUCAGCUUCUGGGUUCA UGAACCCAGAAGCUGAACA 5171
    2352  259 AUCUUGGACUUGAUAUUGG CCAAUAUCAAGUCCAAGAU 5172
     719  260 CGUGCAAUCCCUGAACUGA UCAGUUCAGGGAUUGCACG 5173
     762  261 AGGUGGUGGUUAAUAAGGC GCCUUAUUAACCACCACCU 5174
     599  262 UCUACACAGUUUGAUGCUG CAGCAUCAAACUGUGUAGA 5175
    1704  263 AGAUGGCCCAGAAUGCAGU ACUGCAUUCUGGGCCAUCU 5176
    2270  264 CAAGAUUACAAGAAACGGC GCCGUUUCUUGUAAUCUUG 5177
     662  265 CUGAAACAUGCAGUUGUAA UUACAACUGCAUGUUUCAG 5178
     396  266 CUCCUUCUCUGAGUGGUAA UUACCACUCAGAGAAGGAG 5179
    1199  267 AGCAAGCUCAUCAUACUGG CCAGUAUGAUGAGCUUGCU 5180
    1560  268 AUUAUAAGAACAAGAUGAU AUCAUCUUGUUCUUAUAAU 5181
    1310  269 UCUGUCUGCUCUAGUAAUA UAUUACUAGAGCAGACAGA 5182
    1233  270 AAGCUUUAGUAAAUAUAAU AUUAUAUUUACUAAAGCUU 5183
    1330  271 GCCGGCUAUUGUAGAAGCU AGCUUCUACAAUAGCCGGC 5184
    1312  272 UGUCUGCUCUAGUAAUAAG CUUAUUACUAGAGCAGACA 5185
    1556  273 AAUAAUUAUAAGAACAAGA UCUUGUUCUUAUAAUUAUU 5186
    2438  274 UAUGGCCAGGAUGCCUUGG CCAAGGCAUCCUGGCCAUA 5187
    1826  275 UGUCCCGCAAAUCAUGCAC GUGCAUGAUUUGCGGGACA 5188
    1397  276 CUUGUUCAGAACUGUCUUU AAAGACAGUUCUGAACAAG 5189
    3181  277 GCUGUGAUACGAUGCUUCA UGAAGCAUCGUAUCACAGC 5190
    1912  278 GCGCCGUACGUCCAUGGGU ACCCAUGGACGUACGGCGC 5191
     846  279 AGAUGGUGUCUGCUAUUGU ACAAUAGCAGACACCAUCU 5192
    1404  280 AGAACUGUCUUUGGACUCU AGAGUCCAAAGACAGUUCU 5193
     586  281 CAUGCAGAUCCCAUCUACA UGUAGAUGGGAUCUGCAUG 5194
    1469  282 CUCCUUGGGACUCUUGUUC GAACAAGAGUCCCAAGGAG 5195
     380  283 GGUGCCACUACCACAGCUC GAGCUGUGGUAGUGGCACC 5196
    1345  284 AGCUGGUGGAAUGCAAGCU AGCUUGCAUUCCACCAGCU 5197
    1863  285 CCAUUCCACGACUAGUUCA UGAACUAGUCGUGGAAUGG 5198
     635  286 CAGCGUUUGGCUGAACCAU AUGGUUCAGCCAAACGCUG 5199
     959  287 AUCUUUAAGUCUGGAGGCA UGCCUCCAGACUUAAAGAU 5200
    2440  288 UGGCCAGGAUGCCUUGGGU ACCCAAGGCAUCCUGGCCA 5201
     877  289 GAAUACAAAUGAUGUAGAA UUCUACAUCAUUUGUAUUC 5202
    2556  290 UGGAUGGGCUGCCUCCAGG CCUGGAGGCAGCCCAUCCA 5203
    1916  291 CGUACGUCCAUGGGUGGGA UCCCACCCAUGGACGUACG 5204
     850  292 GGUGUCUGCUAUUGUACGU ACGUACAAUAGCAGACACC 5205
    1303  293 GGUGCUAUCUGUCUGCUCU AGAGCAGACAGAUAGCACC 5206
    1726  294 CCUUCACUAUGGACUACCA UGGUAGUCCAUAGUGAAGG 5207
    1477  295 GACUCUUGUUCAGCUUCUG CAGAAGCUGAACAAGAGUC 5208
     598  296 AUCUACACAGUUUGAUGCU AGCAUCAAACUGUGUAGAU 5209
    2062  297 GUUUGUGCAGCUGCUUUAU AUAAAGCAGCUGCACAAAC 5210
    2278  298 CAAGAAACGGCUUUCAGUU AACUGAAAGCCGUUUCUUG 5211
    1877  299 GUUCAGUUGCUUGUUCGUG CACGAACAAGCAACUGAAC 5212
    1499  300 UCAGAUGAUAUAAAUGUGG CCACAUUUAUAUCAUCUGA 5213
    1136  301 AAUGUUAAAUUCUUGGCUA UAGCCAAGAAUUUAACAUU 5214
    1494  302 UGGGUUCAGAUGAUAUAAA UUUAUAUCAUCUGAACCCA 5215
    1972  303 AAUAGUUGAAGGUUGUACC GGUACAACCUUCAACUAUU 5216
     668  304 CAUGCAGUUGUAAACUUGA UCAAGUUUACAACUGCAUG 5217
    2945  305 AAUCUGAAUAAAGUGUAAC GUUACACUUUAUUCAGAUU 5218
    2492  306 CACCACCCUGGUGCUGACU AGUCAGCACCAGGGUGGUG 5219
     293  307 GAGUUGGACAUGGCCAUGG CCAUGGCCAUGUCCAACUC 5220
    1905  308 AUACCCAGCGCCGUACGUC GACGUACGGCGCUGGGUAU 5221
     944  309 GAGGGCUUACUGGCCAUCU AGAUGGCCAGUAAGCCCUC 5222
     581  310 GAGGGCAUGCAGAUCCCAU AUGGGAUCUGCAUGCCCUC 5223
    1454  311 GAAGGGAUGGAAGGUCUCC GGAGACCUUCCAUCCCUUC 5224
    2254  312 GUCUGAGGACAAGCCACAA UUGUGGCUUGUCCUCAGAC 5225
    1837  313 UCAUGCACCUUUGCGUGAG CUCACGCAAAGGUGCAUGA 5226
    1425  314 GGAAUCUUUCAGAUGCUGC GCAGCAUCUGAAAGAUUCC 5227
    1372  315 UCACCUGACAGAUCCAAGU ACUUGGAUCUGUCAGGUGA 5228
    1298  316 CUGAAGGUGCUAUCUGUCU AGACAGAUAGCACCUUCAG 5229
    1674  317 GUCAUCUGACCAGCCGACA UGUCGGCUGGUCAGAUGAC 5230
    1864  318 CAUUCCACGACUAGUUCAG CUGAACUAGUCGUGGAAUG 5231
    2404  319 UGAUCCUAGCUAUCGUUCU AGAACGAUAGCUAGGAUCA 5232
    1992  320 GAGCCCUUCACAUCCUAGC GCUAGGAUGUGAAGGGCUC 5233
     578  321 GAUGAGGGCAUGCAGAUCC GGAUCUGCAUGCCCUCAUC 5234
    3091  322 AUGGGUAGGGUAAAUCAGU ACUGAUUUACCCUACCCAU 5235
     720  323 GUGCAAUCCCUGAACUGAC GUCAGUUCAGGGAUUGCAC 5236
    2054  324 AUUCCAUUGUUUGUGCAGC GCUGCACAAACAAUGGAAU 5237
     374  325 CAUUCUGGUGCCACUACCA UGGUAGUGGCACCAGAAUG 5238
     686  326 UACCAUGCAGAAUACAAAU AUUUGUAUUCUGCAUGGUA 5239
    1716  327 AUGCAGUUCGCCUUCACUA UAGUGAAGGCGAACUGCAU 5240
     950  328 UUACUGGCCAUCUUUAAGU ACUUAAAGAUGGCCAGUAA 5241
    1489  329 GCUUCUGGGUUCAGAUGAU AUCAUCUGAACCCAGAAGC 5242
    1451  330 CAGGAAGGGAUGGAAGGUC GACCUUCCAUCCCUUCCUG 5243
    1181  331 GCUUAUGGCAACCAAGAAA UUUCUUGGUUGCCAUAAGC 5244
    1633  332 UGACAGGGAAGACAUCACU AGUGAUGUCUUCCCUGUCA 5245
    2394  333 AUCGCCAGGAUGAUCCUAG CUAGGAUCAUCCUGGCGAU 5246
    1322  334 AGUAAUAAGCCGGCUAUUG CAAUAGCCGGCUUAUUACU 5247
     884  335 AAUGAUGUAGAAACAGCUC GAGCUGUUUCUACAUCAUU 5248
    2255  336 UCUGAGGACAAGCCACAAG CUUGUGGCUUGUCCUCAGA 5249
    1466  337 GGUCUCCUUGGGACUCUUG CAAGAGUCCCAAGGAGACC 5250
    1399  338 UGUUCAGAACUGUCUUUGG CCAAAGACAGUUCUGAACA 5251
     378  339 CUGGUGCCACUACCACAGC GCUGUGGUAGUGGCACCAG 5252
    1920  340 GUCCAUGGGUGGGACACAG CUGUGUCCCACCCAUGGAC 5253
    1085  341 GUGCGUUUAGCUGGUGGGC GCCCACCAGCUAAACGCAC 5254
     865  342 ACGUACCAUGCAGAAUACA UGUAUUCUGCAUGGUACGU 5255
    2015  343 GAUGUUCACAACCGAAUUG CAAUUCGGUUGUGAACAUC 5256
    1195  344 AGAAAGCAAGCUCAUCAUA UAUGAUGAGCUUGCUUUCU 5257
    1484  345 GUUCAGCUUCUGGGUUCAG CUGAACCCAGAAGCUGAAC 5258
    1855  346 GCAGGGUGCCAUUCCACGA UCGUGGAAUGGCACCCUGC 5259
    1341  347 UAGAAGCUGGUGGAAUGCA UGCAUUCCACCAGCUUCUA 5260
    1963  348 CAUGGAAGAAAUAGUUGAA UUCAACUAUUUCUUCCAUG 5261
    2362  349 UGAUAUUGGUGCCCAGGGA UCCCUGGGCACCAAUAUCA 5262
     584  350 GGCAUGCAGAUCCCAUCUA UAGAUGGGAUCUGCAUGCC 5263
    1613  351 CGUACUGUCCUUCGGGCUG CAGCCCGAAGGACAGUACG 5264
    1155  352 UUACGACAGACUGCCUUCA UGAAGGCAGUCUGUCGUAA 5265
     334  353 UAGUCACUGGCAGCAACAG CUGUUGCUGCCAGUGACUA 5266
    1031  354 GCCAUUACAACUCUCCACA UGUGGAGAGUUGUAAUGGC 5267
    1725  355 GCCUUCACUAUGGACUACC GGUAGUCCAUAGUGAAGGC 5268
    2018  356 GUUCACAACCGAAUUGUUA UAACAAUUCGGUUGUGAAC 5269
     914  357 GGGACCUUGCAUAACCUUU AAAGGUUAUGCAAGGUCCC 5270
    2264  358 AAGCCACAAGAUUACAAGA UCUUGUAAUCUUGUGGCUU 5271
     343  359 GCAGCAACAGUCUUACCUG CAGGUAAGACUGUUGCUGC 5272
    1056  360 UAUUACAUCAAGAAGGAGC GCUCCUUCUUGAUGUAAUA 5273
     772  361 UAAUAAGGCUGCAGUUAUG CAUAACUGCAGCCUUAUUA 5274
     763  362 GGUGGUGGUUAAUAAGGCU AGCCUUAUUAACCACCACC 5275
     628  363 UAAUGUCCAGCGUUUGGCU AGCCAAACGCUGGACAUUA 5276
     399  364 CUUCUCUGAGUGGUAAAGG CCUUUACCACUCAGAGAAG 5277
    1682  365 ACCAGCCGACACCAAGAAG CUUCUUGGUGUCGGCUGGU 5278
     441  366 AUACCUCCCAAGUCCUGUA UACAGGACUUGGGAGGUAU 5279
    1729  367 UCACUAUGGACUACCAGUU AACUGGUAGUCCAUAGUGA 5280
    1902  368 AGGAUACCCAGCGCCGUAC GUACGGCGCUGGGUAUCCU 5281
    1637  369 AGGGAAGACAUCACUGAGC GCUCAGUGAUGUCUUCCCU 5282
    2391  370 GAUAUCGCCAGGAUGAUCC GGAUCAUCCUGGCGAUAUC 5283
     501  371 AAGUAGCUGAUAUUGAUGG CCAUCAAUAUCAGCUACUU 5284
    1358  372 CAAGCUUUAGGACUUCACC GGUGAAGUCCUAAAGCUUG 5285
    1821  373 CCCUUUGUCCCGCAAAUCA UGAUUUGCGGGACAAAGGG 5286
     575  374 UUAGAUGAGGGCAUGCAGA UCUGCAUGCCCUCAUCUAA 5287
     528  375 CAAUGACUCGAGCUCAGAG CUCUGAGCUCGAGUCAUUG 5288
    2433  376 GUGGAUAUGGCCAGGAUGC GCAUCCUGGCCAUAUCCAC 5289
    1497  377 GUUCAGAUGAUAUAAAUGU ACAUUUAUAUCAUCUGAAC 5290
    2134  378 UCAGGACAAGGAAGCUGCA UGCAGCUUCCUUGUCCUGA 5291
    2160  379 UUGAAGCUGAGGGAGCCAC GUGGCUCCCUCAGCUUCAA 5292
     291  380 UGGAGUUGGACAUGGCCAU AUGGCCAUGUCCAACUCCA 5293
     657  381 AGAUGCUGAAACAUGCAGU ACUGCAUGUUUCAGCAUCU 5294
    1575  382 UGAUGGUCUGCCAAGUGGG CCCACUUGGCAGACCAUCA 5295
     667  383 ACAUGCAGUUGUAAACUUG CAAGUUUACAACUGCAUGU 5296
    2190  384 CAGAGUUACUUCACUCUAG CUAGAGUGAAGUAACUCUG 5297
     532  385 GACUCGAGCUCAGAGGGUA UACCCUCUGAGCUCGAGUC 5298
     953  386 CUGGCCAUCUUUAAGUCUG CAGACUUAAAGAUGGCCAG 5299
    3188  387 UACGAUGCUUCAAGAGAAA UUUCUCUUGAAGCAUCGUA 5300
    2301  388 UGACCAGCUCUCUCUUCAG CUGAAGAGAGAGCUGGUCA 5301
    2310  389 CUCUCUUCAGAACAGAGCC GGCUCUGUUCUGAAGAGAG 5302
    2287  390 GCUUUCAGUUGAGCUGACC GGUCAGCUCAACUGAAAGC 5303
    1927  391 GGGUGGGACACAGCAGCAA UUGCUGCUGUGUCCCACCC 5304
     712  392 UGCCACACGUGCAAUCCCU AGGGAUUGCACGUGUGGCA 5305
    2121  393 UCUGUGAACUUGCUCAGGA UCCUGAGCAAGUUCACAGA 5306
    2898  394 UGAGUAAUGGUGUAGAACA UGUUCUACACCAUUACUCA 5307
    1799  395 GUUGGAUUGAUUCGAAAUC GAUUUCGAAUCAAUCCAAC 5308
    1036  396 UACAACUCUCCACAACCUU AAGGUUGUGGAGAGUUGUA 5309
     449  397 CAAGUCCUGUAUGAGUGGG CCCACUCAUACAGGACUUG 5310
    1452  398 AGGAAGGGAUGGAAGGUCU AGACCUUCCAUCCCUUCCU 5311
    1203  399 AGCUCAUCAUACUGGCUAG CUAGCCAGUAUGAUGAGCU 5312
    1357  400 GCAAGCUUUAGGACUUCAC GUGAAGUCCUAAAGCUUGC 5313
    1512  401 AUGUGGUCACCUGUGCAGC GCUGCACAGGUGACCACAU 5314
     275  402 ACUCAAGCUGAUUUGAUGG CCAUCAAAUCAGCUUGAGU 5315
     299  403 GACAUGGCCAUGGAACCAG CUGGUUCCAUGGCCAUGUC 5316
    1241  404 GUAAAUAUAAUGAGGACCU AGGUCCUCAUUAUAUUUAC 5317
    1961  405 CGCAUGGAAGAAAUAGUUG CAACUAUUUCUUCCAUGCG 5318
    1436  406 GAUGCUGCAACUAAACAGG CCUGUUUAGUUGCAGCAUC 5319
    2469  407 UGAUGGAACAUGAGAUGGG CCCAUCUCAUGUUCCAUCA 5320
     760  408 CCAGGUGGUGGUUAAUAAG CUUAUUAACCACCACCUGG 5321
    2257  409 UGAGGACAAGCCACAAGAU AUCUUGUGGCUUGUCCUCA 5322
     952  410 ACUGGCCAUCUUUAAGUCU AGACUUAAAGAUGGCCAGU 5323
    2283  411 AACGGCUUUCAGUUGAGCU AGCUCAACUGAAAGCCGUU 5324
    1794  412 CUACUGUUGGAUUGAUUCG CGAAUCAAUCCAACAGUAG 5325
    1745  413 GUUGUGGUUAAGCUCUUAC GUAAGAGCUUAACCACAAC 5326
    1211  414 AUACUGGCUAGUGGUGGAC GUCCACCACUAGCCAGUAU 5327
    2549  415 GACCUCAUGGAUGGGCUGC GCAGCCCAUCCAUGAGGUC 5328
    2007  416 UAGCUCGGGAUGUUCACAA UUGUGAACAUCCCGAGCUA 5329
    2474  417 GAACAUGAGAUGGGUGGCC GGCCACCCAUCUCAUGUUC 5330
    1712  418 CAGAAUGCAGUUCGCCUUC GAAGGCGAACUGCAUUCUG 5331
    1919  419 ACGUCCAUGGGUGGGACAC GUGUCCCACCCAUGGACGU 5332
    1000  420 UGGUUCACCAGUGGAUUCU AGAAUCCACUGGUGAACCA 5333
    2392  421 AUAUCGCCAGGAUGAUCCU AGGAUCAUCCUGGCGAUAU 5334
    1449  422 AACAGGAAGGGAUGGAAGG CCUUCCAUCCCUUCCUGUU 5335
    2294  423 GUUGAGCUGACCAGCUCUC GAGAGCUGGUCAGCUCAAC 5336
    1135  424 AAAUGUUAAAUUCUUGGCU AGCCAAGAAUUUAACAUUU 5337
    1333  425 GGCUAUUGUAGAAGCUGGU ACCAGCUUCUACAAUAGCC 5338
    1743  426 CAGUUGUGGUUAAGCUCUU AAGAGCUUAACCACAACUG 5339
     600  427 CUACACAGUUUGAUGCUGC GCAGCAUCAAACUGUGUAG 5340
     670  428 UGGAGGCAUUCCUGCCCUG CAGGGCAGGAAUGCCUCCA 5341
    3137  429 GGACAGUUUACCAGUUGCC GGCAACUGGUAAACUGUCC 5342
     372  430 UCCAUUCUGGUGCCACUAC GUAGUGGCACCAGAAUGGA 5343
    1761  431 UACACCCACCAUCCCACUG CAGUGGGAUGGUGGGUGUA 5344
    1650  432 CUGAGCCUGCCAUCUGUGC GCACAGAUGGCAGGCUCAG 5345
     972  433 GAGGCAUUCCUGCCCUGGU ACCAGGGCAGGAAUGCCUC 5346
    1147  434 CUUGGCUAUUACGACAGAC GUCUGUCGUAAUAGCCAAG 5347
     565  435 CCCUGAGACAUUAGAUGAG CUCAUCUAAUGUCUCAGGG 5348
     525  436 AUGCAAUGACUCGAGCUCA UGAGCUCGAGUCAUUGCAU 5349
    1599  437 UAGAGGCUCUUGUGCGUAC GUACGCACAAGAGCCUCUA 5350
    2199  438 UUCACUCUAGGAAUGAAGG CCUUCAUUCCUAGAGUGAA 5351
    2261  439 GACAAGCCACAAGAUUACA UGUAAUCUUGUGGCUUGUC 5352
     705  440 CAGAACUUGCCACACGUGC GCACGUGUGGCAAGUUCUG 5353
     916  441 GACCUUGCAUAACCUUUCC GGAAAGGUUAUGCAAGGUC 5354
     385  442 CACUACCACAGCUCCUUCU AGAAGGAGCUGUGGUAGUG 5355
    3076  443 CUAUUUGGGAUAUGUAUGG CCAUACAUAUCCCAAAUAG 5356
    1396  444 UCUUGUUCAGAACUGUCUU AAGACAGUUCUGAACAAGA 5357
    2447  445 GAUGCCUUGGGUAUGGACC GGUCCAUACCCAAGGCAUC 5358
    1338  446 UUGUAGAAGCUGGUGGAAU AUUCCACCAGCUUCUACAA 5359
    2215  447 AGGUGUGGCGACAUAUGCA UGCAUAUGUCGCCACACCU 5360
     722  448 GCAAUCCCUGAAUCGACAA UUGUCAGUUCAGGGAUUGC 5361
    1316  449 UGCUCUAGUAAUAAGCCGG CCGGCUUAUUACUAGAGCA 5362
    1687  450 CCGACACCAAGAAGCAGAG CUCUGCUUCUUGGUGUCGG 5363
     697  451 AGAUGAUGCAGAACUUGCC GGCAAGUUCUGCAUCAUCU 5364
    2517  452 UUGAUGGGCUGCCAGAUCU AGAUCUGGCAGCCCAUCAA 5365
    1685  453 AGCCGACACCAAGAAGCAG CUGCUUCUUGGUGUCGGCU 5366
    3090  454 UAUGGGUAGGGUAAAUCAG CUGAUUUACCCUACCCAUA 5367
    1205  455 CUCAUCAUACUGGCUAGUG CACUAGCCAGUAUGAUGAG 5368
    1153  456 UAUUACGACAGACUGCCUU AAGGCAGUCUGUCGUAAUA 5369
     723  457 CAAUCCCUGAACUGACAAA UUUGUCAGUUCAGGGAUUG 5370
    1468  458 UCUCCUUGGGACUCUUGUU AACAAGAGUCCCAAGGAGA 5371
    2480  459 GAGAUGGGUGGCCACCACC GGUGGUGGCCACCCAUCUC 5372
    1856  460 CAGGGUGCCAUUCCACGAC GUCGUGGAAUGGCACCCUG 5373
    2193  461 AGUUACUUCACUCUAGGAA UUCCUAGAGUGAAGUAACU 5374
    2355  462 UUGGACUUGAUAUUGGUGC GCACCAAUAUCAAGUCCAA 5375
    1995  463 CCCUUCACAUCCUAGCUCG CGAGCUAGGAUGUGAAGGG 5376
     821  464 AGACACGCUAUCAUGCGUU AACGCAUGAUAGCGUGUCU 5377
    1715  465 AAUGCAGUUCGCCUUCACU AGUGAAGGCGAACUGCAUU 5378
    1182  466 CUUAUGGCAACCAAGAAAG CUUUCUUGGUUGCCAUAAG 5379
     445  467 CUCCCAAGUCCUGUAUGAG CUCAUACAGGACUUGGGAG 5380
    1759  468 CUUACACCCACCAUCCCAC GUGGGAUGGUGGGUGUAAG 5381
    1461  469 UGGAAGGUCUCCUUGGGAC GUCCCAAGGAGACCUUCCA 5382
    1993  470 AGCCCUUCACAUCCUAGCU AGCUAGGAUGUGAAGGGCU 5383
    2558  471 GAUGGGCUGCCUCCAGGUG CACCUGGAGGCAGCCCAUC 5384
    1488  472 AGCUUCUGGGUUCAGAUGA UCAUCUGAACCCAGAAGCU 5385
    1652  473 GAGCCUGCCAUCUGUGCUC GAGCACAGAUGGCAGGCUC 5386
     963  474 UUAAGUCUGGAGGCAUUCC GGAAUGCCUCCAGACUUAA 5387
    1520  475 ACCUGUGCAGCUGGAAUUC GAAUUCCAGCUGCACAGGU 5388
    1828  476 UCCCGCAAAUCAUGCACCU AGGUGCAUGAUUUGCGGGA 5389
    2214  477 AAGGUGUGGCGACAUAUGC GCAUAUGUCGCCACACCUU 5390
    2155  478 AGCUAUUGAAGCUGAGGGA UCCCUCAGCUUCAAUAGCU 5391
     332  479 GUUAGUCACUGGCAGCAAC GUUGCUGCCAGUGACUAAC 5392
    1878  480 UUCAGUUGCUUGUUCGUGC GCACGAACAAGCAACUGAA 5393
    1573  481 GAUGAUGGUCUGCCAAGUG CACUUGGCAGACCAUCAUC 5394
    1446  482 CUAAACAGGAAGGGAUGGA UCCAUCCCUUCCUGUUUAG 5395
    1868  483 CCACGACUAGUUCAGUUGC GCAACUGAACUAGUCGUGG 5396
    1873  484 ACUAGUUCAGUUGCUUGUU AACAAGCAACUGAACUAGU 5397
    1002  485 GUUCACCAGUGGAUUCUGU ACAGAAUCCACUGGUGAAC 5398
     408  486 GUGGUAAAGGCAAUCCUGA UCAGGAUUGCCUUUACCAC 5399
     287  487 UUGAUGGAGUUGGACAUGG CCAUGUCCAACUCCAUCAA 5400
    2128  488 ACUUGCUCAGGACAAGGAA UUCCUUGUCCUGAGCAAGU 5401
    2513  489 CCAGUUGAUGGGCUGCCAG CUGGCAGCCCAUCAACUGG 5402
    1196  490 GAAAGCAAGCUCAUCAUAC GUAUGAUGAGCUUGCUUUC 5403
     572  491 ACAUUAGAUGAGGGCAUGC GCAUGCCCUCAUCUAAUGU 5404
     622  492 UCCCACUAAUGUCCAGCGU ACGCUGGACAUUAGUGGGA 5405
    1187  493 GGCAACCAAGAAAGCAAGC GCUUGCUUUCUUGGUUGCC 5406
    1971  494 AAAUAGUUGAAGGUUGUAC GUACAACCUUCAACUAUUU 5407
    3083  495 GGAUAUGUAUGGGUAGGGU ACCCUACCCAUACAUAUCC 5408
    2944  496 UAAUCUGAAUAAAGUGUAA UUACACUUUAUUCAGAUUA 5409
    1894  497 UGCACAUCAGGAUACCCAG CUGGGUAUCCUGAUGUGCA 5410
    1323  498 GUAAUAAGCCGGCUAUUGU ACAAUAGCCGGCUUAUUAC 5411
    1202  499 AAGCUCAUCAUACUGGCUA UAGCCAGUAUGAUGAGCUU 5412
     718  500 ACGUGCAAUCCCUGAACUG CAGUUCAGGGAUUGCACGU 5413
    1744  501 AGUUGUGGUUAAGCUCUUA UAAGAGCUUAACCACAACU 5414
     756  502 AGGACCAGGUGGUGGUUAA UUAACCACCACCUGGUCCU 5415
    1317  503 GCUCUAGUAAUAAGCCGGC GCCGGCUUAUUACUAGAGC 5416
     284  504 GAUUUGAUGGAGUUGGACA UGUCCAACUCCAUCAAAUC 5417
     886  505 UGAUGUAGAAACAGCUCGU ACGAGCUGUUUCUACAUCA 5418
    2430  506 CUGGUGGAUAUGGCCAGGA UCCUGGCCAUAUCCACCAG 5419
    1207  507 CAUCAUACUGGCUAGUGGU ACCACUAGCCAGUAUGAUG 5420
     592  508 GAUCCCAUCUACACAGUUU AAACUGUGUAGAUGGGAUC 5421
     824  509 CACGCUAUCAUGCGUUCUC GAGAACGCAUGAUAGCGUG 5422
     519  510 GACAGUAUGCAAUGACUCG CGAGUCAUUGCAUACUGUC 5423
    3166  511 AAGUUGUUGUAACCUGCUG CAGCAGGUUACAACAACUU 5424
    1151  512 GCUAUUACGACAGACUGCC GGCAGUCUGUCGUAAUAGC 5425
    2566  513 GCCUCCAGGUGACAGCAAU AUUGCUGUCACCUGGAGGC 5426
     453  514 UCCUGUAUGAGUGGGAACA UGUUCCCACUCAUACAGGA 5427
     587  515 AUGCAGAUCCCAUCUACAC GUGUAGAUGGGAUCUGCAU 5428
     630  516 UUUCCCAUCAUCGUGAGGG CCCUCACGAUGAUGGGAAA 5429
    1585  517 CCAAGUGGGUGGUAUAGAG CUCUAUACCACCCACUUGG 5430
     915  518 GGACCUUGCAUAACCUUUC GAAAGGUUAUGCAAGGUCC 5431
     446  519 UCCCAAGUCCUGUAUGAGU ACUCAUACAGGACUUGGGA 5432
    1869  520 CACGACUAGUUCAGUUGCU AGCAACUGAACUAGUCGUG 5433
    1960  521 CCGCAUGGAAGAAAUAGUU AACUAUUUCUUCCAUGCGG 5434
    1708  522 GGCCCAGAAUGCAGUUCGC GCGAACUGCAUUCUGGGCC 5435
     306  523 CCAUGGAACCAGACAGAAA UUUCUGUCUGGUUCCAUGG 5436
    2281  524 GAAACGGCUUUCAGUUGAG CUCAACUGAAAGCCGUUUC 5437
    3082  525 GGGAUAUGUAUGGGUAGGG CCCUACCCAUACAUAUCCC 5438
    1473  526 UUGGGACUCUUGUUCAGCU AGCUGAACAAGAGUCCCAA 5439
     559  527 UAUGUUCCCUGAGACAUUA UAAUGUCUCAGGGAACAUA 5440
    1416  528 GGACUCUCAGGAAUCUUUC GAAAGAUUCCUGAGAGUCC 5441
    2145  529 AAGCUGCAGAAGCUAUUGA UCAAUAGCUUCUGCAGCUU 5442
    1994  530 GCCCUUCACAUCCUAGCUC GAGCUAGGAUGUGAAGGGC 5443
    1702  531 AGAGAUGGCCCAGAAUGCA UGCAUUCUGGGCCAUCUCU 5444
     417  532 GCAAUCCUGAGGAAGAGGA UCCUCUUCCUCAGGAUUGC 5445
    2444  533 CAGGAUGCCUUGGGUAUGG CCAUACCCAAGGCAUCCUG 5446
     555  534 CUGCUAUGUUCCCUGAGAC GUCUCAGGGAACAUAGCAG 5447
    2019  535 UUCACAACCGAAUUGUUAU AUAACAAUUCGGUUGUGAA 5448
    1197  536 AAAGCAAGCUCAUCAUACU AGUAUGAUGAGCUUGCUUU 5449
     415  537 AGGCAAUCCUGAGGAAGAG CUCUUCCUCAGGAUUGCCU 5450
    2061  538 UGUUUGUGCAGCUGCUUUA UAAAGCAGCUGCACAAACA 5451
    1352  539 GGAAUGCAAGCUUUAGGAC GUCCUAAAGCUUGCAUUCC 5452
    1331  540 CCGGCUAUUGUAGAAGCUG CAGCUUCUACAAUAGCCGG 5453
    1325  541 AAUAAGCCGGCUAUUGUAG CUACAAUAGCCGGCUUAUU 5454
    1486  542 UCAGCUUCUGGGUUCAGAU AUCUGAACCCAGAAGCUGA 5455
     454  543 CCUGUAUGAGUGGGAACAG CUGUUCCCACUCAUACAGG 5456
     490  544 CACUCAAGAACAAGUAGCU AGCUACUUGUUCUUGAGUG 5457
    1996  545 CCUUCACAUCCUAGCUCGG CCGAGCUAGGAUGUGAAGG 5458
    1839  546 AUGCACCUUUGCGUGAGCA UGCUCACGCAAAGGUGCAU 5459
    1888  547 UGUUCGUGCACAUCAGGAU AUCCUGAUGUGCACGAACA 5460
    1879  548 UCAGUUGCUUGUUCGUGCA UGCACGAACAAGCAACUGA 5461
    1829  549 CCCGCAAAUCAUGCACCUU AAGGUGCAUGAUUUGCGGG 5462
     281  550 GCUGAUUUGAUGGAGUUGG CCAACUCCAUCAAAUCAGC 5463
    2598  551 AUAGAGGCUCUUGUGCGUA UACGCACAAGAGCCUCUAU 5464
    2135  552 CAGGACAAGGAAGCUGCAG CUGCAGCUUCCUUGUCCUG 5465
    1755  553 AGCUCUUACACCCACCAUC GAUGGUGGGUGUAAGAGCU 5466
     651  554 CAUCACAGAUGCUGAAACA UGUUUCAGCAUCUGUGAUG 5467
    1335  555 CUAUUGUAGAAGCUGGUGG CCACCAGCUUCUACAAUAG 5468
    2541  556 AUGCCCAGGACCUCAUGGA UCCAUGAGGUCCUGGGCAU 5469
     531  557 UGACUCGAGCUCAGAGGGU ACCCUCUGAGCUCGAGUCA 5470
     606  558 AGUUUGAUGCUGCUCAUCC GGAUGAGCAGCAUCAAACU 5471
    1620  559 UCCUUCGGGCUGGUGACAG CUGUCACCAGCCCGAAGGA 5472
    2211  560 AUGAAGGUGUGGCGACAUA UAUGUCGCCACACCUUCAU 5473
    2293  561 AGUUGAGCUGACCAGCUCU AGAGCUGGUCAGCUCAACU 5474
     455  562 CUGUAUGAGUGGGAACAGG CCUGUUCCCACUCAUACAG 5475
     540  563 CUCAGAGGGUACGAGCUGC GCAGCUCGUACCCUCUGAG 5476
     416  564 GGCAAUCCUGAGGAAGAGG CCUCUUCCUCAGGAUUGCC 5477
    1210  565 CAUACUGGCUAGUGGUGGA UCCACCACUAGCCAGUAUG 5478
    2262  566 ACAAGCCACAAGAUUACAA UUGUAAUCUUGUGGCUUGU 5479
    1604  567 GCUCUUGUGCGUACUGUCC GGACAGUACGCACAAGAGC 5480
     435  568 AUGUGGAUACCUCCCAAGU ACUUGGGAGGUAUCCACAU 5481
    2060  569 UUGUUUGUGCAGCUGCUUU AAAGCAGCUGCACAAACAA 5482
    2225  570 ACAUAUGCAGCUGCUGUUU AAACAGCAGCUGCAUAUGU 5483
     481  571 UCAGUCCUUCACUCAAGAA UUCUUGAGUGAAGGACUGA 5484
     917  572 ACCUUGCAUAACCUUUCCC GGGAAAGGUUAUGCAAGGU 5485
    2221  573 GGCGACAUAUGCAGCUGCU AGCAGCUGCAUAUGUCGCC 5486
     849  574 UGGUGUCUGCUAUUGUACG CGUACAAUAGCAGACACCA 5487
     562  575 GUUCCCUGAGACAUUAGAU AUCUAAUGUCUCAGGGAAC 5488
    1787  576 AUAAAGGCUACUGUUGGAU AUCCAACAGUAGCCUUUAU 5489
    1860  577 GUGCCAUUCCACGACUAGU ACUAGUCGUGGAAUGGCAC 5490
    1590  578 UGGGUGGUAUAGAGGCUCU AGAGCCUCUAUACCACCCA 5491
     955  579 GGCCAUCUUUAAGUCUGGA UCCAGACUUAAAGAUGGCC 5492
    2365  580 UAUUGGUGCCCAGGGAGAA UUCUCCCUGGGCACCAAUA 5493
     534  581 CUCGAGCUCAGAGGGUACG CGUACCCUCUGAGCUCGAG 5494
     706  582 AGAACUUGCCACACGUGCA UGCACGUGUGGCAAGUUCU 5495
    1740  583 UACCAGUUGUGGUUAAGCU AGCUUAACCACAACUGGUA 5496
     638  584 CGUUUGGCUGAACCAUCAC GUGAUGGUUCAGCCAAACG 5497
    1334  585 GCUAUUGUAGAAGCUGGUG CACCAGCUUCUACAAUAGC 5498
     971  586 GGAGGCAUUCCUGCCCUGG CCAGGGCAGGAAUGCCUCC 5499
    2493  587 ACCACCCUGGUGCUGACUA UAGUCAGCACCAGGGUGGU 5500
    1814  588 AAUCUUGCCCUUUGUCCCG CGGGACAAAGGGCAAGAUU 5501
    1088  589 CGUUUAGCUGGUGGGCUGC GCAGCCCACCAGCUAAACG 5502
    2292  590 CAGUUGAGCUGACCAGCUC GAGCUGGUCAGCUCAACUG 5503
    1504  591 UGAUAUAAAUGUGGUCACC GGUGACCACAUUUAUAUCA 5504
     404  592 CUGAGUGGUAAAGGCAAUC GAUUGCCUUUACCACUCAG 5505
    1301  593 AAGGUGCUAUCUGUCUGCU AGCAGACAGAUAGCACCUU 5506
    2004  594 UCCUAGCUCGGGAUGUUCA UGAACAUCCCGAGCUAGGA 5507
     277  595 UCAAGCUGAUUUGAUGGAG CUCCAUCAAAUCAGCUUGA 5508
    2304  596 CCAGCUCUCUCUUCAGAAC GUUCUGAAGAGAGAGCUGG 5509
     300  597 ACAUGGCCAUGGAACCAGA UCUGGUUCCAUGGCCAUGU 5510
    1906  598 UACCCAGCGCCGUACGUCC GGACGUACGGCGCUGGGUA 5511
    1973  599 AUAGUUGAAGGUUGUACCG CGGUACAACCUUCAACUAU 5512
    1360  600 AGCUUUAGGACUUCACCUG CAGGUGAAGUCCUAAAGCU 5513
    2094  601 ACAUCCAAAGAGUAGCUGC GCAGCUACUCUUUGGAUGU 5514
     920  602 UUGCAUAACCUUUCCCAUC GAUGGGAAAGGUUAUGCAA 5515
    1707  603 UGGCCCAGAAUGCAGUUCG CGAACUGCAUUCUGGGCCA 5516
    1808  604 AUUCGAAAUCUUGCCCUUU AAAGGGCAAGAUUUCGAAU 5517
    1326  605 AUAAGCCGGCUAUUGUAGA UCUACAAUAGCCGGCUUAU 5518
    1158  606 CGACAGACUGCCUUCAAAU AUUUGAAGGCAGUCUGUCG 5519
     781  607 UGCAGUUAUGGUCCAUCAG CUGAUGGACCAUAACUGCA 5520
     607  608 GUUUGAUGCUGCUCAUCCC GGGAUGAGCAGCAUCAAAC 5521
     627  609 CUAAUGUCCAGCGUUUGGC GCCAAACGCUGGACAUUAG 5522
     500  610 CAAGUAGCUGAUAUUGAUG CAUCAAUAUCAGCUACUUG 5523
    2185  611 UCUGACAGAGUUACUUCAC GUGAAGUAACUCUGUCAGA 5524
    1592  612 GGUGGUAUAGAGGCUCUUG CAAGAGCCUCUAUACCACC 5525
     758  613 GACCAGGUGGUGGUUAAUA UAUUAACCACCACCUGGUC 5526
    2551  614 CCUCAUGGAUGGGCUGCCU AGGCAGCCCAUCCAUGAGG 5527
    1409  615 UGUCUUUGGACUCUCAGGA UCCUGAGAGUCCAAAGACA 5528
     497  616 GAACAAGUAGCUGAUAUUG CAAUAUCAGCUACUUGUUC 5529
     381  617 GUGCCACUACCACAGCUCC GGAGCUGUGGUAGUGGCAC 5530
    1841  618 GCACCUUUGCGUGAGCAGG CCUGCUCACGCAAAGGUGC 5531
    1368  619 GACUUCACCUGACAGAUCC GGAUCUGUCAGGUGAAGUC 5532
    2047  620 AAAUACCAUUCCAUUGUUU AAACAAUGGAAUGGUAUUU 5533
     492  621 CUCAAGAACAAGUAGCUGA UCAGCUACUUGUUCUUGAG 5534
    2118  622 UCCUCUGUGAACUUGCUCA UGAGCAAGUUCACAGAGGA 5535
     968  623 UCUGGAGGCAUUCCUGCCC GGGCAGGAAUGCCUCCAGA 5536
     965  624 AAGUCUGGAGGCAUUCCUG CAGGAAUGCCUCCAGACUU 5537
    1977  625 UUGAAGGUUGUACCGGAGC GCUCCGGUACAACCUUCAA 5538
    2001  626 ACAUCCUAGCUCGGGAUGU ACAUCCCGAGCUAGGAUGU 5539
    1191  627 ACCAAGAAAGCAAGCUCAU AUGAGCUUGCUUUCUUGGU 5540
     640  628 UUUGGCUGAACCAUCACAG CUGUGAUGGUUCAGCCAAA 5541
     715  629 CACACGUGCAAUCCCUGAA UUCAGGGAUUGCACGUGUG 5542
    1204  630 GCUCAUCAUACUGGCUAGU ACUAGCCAGUAUGAUGAGC 5543
    3093  631 GGGUAGGGUAAAUCAGUAA UUACUGAUUUACCCUACCC 5544
    1371  632 UUCACCUGACAGAUCCAAG CUUGGAUCUGUCAGGUGAA 5545
     409  633 UGGUAAAGGCAAUCCUGAG CUCAGGAUUGCCUUUACCA 5546
    2405  634 GAUCCUAGCUAUCGUUCUU AAGAACGAUAGCUAGGAUC 5547
    1671  635 UUCGUCAUCUGACCAGCCG CGGCUGGUCAGAUGACGAA 5548
    1427  636 AAUCUUUCAGAUGCUGCAA UUGCAGCAUCUGAAAGAUU 5549
    1717  637 UGCAGUUCGCCUUCACUAU AUAGUGAAGGCGAACUGCA 5550
    2400  638 AGGAUGAUCCUAGCUAUCG CGAUAGCUAGGAUCAUCCU 5551
    2305  639 CAGCUCUCUCUUCAGAACA UGUUCUGAAGAGAGAGCUG 5552
    1928  640 GGUGGGACACAGCAGCAAU AUUGCUGCUGUGUCCCACC 5553
    2399  641 CAGGAUGAUCCUAGCUAUC GAUAGCUAGGAUCAUCCUG 5554
     426  642 AGGAAGAGGAUGUGGAUAC GUAUCCACAUCCUCUUCCU 5555
    1309  643 AUCUGUCUGCUCUAGUAAU AUUACUAGAGCAGACAGAU 5556
     925  644 UAACCUUUCCCAUCAUCGU ACGAUGAUGGGAAAGGUUA 5557
    2072  645 CUGCUUUAUUCUCCCAUUG CAAUGGGAGAAUAAAGCAG 5558
    2939  646 AAUUGUAAUCUGAAUAAAG CUUUAUUCAGAUUACAAUU 5559
    1480  647 UCUUGUUCAGCUUCUGGGU ACCCAGAAGCUGAACAAGA 5560
    1889  648 GUUCGUGCACAUCAGGAUA UAUCCUGAUGUGCACGAAC 5561
     699  649 AUGAUGCAGAACUUGCCAC GUGGCAAGUUCUGCAUCAU 5562
     506  650 GCUGAUAUUGAUGGACAGU ACUGUCCAUCAAUAUCAGC 5563
    1750  651 GGUUAAGCUCUUACACCCA UGGGUGUAAGAGCUUAACC 5564
    1820  652 GCCCUUUGUCCCGCAAAUC GAUUUGCGGGACAAAGGGC 5565
     541  653 UCAGAGGGUACGAGCUGCU AGCAGCUCGUACCCUCUGA 5566
     665  654 AAACAUGCAGUUGUAAACU AGUUUACAACUGCAUGUUU 5567
    1817  655 CUUGCCCUUUGUCCCGCAA UUGCGGGACAAAGGGCAAG 5568
    2275  656 UUACAAGAAACGGCUUUCA UGAAAGCCGUUUCUUGUAA 5569
    2426  657 CACUCUGGUGGAUAUGGCC GGCCAUAUCCACCAGAGUG 5570
     958  658 CAUCUUUAAGUCUGGAGGC GCCUCCAGACUUAAAGAUG 5571
    1657  659 UGCCAUCUGUGCUCUUCGU ACGAAGAGCACAGAUGGCA 5572
    1146  660 UCUUGGCUAUUACGACAGA UCUGUCGUAAUAGCCAAGA 5573
    3078  661 AUUUGGGAUAUGUAUGGGU ACCCAUACAUAUCCCAAAU 5574
    1008  662 CAGUGGAUUCUGUGUUGUU AACAACACAGAAUCCACUG 5575
    1621  663 CCUUCGGGCUGGUGACAGG CCUGUCACCAGCCCGAAGG 5576
    1932  664 GGACACAGCAGCAAUUUGU ACAAAUUGCUGCUGUGUCC 5577
    1909  665 CCAGCGCCGUACGUCCAUG CAUGGACGUACGGCGCUGG 5578
    2279  666 AAGAAACGGCUUUCAGUUG CAACUGAAAGCCGUUUCUU 5579
     574  667 AUUAGAUGAGGGCAUGCAG CUGCAUGCCCUCAUCUAAU 5580
    2303  668 ACCAGCUCUCUCUUCAGAA UUCUGAAGAGAGAGCUGGU 5581
     784  669 AGUUAUGGUCCAUCAGCUU AAGCUGAUGGACCAUAACU 5582
    2507  670 GACUAUCCAGUUGAUGGGC GCCCAUCAACUGGAUAGUC 5583
     995  671 AUGCUUGGUUCACCAGUGG CCACUGGUGAACCAAGCAU 5584
    2006  672 CUAGCUCGGGAUGUUCACA UGUGAACAUCCCGAGCUAG 5585
    1757  673 CUCUUACACCCACCAUCCC GGGAUGGUGGGUGUAAGAG 5586
    2129  674 CUUGCUCAGGACAAGGAAG CUUCCUUGUCCUGAGCAAG 5587
    2272  675 AGAUUACAAGAAACGGCUU AAGCCGUUUCUUGUAAUCU 5588
     389  676 ACCACAGCUCCUUCUCUGA UCAGAGAAGGAGCUGUGGU 5589
    1435  677 AGAUGCUGCAACUAAACAG CUGUUUAGUUGCAGCAUCU 5590
    1752  678 UUAAGCUCUUACACCCACC GGUGGGUGUAAGAGCUUAA 5591
     773  679 AAUAAGGCUGCAGUUAUGG CCAUAACUGCAGCCUUAUU 5592
    3080  680 UUGGGAUAUGUAUGGGUAG CUACCCAUACAUAUCCCAA 5593
    3174  681 GUAACCUGCUGUGAUACGA UCGUAUCACAGCAGGUUAC 5594
    1578  682 UGGUCUGCCAAGUGGGUGG CCACCCACUUGGCAGACCA 5595
     398  683 CCUUCUCUGAGUGGUAAAG CUUUACCACUCAGAGAAGG 5596
    2153  684 GAAGCUAUUGAAGCUGAGG CCUCAGCUUCAAUAGCUUC 5597
     702  685 AUGCAGAACUUGCCACACG CGUGUGGCAAGUUCUGCAU 5598
     503  686 GUAGCUGAUAUUGAUGGAC GUCCAUCAAUAUCAGCUAC 5599
     276  687 CUCAAGCUGAUUUGAUGGA UCCAUCAAAUCAGCUUGAG 5600
    1962  688 GCAUGGAAGAAAUAGUUGA UCAACUAUUUCUUCCAUGC 5601
    1347  689 CUGGUGGAAUGCAAGCUUU AAAGCUUGCAUUCCACCAG 5602
    2544  690 CCCAGGACCUCAUGGAUGG CCAUCCAUGAGGUCCUGGG 5603
    3079  691 UUUGGGAUAUGUAUGGGUA UACCCAUACAUAUCCCAAA 5604
    3164  692 CAAAGUUGUUGUAACCUGC GCAGGUUACAACAACUUUG 5605
    2026  693 CCGAAUUGUUAUCAGAGGA UCCUCUGAUAACAAUUCGG 5606
    2938  694 UAAUUGUAAUCUGAAUAAA UUUAUUCAGAUUACAAUUA 5607
    2940  695 AUUGUAAUCUGAAUAAAGU ACUUUAUUCAGAUUACAAU 5608
    2027  696 CGAAUUGUUAUCAGAGGAC GUCCUCUGAUAACAAUUCG 5609
     448  697 CCAAGUCCUGUAUGAGUGG CCACUCAUACAGGACUUGG 5610
    1328  698 AAGCCGGCUAUUGUAGAAG CUUCUACAAUAGCCGGCUU 5611
    2406  699 AUCCUAGCUAUCGUUCUUU AAAGAACGAUAGCUAGGAU 5612
     924  700 AUAACCUUUCCCAUCAUCG CGAUGAUGGGAAAGGUUAU 5613
    1584  701 GCCAAGUGGGUGGUAUAGA UCUAUACCACCCACUUGGC 5614
    1871  702 CGACUAGUUCAGUUGCUUG CAAGCAACUGAACUAGUCG 5615
     999  703 UUGGUUCACCAGUGGAUUC GAAUCCACUGGUGAACCAA 5616
    1400  704 GUUCAGAACUGUCUUUGGA UCCAAAGACAGUUCUGAAC 5617
    3180  705 UGCUGUGAUACGAUGCUUC GAAGCAUCGUAUCACAGCA 5618
    2569  706 UCCAGGUGACAGCAAUCAG CUGAUUGCUGUCACCUGGA 5619
     787  707 UAUGGUCCAUCAGCUUUCU AGAAAGCUGAUGGACCAUA 5620
    1861  708 UGCCAUUCCACGACUAGUU AACUAGUCGUGGAAUGGCA 5621
    1190  709 AACCAAGAAAGCAAGCUCA UGAGCUUGCUUUCUUGGUU 5622
    1557  710 AUAAUUAUAAGAACAAGAU AUCUUGUUCUUAUAAUUAU 5623
    1751  711 GUUAAGCUCUUACACCCAC GUGGGUGUAAGAGCUUAAC 5624
    2897  712 UUGAGUAAUGGUGUAGAAC GUUCUACACCAUUACUCAA 5625
    2217  713 GUGUGGCGACAUAUGCAGC GCUGCAUAUGUCGCCACAC 5626
    2302  714 GACCAGCUCUCUCUUCAGA UCUGAAGAGAGAGCUGGUC 5627
    1984  715 UUGUACCGGAGCCCUUCAC GUGAAGGGCUCCGGUACAA 5628
     302  716 AUGGCCAUGGAACCAGACA UGUCUGGUUCCAUGGCCAU 5629
    2431  717 UGGUGGAUAUGGCCAGGAU AUCCUGGCCAUAUCCACCA 5630
    2183  718 CCUCUGACAGAGUUACUUC GAAGUAACUCUGUCAGAGG 5631
    2404  719 AUGAUCCUAGCUAUCGUUC GAACGAUAGCUAGGAUCAU 5632
     788  720 AUGGUCCAUCAGCUUUCUA UAGAAAGCUGAUGGACCAU 5633
    1476  721 GGACUCUUGUUCAGCUUCU AGAAGCUGAACAAGAGUCC 5634
     827  722 GCUAUCAUGCGUUCUCCUC GAGGAGAACGCAUGAUAGC 5635
    2299  723 GCUGACCAGCUCUCUCUUC GAAGAGAGAGCUGGUCAGC 5636
    1891  724 UCGUGCACAUCAGGAUACC GGUAUCCUGAUGUGCACGA 5637
    2196  725 UACUUCACUCUAGGAAUGA UCAUUCCUAGAGUGAAGUA 5638
     663  726 UGAAACAUGCAGUUGUAAA UUUACAACUGCAUGUUUCA 5639
    1028  727 UAUGCCAUUACAACUCUCC GGAGAGUUGUAAUGGCAUA 5640
    2032  728 UGUUAUCAGAGGACUAAAU AUUUAGUCCUCUGAUAACA 5641
    1459  729 GAUGGAAGGUCUCCUUGGG CCCAAGGAGACCUUCCAUC 5642
    2095  730 CAUCCAAAGAGUAGCUGCA UGCAGCUACUCUUUGGAUG 5643
    1686  731 GCCGACACCAAGAAGCAGA UCUGCUUCUUGGUGUCGGC 5644
    1412  732 CUUUGGACUCUCAGGAAUC GAUUCCUGAGAGUCCAAAG 5645
    2473  733 GGAACAUGAGAUGGGUGGC GCCACCCAUCUCAUGUUCC 5646
    1080  734 UGGCAGUGCGUUUAGCUGG CCAGCUAAACGCACUGCCA 5647
    2143  735 GGAAGCUGCAGAAGCUAUU AAUAGCUUCUGCAGCUUCC 5648
    2203  736 CUCUAGGAAUGAAGGUGUG CACACCUUCAUUCCUAGAG 5649
     548  737 GUACGAGCUGCUAUGUUCC GGAACAUAGCAGCUCGUAC 5650
    1867  738 UCCACGACUAGUUCAGUUG CAACUGAACUAGUCGUGGA 5651
     843  739 CCUCAGAUGGUGUCUGCUA UAGCAGACACCAUCUGAGG 5652
    2120  740 CUCUGUGAACUUGCUCAGG CCUGAGCAAGUUCACAGAG 5653
     782  741 GCAGUUAUGGUCCAUCAGC GCUGAUGGACCAUAACUGC 5654
    1758  742 UCUUACACCCACCAUCCCA UGGGAUGGUGGGUGUAAGA 5655
    2396  743 CGCCAGGAUGAUCCUAGCU AGCUAGGAUCAUCCUGGCG 5656
    1373  744 CACCUGACAGAUCCAAGUC GACUUGGAUCUGUCAGGUG 5657
    1518  745 UCACCUGUGCAGCUGGAAU AUUCCAGCUGCACAGGUGA 5658
    2557  746 GGAUGGGCUGCCUCCAGGU ACCUGGAGGCAGCCCAUCC 5659
    1987  747 UACCGGAGCCCUUCACAUC GAUGUGAAGGGCUCCGGUA 5660
     568  748 UGAGACAUUAGAUGAGGGC GCCCUCAUCUAAUGUCUCA 5661
    2201  749 CACUCUAGGAAUGAAGGUG CACCUUCAUUCCUAGAGUG 5662
     609  750 UUGAUGCUGCUCAUCCCAC GUGGGAUGAGCAGCAUCAA 5663
     400  751 UUCUCUGAGUGGUAAAGGC GCCUUUACCACUCAGAGAA 5664
     331  752 UGUUAGUCACUGGCAGCAA UUGCUGCCAGUGACUAACA 5665
    1967  753 GAAGAAAUAGUUGAAGGUU AACCUUCAACUAUUUCUUC 5666
    2198  754 CUUCACUCUAGGAAUGAAG CUUCAUUCCUAGAGUGAAG 5667
    1493  755 CUGGGUUCAGAUGAUAUAA UUAUAUCAUCUGAACCCAG 5668
    2260  756 GGACAAGCCACAAGAUUAC GUAAUCUUGUGGCUUGUCC 5669
    2496  757 ACCCUGGUGCUGACUAUCC GGAUAGUCAGCACCAGGGU 5670
    2361  758 UUGAUAUUGGUGCCCAGGG CCCUGGGCACCAAUAUCAA 5671
     443  759 ACCUCCCAAGUCCUGUAUG CAUACAGGACUUGGGAGGU 5672
     523  760 GUAUGCAAUGACUCGAGCU AGCUCGAGUCAUUGCAUAC 5673
    1742  761 CCAGUUGUGGUUAAGCUCU AGAGCUUAACCACAACUGG 5674
     530  762 AUGACUCGAGCUCAGAGGG CCCUCUGAGCUCGAGUCAU 5675
    3169  763 UUGUUGUAACCUGCUGUGA UCACAGCAGGUUACAACAA 5676
    1385  764 CCAAGUCAACGUCUUGUUC GAACAAGACGUUGACUUGG 5677
    2036  765 AUCAGAGGACUAAAUACCA UGGUAUUUAGUCCUCUGAU 5678
    3088  766 UGUAUGGGUAGGGUAAAUC GAUUUACCCUACCCAUACA 5679
    1850  767 CGUGAGCAGGGUGCCAUUC GAAUGGCACCCUGCUCACG 5680
    2518  768 UGAUGGGCUGCCAGAUCUG CAGAUCUGGCAGCCCAUCA 5681
    1886  769 CUUGUUCGUGCACAUCAGG CCUGAUGUGCACGAACAAG 5682
     650  770 CCAUCACAGAUGCUGAAAC GUUUCAGCAUCUGUGAUGG 5683
    3139  771 ACAGUUUACCAGUUGCCUU AAGGCAACUGGUAAACUGU 5684
    2025  772 ACCGAAUUGUUAUCAGAGG CCUCUGAUAACAAUUCGGU 5685
    1082  773 GCAGUGCGUUUAGCUGGUG CACCAGCUAAACGCACUGC 5686
    2475  774 AACAUGAGAUGGGUGGCCA UGGCCACCCAUCUCAUGUU 5687
    1375  775 CCUGACAGAUCCAAGUCAA UUGACUUGGAUCUGUCAGG 5688
    2013  776 GGGAUGUUCACAACCGAAU AUUCGGUUGUGAACAUCCC 5689
    1802  777 GGAUUGAUUCGAAAUCUUG CAAGAUUUCGAAUCAAUCC 5690
    2144  778 GAAGCUGCAGAAGCUAUUG CAAUAGCUUCUGCAGCUUC 5691
     529  779 AAUGACUCGAGCUCAGAGG CCUCUGAGCUCGAGUCAUU 5692
    1482  780 UUGUUCAGCUUCUGGGUUC GAACCCAGAAGCUGAACAA 5693
    1546  781 CCUCACUUGCAAUAAUUAU AUAAUUAUUGCAAGUGAGG 5694
     845  782 CAGAUGGUGUCUGCUAUUG CAAUAGCAGACACCAUCUG 5695
     487  783 CUUCACUCAAGAACAAGUA UACUUGUUCUUGAGUGAAG 5696
     652  784 AUCACAGAUGCUGAAACAU AUGUUUCAGCAUCUGUGAU 5697
    1720  785 AGUUCGCCUUCACUAUGGA UCCAUAGUGAAGGCGAACU 5698
     951  786 UACUGGCCAUCUUUAAGUC GACUUAAAGAUGGCCAGUA 5699
    1232  787 CAAGCUUUAGUAAAUAUAA UUAUAUUUACUAAAGCUUG 5700
    2265  788 AGCCACAAGAUUACAAGAA UUCUUGUAAUCUUGUGGCU 5701
    1698  789 AAGCAGAGAUGGCCCAGAA UUCUGGGCCAUCUCUGCUU 5702
     701  790 GAUGCAGAACUUGCCACAC GUGUGGCAAGUUCUGCAUC 5703
    1428  791 AUCUUUCAGAUGCUGCAAC GUUGCAGCAUCUGAAAGAU 5704
    1930  792 UGGGACACAGCAGCAAUUU AAAUUGCUGCUGUGUCCCA 5705
    1379  793 ACAGAUCCAAGUCAACGUC GACGUUGACUUGGAUCUGU 5706
    1936  794 ACAGCAGCAAUUUGUGGAG CUCCACAAAUUGCUGCUGU 5707
    1441  795 UGCAACUAAACAGGAAGGG CCCUUCCUGUUUAGUUGCA 5708
    2132  796 GCUCAGGACAAGGAAGCUG CAGCUUCCUUGUCCUGAGC 5709
    2043  797 GACUAAAUACCAUUCCAUU AAUGGAAUGGUAUUUAGUC 5710
     608  798 UUUGAUGCUGCUCAUCCCA UGGGAUGAGCAGCAUCAAA 5711
     341  799 UGGCAGCAACAGUCUUACC GGUAAGACUGUUGCUGCCA 5712
    1194  800 AAGAAAGCAAGCUCAUCAU AUGAUGAGCUUGCUUUCUU 5713
    2350  801 UGAUCUUGGACUUGAUAUU AAUAUCAAGUCCAAGAUCA 5714
    2948  802 CUGAAUAAAGUGUAACAAU AUUGUUACACUUUAUUCAG 5715
    2044  803 ACUAAAUACCAUUCCAUUG CAAUGGAAUGGUAUUUAGU 5716
     621  804 AUCCCACUAAUGUCCAGCG CGCUGGACAUUAGUGGGAU 5717
     384  805 CCACUACCACAGCUCCUUC GAAGGAGCUGUGGUAGUGG 5718
    1898  806 CAUCAGGAUACCCAGCGCC GGCGCUGGGUAUCCUGAUG 5719
     653  807 UCACAGAUGCUGAAACAUG CAUGUUUCAGCAUCUGUGA 5720
    1846  808 UUUGCGUGAGCAGGGUGCC GGCACCCUGCUCACGCAAA 5721
    2348  809 GCUGAUCUUGGACUUGAUA UAUCAAGUCCAAGAUCAGC 7522
    1150  810 GGCUAUUACGACAGACUGC GCAGUCUGUCGUAAUAGCC 5723
     298  811 GGACAUGGCCAUGGAACCA UGGUUCCAUGGCCAUGUCC 5724
    1568  812 AACAAGAUGAUGGUCUGCC GGCAGACCAUCAUCUUGUU 5725
    1058  813 UUACAUCAAGAAGGAGCUA UAGCUCCUUCUUGAUGUAA 5726
    1835  814 AAUCAUGCACCUUUGCGUG CACGCAAAGGUGCAUGAUU 5727
    1832  815 GCAAAUCAUGCACCUUUGC GCAAAGGUGCAUGAUUUGC 5728
     406  816 GAGUGGUAAAGGCAAUCCU AGGAUUGCCUUUACCACUC 5729
    1723  817 UCGCCUUCACUAUGGACUA UAGUCCAUAGUGAAGGCGA 5730
     371  818 AUCCAUUCUGGUGCCACUA UAGUGGCACCAGAAUGGAU 5731
    1899  819 AUCAGGAUACCCAGCGCCG CGGCGCUGGGUAUCCUGAU 5732
     522  820 AGUAUGCAAUGACUCGAGC GCUCGAGUCAUUGCAUACU 5733
    2285  821 CGGCUUUCAGUUGAGCUGA UCAGCUCAACUGAAAGCCG 5734
     779  822 GCUGCAGUUAUGGUCCAUC GAUGGACCAUAACUGCAGC 5735
    2896  823 AUUGAGUAAUGGUGUAGAA UUCUACACCAUUACUCAAU 5736
    2943  824 GUAAUCUGAAUAAAGUGUA UACACUUUAUUCAGAUUAC 5737
     513  825 UUGAUGGACAGUAUGCAAU AUUGCAUACUGUCCAUCAA 5738
    3084  826 GAUAUGUAUGGGUAGGGUA UACCCUACCCAUACAUAUC 5739
    1567  827 GAACAAGAUGAUGGUCUGC GCAGACCAUCAUCUUGUUC 5740
    2034  828 UUAUCAGAGGACUAAAUAC GUAUUUAGUCCUCUGAUAA 5741
    1003  829 UUCACCAGUGGAUUCUGUG CACAGAAUCCACUGGUGAA 5742
    1980  830 AAGGUUGUACCGGAGCCCU AGGGCUCCGGUACAACCUU 5743
    1340  831 GUAGAAGCUGGUGGAAUGC GCAUUCCACCAGCUUCUAC 5744
    1437  832 AUGCUGCAACUAAACAGGA UCCUGUUUAGUUGCAGCAU 5745
    2425  833 UCACUCUGGUGGAUAUGGC GCCAUAUCCACCAGAGUGA 5746
     282  834 CUGAUUUGAUGGAGUUGGA UCCAACUCCAUCAAAUCAG 5747
    1206  835 UCAUCAUACUGGCUAGUGG CCACUAGCCAGUAUGAUGA 5748
    1885  836 GCUUGUUCGUGCACAUCAG CUGAUGUGACGAACAAGC 5749
    1314  837 UCUGCUCUAGUAAUAAGGC GGCUUAUUACUAGAGCAGA 5750
    1308  838 UAUCUGUCUGCUCUAGUAA UUACUAGAGCAGACAGAUA 5751
    1200  839 GCAAGCUCAUCAUACUGGC GCCAGUAUGAUGAGCUUGC 5752
     543  840 AGAGGGUACGAGCUGCUAU AUAGCAGCUCGUACCCUCU 5753
    1609  841 UGUGCGUACUGUCCUUCGG CCGAAGGACAGUACGCACA 5754
    1453  842 GGAAGGGAUGGAAGGUCUC GAGACCUUCCAUCCCUUCC 5755
     833  843 AUGCGUUCUCCUCAGAUGG CCAUCUGAGGAGAACGCAU 5756
    2188  844 GACAGAGUUACUUCACUCU AGAGUGAAGUAACUCUGUC 5757
    1148  845 UUGGCUAUUACGACAGACU AGUCUGUCGUAAUAGCCAA 5758
    1736  846 GGACUACCAGUUGUGGUUA UAACCACAACUGGUAGUCC 5759
    1401  847 UUCAGAACUGUCUUUGGAC GUCCAAAGACAGUUCUGAA 5760
    1677  848 AUCUGACCAGCCGACACCA UGGUGUCGGCUGGUCAGAU 5761
    1934  849 ACACAGCAGCAAUUUGUGG CCACAAAUUGCUGCUGUGU 5762
     388  850 UACCACAGCUCCUUCUCUG CAGAGAAGGAGCUGUGGUA 5763
    1920  851 CUGCCAUGGGUGGGACACA UGUGUCCCACCCAUGGACG 5764
    1747  852 UGUGGUUAAGCUCUUACAC GUGUAAGAGCUUAACCACA 5765
     861  853 UUGUACGUACCAUGCAGAA UUCUGCAUGGUACGUACAA 5766
    1904  854 GAUACCCAGCGCCGUACGU ACGUACGGCGCUGGGUAUC 5767
     831  855 UCAUGCGUUCUCCUCAGAU AUCUGAGGAGAACGCAUGA 5768
    1895  856 GCACAUCAGGAUACCCAGC GCUGGGUAUCCUGAUGUGC 5769
    2273  857 GAUUACAAGAAACGGCUUU AAAGCCGUUUCUUGUAAUC 5770
    1738  858 ACUACCAGUUGUGGUUAAG CUUAACCACAACUGGUAGU 5771
    1395  859 GUCUUGUUCAGAACUGUCU AGACAGUUCUGAACAAGAC 5772
    1675  860 UCAUCUGACCAGCCGACAC GUGUCGGCUGGUCAGAUGA 5773
    1845  861 CUUUGCGUGAGCAGGGUGC GCACCCUGCUCACGCAAAG 5774
    1408  862 CUGUCUUUGGACUCUCAGG CCUGAGAGUCCAAAGACAG 5775
    1059  863 UACAUCAAGAAGGAGCUAA UUAGCUCCUUCUUGAUGUA 5776
    1381  864 AGAUCCAAGUCAACGUCUU AAGACGUUGACUUGGAUCU 5777
    1386  865 CAAGUCAACGUCUUGUUCA UGAACAAGACGUUGACUUG 5778
    1470  866 UCCUUGGGACUCUUGUUCA UGAACAAGAGUCCCAAGGA 5779
    1349  867 GGUGGAAUGCAAGCUUUAG CUAAAGCUUGCAUUCCACC 5780
    1440  868 CUGCAACUAAACAGGAAGG CCUUCCUGUUUAGUUGCAG 5781
    1364  869 UUAGGACUUCACCUGACAG CUGUCAGGUGAAGUCCUAA 5782
     502  870 AGUAGCUGAUAUUGAUGGA UCCAUCAAUAUCAGCUACU 5783
    1246  871 UAUAAUGAGGACCUAUACU AGUAUAGGUCCUCAUUAUA 5784
    3178  872 CCUGCUGUGAUACGAUGCU AGCAUCGUAUCACAGCAGG 5785
    2483  873 AUGGGUGGCCACCACCCUG CAGGGUGGUGGCCACCCAU 5786
    1417  874 GACUCUCAGGAAUCUUUCA UGAAAGAUUCCUGAGAGUC 5787
    1893  875 GUGCACAUCAGGAUACCCA UGGGUAUCCUGAUGUGCAC 5788
     817  876 UUCCAGACACGCUAUCAUG CAUGAUAGCGUGUCUGGAA 5789
     711  877 UUGCCACACGUGCAAUCCC GGGAUUGCACGUGUGGCAA 5790
    1433  878 UCAGAUGCUGCAACUAAAC GUUUAGUUGCAGCAUCUGA 5791
    1362  879 CUUUAGGACUUCACCUGAC GUCAGGUGAAGUCCUAAAG 5792
    1838  880 CAUGCACCUUUGCGUGAGC GCUCACGCAAAGGUGCAUG 5793
    1037  881 ACAACUCUCCACAACCUUU AAAGGUUGUGGAGAGUUGU 5794
    1474  882 UGGGACUCUUGUUCAGCUU AAGCUGAACAAGAGUCCCA 5795
     997  883 GCUUGGUUCACCAGUGGAU AUCCACUGGUGAACCAAGC 5796
     931  884 UUCCCAUCAUCGUGAGGGC GCCCUCACGAUGAUGGGAA 5797
    1313  885 GUCUGCUCUAGUAAUAAGC GCUUAUUACUAGAGCAGAC 5798
    1487  886 CAGCUUCUGGGUUCAGAUG CAUCUGAACCCAGAAGCUG 5799
    1673  887 CGUCAUCUGACCAGCCGAC GUCGGCUGGUCAGAUGACG 5800
     561  888 UGUUCCCUGAGACAUUAGA UCUAAUGUCUCAGGGAACA 5801
    1188  889 GCAACCAAGAAAGCAAGCU AGCUUGCUUUCUUGGUUGC 5802
     292  890 GGAGUUGGACAUGGCCAUG CAUGGCCAUGUCCAACUCC 5803
    1958  891 GUCCGCAUGGAAGAAAUAG CUAUUUCUUCCAUGCGGAC 5804
    2349  892 CUGAUCUUGGACUUGAUAU AUAUCAAGUCCAAGAUCAG 5805
    1460  893 AUGGAAGGUCUCCUUGGGA UCCCAAGGAGACCUUCCAU 5806
    1576  894 GAUGGUCUGCCAAGUGGGU ACCCACUUGGCAGACCAUC 5807
     590  895 ACUAUCAAGAUGAUGCAGA UCUGCAUCAUCUUGAUAGU 5808
     655  896 ACAGAUGCUGAAACAUGCA UGCAUGUUUCAGCAUCUGU 5809
    2290  897 UUCAGUUGAGCUGACCAGC GCUGGUCAGCUCAACUGAA 5810
    1600  898 AGAGGCUCUUGUGCGUACU AGUACGCACAAGAGCCUCU 5811
    2432  899 GGUGGAUAUGGCCAGGAUG CAUCCUGGCCAUAUCCACC 5812
     710  900 CUUGCCACACGUGCAAUCC GGAUUGCACGUGUGGCAAG 5813
    1714  901 GAAUGCAGUUCGCCUUCAC GUGAAGGCGAACUGCAUUC 5814
    2005  902 CCUAGCUCGGGAUGUUCAC GUGAACAUCCCGAGCUAGG 5815
    1728  903 UUCACUAUGGACUACCAGU ACUGGUAGUCCAUAGUGAA 5816
    2482  904 GAUGGGUGGCCACCACCCU AGGGUGGUGGCCACCCAUC 5817
     768  905 UGGUUAAUAAGGCUGCAGU ACUGCAGCCUUAUUAACCA 5818
     693  906 AUCAAGAUGAUGCAGAACU AGUUCUGCAUCAUCUUGAU 5819
    3179  907 CUGCUGUGAUACGAUGCUU AAGCAUCGUAUCACAGCAG 5820
    2448  908 AUGCCUUGGGUAUGGACCC GGGUCCAUACCCAAGGCAU 5821
    3183  909 UGUGAUACGAUGCUUCAAG CUUGAAGCAUCGUAUCACA 5822
    1293  910 GAGUGCUGAAGGUGCUAUC GAUAGCACCUUCAGCACUC 5823
     544  911 GAGGGUACGAGCUGCUAUG CAUAGCAGCUCGUACCCUC 5824
    2937  912 UUAAUUGUAAUCUGAAUAA UUAUUCAGAUUACAAUUAA 5825
    1691  913 CACCAAGAAGCAGAGAUGG CCAUCUCUGCUUCUUGGUG 5826
    1353  914 GAAUGCAAGCUUUAGGACU AGUCCUAAAGCUUGCAUUC 5827
    1843  915 ACCUUUGCGUGAGCAGGGU ACCCUGCUCACGCAAAGGU 5828
    1302  916 AGGUGCUAUCUGUCUGCUC GAGCAGACAGAUAGCACCU 5829
    2130  917 UUGCUCAGGACAAGGAAGC GCUUCCUUGUCCUGAGCAA 5830
    2165  918 GCUGAGGGAGCCACAGCUC GAGCUGUGGCUCCCUCAGC 5831
     387  919 CUACCACAGCUCCUUCUCU AGAGAAGGAGCUGUGGUAG 5832
    2474  920 UGGAACAUGAGAUGGGUGG CCACCCAUCUCAUGUUCCA 5833
     857  921 GCUAUUGUACGUACCAUGC GCAUGGUACGUACAAUAGC 5834
    1816  922 UCUUGCCCUUUGUCCCGCA UGCGGGACAAAGGGCAAGA 5835
    1561  923 UUAUAAGAACAAGAUGAUG CAUCAUCUUGUUCUUAUAA 5836
     811  924 GGAAGCUUCCAGACACGCU AGCGUGUCUGGAAGCUUCC 5837
    1327  925 UAAGCCGGCUAUUGUAGAA UUCUACAAUAGCCGGCUUA 5838
     757  926 GGACCAGGUGGUGGUUAAU AUUAACCACCACCUGGUCC 5839
     507  927 CUGAUAUUGAUGGACAGUA UACUGUCCAUCAAUAUCAG 5840
    3092  928 UGGGUAGGGUAAAUCAGUA UACUGAUUUACCCUACCCA 5841
    2359  929 ACUUGAUAUUGGUGCCCAG CUGGGCACCAAUAUCAAGU 5842
    1753  930 UAAGCUCUUACACCCACCA UGGUGGGUGUAAGAGCUUA 5843
     273  931 CUACUCAAGCUGAUUUGAU AUCAAAUCAGCUUGAGUAG 5844
    1859  932 GGUGCCAUUCCACGACUAG CUAGUCGUGGAAUGGCACC 5845
     296  933 UUGGACAUGGCCAUGGAAC GUUCCAUGGCCAUGUCCAA 5846
     615  934 CUGCUCAUCCCACUAAUGU ACAUUAGUGGGAUGAGCAG 5847
     301  935 CAUGGCCAUGGAACCAGAC GUCUGGUUCCAUGGCCAUG 5848
    1184  936 UAUGGCAACCAAGAAAGCA UGCUUUCUUGGUUGCCAUA 5849
    1006  937 ACCAGUGGAUUCUGUGUUG CAACACAGAAUCCACUGGU 5850
    2189  938 ACAGAGUUACUUCACUCUA UAGAGUGAAGUAACUCUGU 5851
    1365  939 UAGGACUUCACCUGACAGA UCUGUCAGGUGAAGUCCUA 5852
    2442  940 GCCAGGAUGCCUUGGGUAU AUACCCAAGGCAUCCUGGU 5853
    1249  941 AAUGAGGACCUAUACUUAC GUAAGUAUAGGUCCUCAUU 5854
    1144  942 AUUCUUGGCUAUUACGACA UGUCGUAAUAGCCAAGAAU 5855
    2075  943 CUUUAUUCUCCCAUUGAAA UUUCAAUGGGAGAAUAAAG 5856
     504  944 UAGCUGAUAUUGAUGGACA UGUCCAUCAAUAUCAGCUA 5857
    1405  945 GAACUGUCUUUGGACUCUC GAGAGUCCAAAGACAGUUC 5858
     333  946 UUAGUCACUGGCAGCAACA UGUUGCUGCCAGUGACUAA 5859
    1032  947 CCAUUACAACUCUCCACAA UUGUGGAGAGUUGUAAUGG 5860
    1748  948 GUGGUUAAGCUCUUACACC GGUGUAAGAGCUUAACCAC 5861
     283  949 UGAUUUGAUGGAGUUGGAC GUCCAACUCCAUCAAAUCA 5862
    1700  950 GCAGAGAUGGCCCAGAAUG CAUUCUGGGCCAUCUCUGC 5863
    1445  951 ACUAAACAGGAAGGGAUGG CCAUCCCUUCCUGUUUAGU 5864
    1133  952 ACAAAUGUUAAAUUCUUGG CCAAGAAUUUAACAUUUGU 5865
     527  953 GCAAUGACUCGAGCUCAGA UCUGAGCUCGAGUCAUUGC 5866
    2010  954 CUCGGGAUGUUCACAACCG CGGUUGUGAACAUCCCGAG 5867
     851  955 GUGUCUGCUAUUGUACGUA UACGUACAAUAGCAGACAC 5868
     436  956 UGUGGAUACCUCCCAAGUC GACUUGGGAGGUAUCCACA 5869
    2446  957 GGAUGCCUUGGGUAUGGAC GUCCAUACCCAAGGCAUCC 5870
    1142  958 AAAUUCUUGGCUAUUACGA UCGUAAUAGCCAAGAAUUU 5871
     549  959 UACGAGCUGCUAUGUUCCC GGGAACAUAGCAGCUCGUA 5872
    1083  960 CAGUGCGUUUAGCUGGUGG CCACCAGCUAAACGCACUG 5873
     695  961 CAAGAUGAUGCAGAACUUG CAAGUUCUGCAUCAUCUUG 5874
     885  962 AUGAUGUAGAAACAGCUCG CGAGCUGUUUCUACAUCAU 5875
    2067  963 UGCAGCUGCUUUAUUCUCC GGAGAAUAAAGCAGCUGCA 5876
     390  964 CCACAGCUCCUUCUCUGAG CUCAGAGAAGGAGCUGUGG 5877
    1719  965 CAGUUCGCCUUCACUAUGG CCAUAGUGAAGGCGAACUG 5878
     813  966 AAGCUUCCAGACACGCUAU AUAGCGUGUCUGGAAGCUU 5879
    2289  967 UUUCAGUUGAGCUGACCAG CUGGUCAGCUCAACUGAAA 5880
     377  968 UCUGGUGCCACUACCACAG CUGUGGUAGUGGCACCAGA 5881
     826  969 CGCUAUCAUGCGUUCUCCU AGGAGAACGCAUGAUAGCG 5882
    1634  970 GACAGGGAAGACAUCACUG CAGUGAUGUCUUCCCUGUC 5883
    1208  971 AUCAUACUGGCUAGUGGUG CACCACUAGCCAGUAUGAU 5884
    1628  972 GCUGGUGACAGGGAAGACA UGUCUUCCCUGUCACCAGC 5885
    2003  973 AUCCUAGCUCGGGAUGUUC GAACAUCCCGAGCUAGGAU 5886
     452  974 GUCCUGUAUGAGUGGGAAC GUUCCCACUCAUACAGGAC 5887
    3081  975 UGGGAUAUGUAUGGGUAGG CCUACCCAUACAUAUCCCA 5888
    2354  976 CUUGGACUUGAUAUUGGUG CACCAAUAUCAAGUCCAAG 5889
    1822  977 CCUUUGUCCCGCAAAUCAU AUGAUUUGCGGGACAAAGG 5890
    1299  978 UGAAGGUGCUAUCUGUCUG CAGACAGAUAGCACCUUCA 5891
     486  979 CCUUCACUCAAGAACAAGU ACUUGUUCUUGAGUGAAGG 5892
    1463  980 GAAGGUCUCCUUGGGACUC GAGUCCCAAGGAGACCUUC 5893
    2280  981 AGAAACGGCUUUCAGUUGA UCAACUGAAAGCCGUUUCU 5894
    1907  982 ACCCAGCGCCGUACGUCCA UGGACGUACGGCGCUGGGU 5895
     923  983 CAUAACCUUUCCCAUCAUC GAUGAUGGGAAAGGUUAUG 5896
    1979  984 GAAGGUUGUACCGGAGCCC GGGCUCCGGUACAACCUUC 5897
    1827  985 GUCCCGCAAAUCAUGCACC GGUGCAUGAUUUGCGGGAC 5898
    1201  986 CAAGCUCAUCAUACUGGCU AGCCAGUAUGAUGAGCUUG 5899
    1913  987 CGCCGUACGUCCAUGGGUG CACCCAIGGACGIACGGCG 5900
    2191  988 AGAGUUACUUCACUCUAGG CCUAGAGUGAAGUAACUCU 5901
     295  989 GUUGGACAUGGCCAUGGAA UUCCAUGGCCAUGUCCAAC 5902
    1149  990 UGGCUAUUACGACAGACUG CAGUCUGUCGUAAUAGCCA 5903
     533  991 ACUCGAGCUCAGAGGGUAC GUACCCUCUGAGCUCGAGU 5904
     604  992 ACAGUUUGAUGCUGCUCAU AUGAGCAGCAUCAAACUGU 5905
     766  993 GGUGGUUAAUAAGGCUGCA UGCAGCCUUAUUAACCACC 5906
    1823  994 CUUUGUCCCGCAAAUCAUG CAUGAUUUGCGGGACAAAG 5907
    2048  995 AAUACCAUUCCAUUGUUUG CAAACAAUGGAAUGGUAUU 5908
     714  996 CCACACGUGCAAUCCCUGA UCAGGGAUUGCACGUGUGG 5909
    2439  997 AUGGCCAGGAUGCCUUGGG CCCAAGGCAUCCUGGCCAU 5910
    1903  998 GGAUACCCAGCGCCGUACG CGUACGGCGCUGGGUAUCC 5911
    2395  999 UCGCCAGGAUGAUCCUAGC GCUAGGAUCAUCCUGGCGA 5912
     789 1000 UGGUCCAUCAGCUUUCUAA UUAGAAAGCUGAUGGACCA 5913
    3085 1001 AUAUGUAUGGGUAGGGUAA UUACCCUACCCAUACAUAU 5914
    1710 1002 CCCAGAAUGCAGUUCGCCU AGGCGAACUGCAUUCUGGG 5915
    1336 1003 UAUUGUAGAAGCUGGUGGA UCCACCAGCUUCUACAAUA 5916
    3089 1004 GUAUGGGUAGGGUAAAUCA UGAUUUACCCUACCCAUAC 5917
    2351 1005 GAUCUUGGACUUGAUAUUG CAAUAUCAAGUCCAAGAUC 5918
     716 1006 ACACGUGCAAUCCCUGAAC GUUCAGGGAUUGCACGUGU 5919
    1911 1007 AGCGCCGUACGUCCAUGGG CCCAUGGACGUACGGCGCU 5920
    1985 1008 UGUACCGGAGCCCUUCACA UGUGAAGGGCUCCGGUACA 5921
    2516 1009 GUUGAUGGGCUGCCAGAUC GAUCUGGCAGCCCAUCAAC 5922
    1762 1010 ACACCCACCAUCCCACUGG CCAGUGGGAUGGUGGGUGU 5923
    1156 1011 UACGACAGACUGCCUUCAA UUGAAGGCAGUCUGUCGUA 5924
    1887 1012 UUGUUCGUGCACAUCAGGA UCCUGAUGUGCACGAACAA 5925
    1833 1013 CAAAUCAUGCACCUUUGCG CGCAAAGGUGCAUGAUUUG 5926
     967 1014 GUCUGGAGGCAUUCCUGCC GGCAGGAAUGCCUCCAGAC 5927
    1730 1015 CACUAUGGACUACCAGUUG CAACUGGUAGUCCAUAGUG 5928
     829 1016 UAUCAUGCGUUCUCCUCAG CUGAGGAGAACGCAUGAUA 5929
     890 1017 GUAGAAACAGCUCUGGUGA UACAACGAGCUGUUUCUAC 5930
    2181 1018 CUCCUCUGACAGAGUUACU AGUAACUCUGUCAGAGGAG 5931
    2131 1019 UGCUCAGGACAAGGAAGCU AGCUUCCUUGUCCUGAGCA 5932
    1586 1020 CAAGUGGGUGGUAUAGAGG CCUCUAUACCACCCACUUG 5933
     765 1021 UGGUGGUUAAUAAGGCUGC GCAGCCUUAUUAACCACCA 5934
    1369 1022 ACUUCACCUGACAGAUCCA UGGAUCUGUCAGGUGAAGU 5935
    1724 1023 CGCCUUCACUAUGGACUAC GUAGUCCAUAGUGAAGGCG 5936
     834 1024 UGCGUUCUCCUCAGAUGGU ACCAUCUGAGGAGAACGCA 5937
    1983 1025 GUUGUACCGGAGCCCUUCA UGAAGGGCUCCGGUACAAC 5938
    1688 1026 CGACACCAAGAAGCAGAGA UCUCUGCUUCUUGGUGUCG 5939
    1004 1027 UCACCAGUGGAUUCUGUGU ACACAGAAUCCACUGGUGA 5940
    1631 1028 GGUGACAGGGAAGACAUCA UGAUGUCUUCCCUGUCACC 5941
    1319 1029 UCUAGUAAUAAGCCGGCUA UAGCCGGCUUAUUACUAGA 5942
     767 1030 GUGGUUAAUAAGGCUGCAG CUGCAGCCUUAUUAACCAC 5943
     841 1031 UCCUCAGAUGGUGUCUGCU AGCAGACACCAUCUGAGGA 5944
     516 1032 AUGGACAGUAUGCAAUGAC GUCAUUGCAUACUGUCCAU 5945
    1848 1033 UGCGUGAGCAGGGUGCCAU AUGGCACCCUGCUCACGCA 5946
    2202 1034 ACUCUAGGAAUGAAGGUGU ACACCUUCAUUCCUAGAGU 5947
     571 1035 GACAUUAGAUGAGGGCAUG CAUGCCCUCAUCUAAUGUC 5948
    1629 1036 CUGGUGACAGGGAAGACAU AUGUCUUCCCUGUCACCAG 5949
    1806 1037 UGAUUCGAAAUCUUGCCCU AGGGCAAGAUUUCGAAUCA 5950
    1756 1038 GCUCUUACACCCACCAUCC GGAUGGUGGGUGUAAGAGC 5951
    1619 1039 GUCCUUCGGGCUGGUGACA UGUCACCAGCCCGAAGGAC 5952
    1610 1040 GUGCGUACUGUCCUUCGGG CCCGAAGGACAGUACGCAC 5953
    2500 1041 UGGUGCUGACUAUCCAGUU AACUGGAUAGUCAGCACCA 5954
    2156 1042 GCUAUUGAAGCUGAGGGAG CUCCCUCAGCUUCAAUAGC 5955
    1189 1043 CAACCAAGAAAGCAAGCUC GAGCUUGCUUUCUUGGUUG 5956
    2066 1044 GUGCAGCUGCUUUAUUCUC GAGAAUAAAGCAGCUGCAC 5957
    1307 1045 CUAUCUGUCUGCUCUAGUA UACUAGAGCAGACAGAUAG 5958
    1448 1046 AAACAGGAAGGGAUGGAAG CUUCCAUCCCUUCCUGUUU 5959
    1213 1047 ACUGGCUAGUGGUGGACCC GGGUCCACCACUAGCCAGU 5960
    2119 1048 CCUCUGUGAACUUGCUCAG CUGAGCAAGUUCACAGAGG 5961
     889 1049 UGUAGAAACAGCUCGUUGU ACAACGAGCUGUUUCUACA 5962
    1376 1050 CUGACAGAUCCAAGUCAAC GUUGACUUGGAUCUGUCAG 5963
     427 1051 GGAAGAGGAUGUGGAUACC GGUAUCCACAUCCUCUUCC 5964
     649 1052 ACCAUCACAGAUGCUGAAA UUUCAGCAUCUGUGAUGGU 5965
    1915 1053 CCGUACGUCCAUGGGUGGG CCCACCCAUGGACGUACGG 5966
    2053 1054 CAUUCCAUUGUUUGUGCAG CUGCACAAACAAUGGAAUG 5967
    2568 1055 CUCCAGGUGACAGCAAUCA UGAUUGCUGUCACCUGGAG 5968
    1739 1056 CUACCAGUUGUGGUUAAGC GCUUAACCACAACUGGUAG 5969
    1746 1057 UUGUGGUUAAGCUCUUACA UGUAAGAGCUUAACCACAA 5970
    1321 1058 UAGUAAUAAGCCGGCUAUU AAUAGCCGGCUUAUUACUA 5971
     482 1059 CAGUCCUUCACUCAAGAAC GUUCUUGAGUGAAGGACUG 5972
     280 1060 AGCUGAUUUGAUGGAGUUG CAACUCCAUCAAAUCAGCU 5973
    1465 1061 AGGUCUCCUUGGGACUCUU AAGAGUCCCAAGGAGACCU 5974
    1731 1062 ACUAUGGACUACCAGUUGU ACAACUGGUAGUCCAUAGU 5975
    1937 1063 CAGCAGCAAUUUGUGGAGG CCUCCACAAAUUGCUGCUG 5976
    1892 1064 CGUGCACAUCAGGAUACCC GGGUAUCCUGAUGUGCACG 5977
     836 1065 CGUUCUCCUCAGAUGGUGU ACACCAUCUGAGGAGAACG 5978
     521 1066 CAGUAUGCAAUGACUCGAG CUCGAGUCAUUGCAUACUG 5979
    1595 1067 GGUAUAGAGGCUCUUGUGC GCACAAGAGCCUCUAUACC 5980
    2511 1068 AUCCAGUUGAUGGGCUGCC GGCAGCCCAUCAACUGGAU 5981
    1583 1069 UGCCAAGUGGGUGGUAUAG CUAUACCACCCACUUGGCA 5982
    1897 1070 ACAUCAGGAUACCCAGCGC GCGCUGGGUAUCCUGAUGU 5983
     956 1071 GCCAUCUUUAAGUCUGGAG CUCCAGACUUAAAGAUGGC 5984
     923 1072 AACCUUUCCCAUCAUCGUG CACGAUGAUGGGAAAGGUU 5985
    1874 1073 CUAGUUCAGUUGCUUGUUC GAACAAGCAACUGAACUAG 5986
     488 1074 UUCACUCAAGAACAAGUAG CUACUUGUUCUUGAGUGAA 5987
    1695 1075 AAGAAGCAGAGAUGGCCCA UGGGCCAUCUCUGCUUCUU 5988
    2182 1076 UCCUCUGACAGAGUUACUU AAGUAACUCUGUCAGAGGA 5989
    2029 1077 AAUUGUUAUCAGAGGACUA UAGUCCUCUGAUAACAAUU 5990
     479 1078 UCUCAGUCCUUCACUCAAG CUUGAGUGAAGGACUGAGA 5991
     818 1079 UCCAGACACGCUAUCAUGC GCAUGAUAGCGUGUCUGGA 5992
     625 1080 CACUAAUGUCCAGCGUUUG CAAACGCUGGACAUUAGUG 5993
    3172 1081 UUGUAACCUGCUGUGAUAC GUAUCACAGCAGGUUACAA 5994
    1490 1082 CUUCUGGGUUCAGAUGAUA UAUCAUCUGAACCCAGAAG 5995
    1914 1083 GCCGUACGUCCAUGGGUGG CCACCCAUGGACGUACGGC 5996
     974 1084 UAGUUGAAGGUUGUACCGG CCGGUACAACCUUCAACUA 5997
    2258 1085 GAGGACAAGCCACAAGAUU AAUCUUGUGGCUUGUCCUC 5998
    2170 1086 GGGAGCCACAGCUCCUCUG CAGAGGAGCUGUGGCUCCC 5999
    1370 1087 CUUCACCUGACAGAUCCAA UUGGAUCUGUCAGGUGAAG 6000
    1429 1088 UCUUUCAGAUGCUGCAACU AGUUGCAGCAUCUGAAAGA 6001
    3173 1089 UGUAACCUGCUGUGAUACG CGUAUCACAGCAGGUUACA 6002
     444 1090 CCUCCCAAGUCCUGUAUGA UCAUACAGGACUUGGGAGG 6003
    1081 1091 GGCAGUGCGUUUAGCUGGU ACCAGCUAAACGCACUGGC 6004
    1318 1092 CUCUAGUAAUAAGCCGGCU AGCCGGCUUAUUACUAGAG 6005
     329 1093 GCUGUUAGUCACUGGCAGC GCUGCCAGUGACUAACAGC 6006
    1389 1094 GUCAACGUCUUGUUCAGAA UUCUGAACAAGACGUUGAC 6007
     428 1095 GAAGAGGAUGUGGAUACCU AGGUAUCCACAUCCUCUUC 6008
    3175 1096 UAACCUGCUGUGAUACGAU AUCGUAUCACAGCAGGUUA 6009
    3117 1097 GUUAUUUGGAACCUUGUUU AAACAAGGUUCCAAAUAAC 6010
    2020 1098 UCACAACCGAAUUGUUAUC GAUAACAAUUCGGUUGUGA 6011
    1625 1099 CGGGCUGGUGACAGGGAAG CUUCCCUGUCACCAGCCCG 6012
    2022 1100 ACAACCGAAUUGUUAUCAG CUGAUAACAAUUCGGUUGU 6013
     624 1101 CCACUAAUGUCCAGCGUUU AAACGCUGGACAUUAGUGG 6014
    1648 1102 CACUGAGCCUGCCAUCUGU ACAGAUGGCAGGCUCAGUG 6015
     790 1103 GGUCCAUCAGCUUUCUAAA UUUAGAAAGCUGAUGGACC 6016
    3160 1104 AUCCCAAAGUUGUUGUAAC GUUACAACAACUUUGGGAU 6017
    1251 1105 UGAGGACCUAUACUUACGA UCGUAAGUAUAGGUCCUCA 6018
    2253 1106 UGUCUGAGGACAAGCCACA UGUGGCUUGUCCUCAGACA 6019
    2515 1107 AGUUGAUGGGCUGCCAGAU AUCUGGCAGCCCAUCAACU 6020
    1680 1108 UGACCAGCCGACACCAAGA UCUUGGUGUCGGCUGGUCA 6021
    2169 1109 AGGGAGCCACAGCUCCUCU AGAGGAGCUGUGGCUCCCU 6022
    3165 1110 AAAGUUGUUGUAACCUGCU AGCAGGUUACAACAACUUU 6023
     780 1111 CUGCAGUUAUGGUCCAUCA UGAUGGACCAUAACUGCAG 6024
    1978 1112 UGAAGGUUGUACCGGAGCC GGCUCCGGUACAACCUUCA 6025
     563 1113 UUCCCUGAGACAUUAGAUG CAUCUAAUGUCUCAGGGAA 6026
    1622 1114 CUUCGGGCUGGUGACAGGG CCCUGUCACCAGCCCGAAG 6027
    2295 1115 UUGAGCUGACCAGCUCUCU AGAGAGCUGGUCAGCUCAA 6028
    2126 1116 GAACUUGCUCAGGACAAGG CCUUGUCCUGAGCAAGUUC 6029
    1683 1117 CCAGCCGACACCAAGAAGC GCUUCUUGGUGUCGGCUGG 6030
    1857 1118 AGGGUGCCAUUCCACGACU AGUCGUGGAAUGGCACCCU 6031
    2064 1119 UUGUGCAGCUGCUUUAUUC GAAUAAAGCAGCUGCACAA 6032
     489 1120 UCACUCAAGAACAAGUAGC GCUACUUGUUCUUGAGUGA 6033
    1346 1121 GCUGGUGGAAUGCAAGCUU AAGCUUGCAUUCCACCAGC 6034
    1442 1122 GCAACUAAACAGGAAGGGA UCCCUUCCUGUUUAGUUGC 6035
    1981 1123 AGGUUGUACCGGAGCCCUU AAGGGCUCCGGUACAACCU 6036
     777 1124 AGGCUGCAGUUAUGGUCCA UGGACCAUAACUGCAGCCU 6037
     589 1125 GCAGAUCCCAUCUACACAG CUGUGUAGAUGGGAUCUGC 6038
    2205 1126 CUAGGAAUGAAGGUGUGGC GCCACACCUUCAUUCCUAG 6038
     394 1127 AGCUCCUUCUCUGAGUGGU ACCACUCAGAGAAGGAGCU 6040
    1035 1128 UUACAACUCUCCACAACCU AGGUUGUGGAGAGUUGUAA 6041
     410 1129 GGUAAAGGCAAUCCUGAGG CCUCAGGAUUGCCUUUACC 6042
    1721 1130 GUUCGCCUUCACUAUGGAC GUCCAUAGUGAAGGCGAAC 6043
    1134 1131 CAAAUGUUAAAUUCUUGGC GCCAAGAAUUUAACAUUUG 6044
    3182 1132 CUGUGAUACGAUGCUUCAA UUGAAGCAUCGUAUCACAG 6045
     881 1133 ACAAAUGAUGUAGAAACAG CUGUUUCUACAUCAUUUGU 6046
     547 1134 GGUACGAGCUGCUAUGUUC GAACAUAGCAGCUCGUACC 6047
    2028 1135 GAAUUGUUAUCAGAGGACU AGUCCUCUGAUAACAAUUC 6048
    2023 1136 CAACCGAAUUGUUAUCAGA UCUGAUAACAAUUCGGUUG 6049
    3184 1137 GUGAUACGAUGCUUCAAGA UCUUGAAGCAUCGUAUCAC 6050
     413 1138 AAAGGCAAUCCUGAGGAAG CUUCCUCAGGAUUGCCUUU 6051
    2178 1139 CAGCUCCUCUGACAGAGUU AACUCUGUCAGAGGAGCUG 6052
    1577 1140 AUGGUCUGCCAAGUGGGUG CACCCACUUGGCAGACCAU 6053
    1793 1141 GCUACUGUUGGAUUGAUUC GAAUCAAUCCAACAGUAGC 6054
     526 1142 UGCAAUGACUCGAGCUCAG CUGAGCUCGAGUCAUUGCA 6055
    2358 1143 GACUUGAUAUUGGUGCCCA UGGGCACCAAUAUCAAGUC 6056
    1403 1144 CAGAACUGUCUUUGGACUC GAGUCCAAAGACAGUUCUG 6057
    1875 1145 UAGUUCAGUUGCUUGUUCG CGAACAAGCAACUGAACUA 6058
    1160 1146 ACAGACUGCCUUCAAAUUU AAAUUUGAAGGCAGUCUGU 6059
    1591 1147 GGGUGGUAUAGAGGCUCUU AAGAGCCUCUAUACCACCC 6060
    1734 1148 AUGGACUACCAGUUGUGGU ACCACAACUGGUAGUCCAU 6061
    2030 1149 AUUGUUAUCAGAGGACUAA UUAGUCCUCUGAUAACAAU 6062
     775 1150 UAAGGCUGCAGUUAUGGUC GACCAUAACUGCAGCCUUA 6063
    1813 1151 AAAUCUUGCCCUUUGUCCC GGGACAAAGGGCAAGAUUU 6064
    1938 1152 AGCAGCAAUUUGUGGAGGG CCCUCCACAAAUUGCUGCU 6065
    2039 1153 AGAGGACUAAAUACCAUUC GAAUGGUAUUUAGUCCUCU 6066
    1297 1154 GCUGAAGGUGCUAUCUGUC GACAGAUAGCACCUUCAGC 6067
     456 1155 UGUAUGAGUGGGAACAGGG CCCUGUUCCCACUCAUACA 6068
     590 1156 CAGAUCCCAUCUACACAGU ACUGUGUAGAUGGGAUCUG 6069
    1933 1157 GACACAGCAGCAAUUUGUG CACAAAUUGCUGCUGUGUC 6070
     583 1158 GGGCAUGCAGAUCCCAUCU AGAUGGGAUCUGCAUGCCC 6071
    2540 1159 CAUGCCCAGGACCUCAUGG CCAUGAGGUCCUGGGCAUG 6072
    2162 1160 GAAGCUGAGGGAGCCACAG CUGUGGCUCCCUCAGCUUC 6073
     330 1161 CUGUUAGUCACUGGCAGCA UGCUGCCAGUGACUAACAG 6074
    1481 1162 CUUGUUCAGCUUCUGGGUU AACCCAGAAGCUGAACAAG 6075
    1344 1163 AAGCUGGUGGAAUGCAAGC GCUUGCAUUCCACCAGCUU 6076
     431 1164 GAGGAUGUGGAUACCUCCC GGGAGGUAUCCACAUCCUC 6077
    1508 1165 AUAAAUGUGGUCACCUGUG CACAGGUGACCACAUUUAU 6078
    1918 1166 UACGUCCAUGGGUGGGACA UGUCCCACCCAUGGACGUA 6079
     289 1167 GAUGGAGUUGGACAUGGCC GGCCAUGUCCAACUCCAUC 6080
     631 1168 UGUCCAGCGUUUGGCUGAA UUCAGCCAAACGCUGGACA 6081
    1853 1169 GAGCAGGGUGCCAUUCCAC GUGGAAUGGCACCCUGCUC 6082
    1243 1170 AAAUAUAAUGAGGACCUAU AUAGGUCCUCAUUAUAUUU 6083
    1212 1171 UACUGGCUAGUGGUGGACC GGUCCACCACUAGCCAGUA 6084
     996 1172 UGCUUGGUUCACCAGUGGA UCCACUGGUGAACCAAGCA 6085
    2256 1173 CUGAGGACAAGCCACAAGA UCUUGUGGCUUGUCCUCAG 6086
    1607 1174 CUUGUGCGUACUGUCCUUC GAAGGACAGUACGCACAAG 6087
    3116 1175 UGUUAUUUGGAACCUUGUU AACAAGGUUCCAAAUAACA 6088
    1179 1176 UAGCUUAUGGCAACCAAGA UCUUGGUUGCCAUAAGCUA 6089
    3185 1177 UGAUACGAUGCUUCAAGAG CUCUUGAAGCAUCGUAUCA 6090
    1594 1178 UGGUAUAGAGGCUCUUGUG CACAAGAGCCUCUAUACCA 6091
     887 1179 GAUGUAGAAACAGCUCGUU AACGAGCUGUUUCUACAUC 6092
     928 1180 CCUUUCCCAUCAUCGUGAG CUCACGAUGAUGGGAAAGG 6093
     835 1181 GCGUUCUCCUCAGAUGGUG CACCAUCUGAGGAGAACGC 6094
    1900 1182 UCAGGAUACCCAGCGCCGU ACGGCGCUGGGUAUCCUGA 6095
    2284 1183 ACGGCUUUCAGUUGAGCUG CAGCUCAACUGAAAGCCGU 6096
    1976 1184 GUUGAAGGUUGUACCGGAG CUCCGGUACAACCUUCAAC 6097
    2393 1185 UAUCGCCAGGAUGAUCCUA UAGGAUCAUCCUGGCGAUA 6098
    1295 1186 GUGCUGAAGGUGCUAUCUG CAGAUAGCACCUUCAGCAC 6099
    1410 1187 GUCUUUGGACUCUCAGGAA UUCCUGAGAGUCCAAAGAC 6100
    1457 1188 GGGAUGGAAGGUCUCCUUG CAAGGAGACCUUCCAUCCC 6101
    2296 1189 UGAGCUGACCAGCUCUCUC GAGAGAGCUGGUCAGCUCA 6102
     929 1190 CUUUCCCAUCAUCGUGAGG CCUCACGAUGAUGGGAAAG 6103
    1359 1191 AAGCUUUAGGACUUCACCU AGGUGAAGUCCUAAAGCUU 6104
    1351 1192 UGGAAUGCAAGCUUUAGGA UCCUAAAGCUUGCAUUCCA 6105
     969 1193 CUGGAGGCAUUCCUGCCCU AGGGCAGGAAUGCCUCCAG 6106
    1876 1194 AGUUCAGUUGCUUGUUCGU ACGAACAAGCAACUGAACU 6107
     552 1195 GAGCUGCUAUGUUCCCUGA UCAGGGAACAUAGCAGCUC 6108
    2441 1196 GGCCAGGAUGCCUUGGGUA UACCCAAGGCAUCCUGGCC 6109
    2402 1197 GAUGAUCCUAGCUAUCGUU AACGAUAGCUAGGAUCAUC 6110
    1803 1198 GAUUGAUUCGAAAUCUUGC GCAAGAUUUCGAAUCAAUC 6111
    1701 1199 CAGAGAUGGCCCAGAAUGC GCAUUCUGGGCCAUCUCUG 6112
    1910 1200 CAGCGCCGUACGUCCAUGG CCAUGGACGUACGGCGCUG 6113
     888 1201 AUGUAGAAACAGCUCGUUG CAACGAGCUGUUUCUACAU 6114
    1294 1202 AGUGCUGAAGGUGCUAUCU AGAUAGCACCUUCAGCACU 6115
    1737 1203 GACUACCAGUUGUGGUUAA UUAACCACAACUGGUAGUC 6116
    1450 1204 ACAGGAAGGGAUGGAAGGU ACCUUCCAUCCCUUCCUGU 6117
     761 1205 CAGGUGGUGGUUAAUAAGG CCUUAUUAACCACCACCUG 6118
     776 1206 AAGGCUGCAGUUAUGGUCC GGACCAUAACUGCAGCCUU 6119
    1509 1207 UAAAUGUGGUCACCUGUGC GCACAGGUGACCACAUUUA 6120
    1788 1208 UAAAGGCUACUGUUGGAUU AAUCCAACAGUAGCCUUUA 6121
     515 1209 GAUGGACAGUAUGCAAUGA UCAUUGCAUACUGUCCAUC 6122
    1491 1210 UUCUGGGUUCAGAUGAUAU AUAUCAUCUGAACCCAGAA 6123
    1614 1211 GUACUGUCCUUCGGGCUGG CCAGCCCGAAGGACAGUAC 6124
     998 1212 CUUGGUUCACCAGUGGAUU AAUCCACUGGUGAACCAAG 6125
    2158 1213 UAUUGAAGCUGAGGGAGCC GGCUCCCUCAGCUUCAAUA 6126
    3168 1214 GUUGUUGUAACCUGCUGUG CACAGCAGGUUACAACAAC 6127
    1854 1215 AGCAGGGUGCCAUUCCACG CGUGGAAUGGCACCCUGCU 6128
    2117 1216 GUCCUCUGUGAACUUGCUC GAGCAAGUUCACAGAGGAC 6129
    1678 1217 UCUGACCAGCCGACACCAA UUGGUGUCGGCUGGUCAGA 6130
     305 1218 GCCAUGGAACCAGACAGAA UUCUGUCUGGUUCCAUGGC 6131
    2154 1219 AAGCUAUUGAAGCUGAGGG CCCUCAGCUUCAAUAGCUU 6132
    1807 1220 GAUUCGAAAUCUUGCCCUU AAGGGCAAGAUUUCGAAUC 6133
    1881 1221 AGUUGCUUGUUCGUGCACA UGUGCACGAACAAGCAACU 6134
    1565 1222 AAGAACAAGAUGAUGGUCU AGACCAUCAUCUUGUUCUU 6135
     407 1223 AGUGGUAAAGGCAAUCCUG CAGGAUUGCCUUUACCACU 6136
    1434 1224 CAGAUGCUGCAACUAAACA UGUUUAGUUGCAGCAUCUG 6137
     566 1225 CCUGAGACAUUAGAUGAGG CCUCAUCUAAUGUCUCAGG 6138
    3161 1226 UCCCAAAGUUGUUGUAACC GGUUACAACAACUUUGGGA 6139
    1678 1227 CUGACCAGCCGACACCAAG CUUGGUGUCGGCUGGUCAG 6140
    2096 1228 AUCCAAAGAGUAGCUGCAG CUGCAGCUACUCUUUGGAU 6141
     630 1229 AUGUCCAGCGUUUGGCUGA UCAGCCAAACGCUGGACAU 6142
    1606 1230 UCUUGUGCGUACUGUCCUU AAGGACAGUACGCACAAGA 6143
     432 1231 AGGAUGUGGAUACCUCCCA UGGGAGGUAUCCACAUCCU 6144
     778 1232 GGCUGCAGUUAUGGUCCAU AUGGACCAUAACUGCAGCC 6145
    1999 1233 UCACAUCCUAGCUCGGGAU AUCCCGAGCUAGGAUGUGA 6146
    1692 1234 ACCAAGAAGCAGAGAUGGC GCCAUCUCUGCUUCUUGGU 6147
    2490 1235 GCCACCACCCUGGUGCUGA UCAGCACCAGGGUGGUGGC 6148
     623 1236 CCCACUAAUGUCCAGCGUU AACGCUGGACAUUAGUGGG 6149
     339 1237 ACUGGCAGCAACAGUCUUA UAAGACUGUUGCUGCCAGU 6150
    2946 1238 AUCUGAAUAAAGUGUAACA UGUUACACUUUAUUCAGAU 6151
    1654 1239 GCCUGCCAUCUGUGCUCUU AAGAGCACAGAUGGCAGGC 6152
    1033 1240 CAUUACAACUCUCCACAAC GUUGUGGAGAGUUGUAAUG 6153
     840 1241 CUCCUCAGAUGGUGUCUGC GCAGACACCAUCUGAGGAG 6154
    1880 1242 CAGUUGCUUGUUCGUGCAC GUGCACGAACAAGCAACUG 6155
     420 1243 AUCCUGAGGAAGAGGAUGU ACAUCCUCUUCCUCAGGAU 6156
    1005 1244 CACCAGUGGAUUCUGUGUU AACACAGAAUCCACUGGUG 6157
    1193 1245 CAAGAAAGCAAGCUCAUCA UGAUGAGCUUGCUUUCUUG 6158
     919 1246 CUUGCAUAACCUUUCCCAU AUGGGAAAGGUUAUGCAAG 6159
    1727 1247 CUUCACUAUGGACUACCAG CUGGUAGUCCAUAGUGAAG 6160
    1883 1248 UUGCUUGUUCGUGCACAUC GAUGUGCACGAACAAGCAA 6161
     859 1249 UAUUGUACGUACCAUGCAG CUGCAUGGUACGUACAAUA 6162
    1812 1250 GAAAUCUUGCCCUUUGUCC GGACAAAGGGCAAGAUUUC 6163
    1605 1251 CUCUUGUGCGUACUGUCCU AGGACAGUACGCACAAGAG 6164
    2021 1252 CACAACCGAAUUGUUAUCA UGAUAACAAUUCGGUUGUG 6165
    2180 1253 GCUCCUCUGACAGAGUUAC GUAACUCUGUCAGAGGAGC 6166
     636 1254 AGCGUUUGGCUGAACCAUC GAUGGUUCAGCCAAACGCU 6167
    2282 1255 AAACGGCUUUCAGUUGAGC GCUCAACUGAAAGCCGUUU 6168
    1824 1256 UUUGUCCCGCAAAUCAUGC GCAUGAUUUGCGGGACAAA 6169
    2204 1257 UCUAGGAAUGAAGGUGUGG CCACACCUUCAUUCCUAGA 6170
     450 1258 AAGUCCUGUAUGAGUGGGA UCCCACUCAUACAGGACUU 6171
    1001 1259 GGUUCACCAGUGGAUUCUG CAGAAUCCACUGGUGAACC 6172
    1579 1260 GGUCUGCCAAGUGGGUGGU ACCACCCACUUGGCAGACC 6173
    2189 1261 AGCUCCUCUGACAGAGUUA UAACUCUGUCAGAGGAGCU 6174
     376 1262 UUCUGGUGCCACUACCACA UGUGGUAGUGGCACCAGAA 6175
     556 1263 UGCUAUGUUCCCUGAGACA UGUCUCAGGGAACAUAGCA 6176
    1804 1264 AUUGAUUCGAAAUCUUGCC GGCAAGAUUUCGAAUCAAU 6177
    2552 1265 CUCAUGGAUGGGCUGCCUC GAGGCAGCCCAUCCAUGAG 6178
    2071 1266 GCUGCUUUAUUCUCCCAUU AAUGGGAGAAUAAAGCAGC 6179
    1836 1267 AUCAUGCACCUUUGCGUGA UCACGCAAAGGUGCAUGAU 6180
     336 1268 GUCACUGGCAGCAACAGUC GACUGUUGCUGCCAGUGAC 6181
     460 1269 UGAGUGGGAACAGGGAUUU AAAUCCCUGUUCCCACUCA 6182
    1559 1270 AAUUAUAAGAACAAGAUGA UCAUCUUGUUCUUAUAAUU 6183
    3136 1271 UGGACAGUUUACCAGUUGC GCAACUGGUAAACUGUCCA 6184
    1250 1272 AUGAGGACCUAUACUUACG CGUAAGUAUAGGUCCUCAU 6185
    1462 1273 GGAAGGUCUCCUUGGGACU AGUCCCAAGGAGACCUUCC 6186
    1965 1274 UGGAAGAAAUAGUUGAAGG CCUUCAACUAUUUCUUCCA 6187
    3114 1275 GGUGUUAUUUGGAACCUUG CAAGGUUCCAAAUAACACC 6188
    1665 1276 GUGCUCUUCGUCAUCUGAC GUCAGAUGACGAAGAGCAC 6189
     307 1277 GGCCAUGGAACCAGACAGA UCUGUCUGGUUCCAUGGCC 6190
     327 1278 CGGCUGUUAGUCACUGGCA UGCCAGUGACUAACAGCCG 6191
    1866 1279 UUCCACGACUAGUUCAGUU AACUGAACUAGUCGUGGAA 6192
    1699 1280 AGCAGAGAUGGCCCAGAAU AUUCUGGGCCAUCUCUGCU 6193
    2397 1281 GCCAGGAUGAUCCUAGCUA UAGCUAGGAUCAUCCUGGC 6194
    1658 1282 GCCAUCUGUGCUCUUCGUC GACGAAGAGCACAGAUGGC 6195
     891 1283 UAGAAACAGCUCGUUGUAC GUACAACGAGCUGUUUCUA 6196
    1572 1284 AGAUGAUGGUCUGCCAAGU ACUUGGCAGACCAUCAUCU 6197
     927 1285 ACCUUUCCCAUCAUCGUGA UCACGAUGAUGGGAAAGGU 6198
     290 1286 AUGGAGUUGGACAUGGCCA UGGCCAUGUCCAACUCCAU 6199
    1663 1287 CUGUGCUCUUCGUCAUCUG CAGAUGACGAAGAGCACAG 6200
    1562 1288 UAUAAGAACAAGAUGAUGG CCAUCAUCUUGUUCUUAUA 6201
    2947 1289 UCUGAAUAAAGUGUAACAA UUGUUACACUUUAUUCAGA 6202
    1711 1290 CCAGAAUGCAGUUCGCCUU AAGGCGAACUGCAUUCUGG 6203
    1566 1291 AGAACAAGAUGAUGGUCUG CAGACCAUCAUCUUGUUCU 6204
    1815 1292 AUCUUGCCCUUUGUCCCGC GCGGGACAAAGGGCAAGAU 6205
    1087 1293 GCGUUUAGCUGGUGGGCUG CAGCCCACCAGCUAAACGC 6206
    1495 1294 GGGUUCAGAUGAUAUAAAU AUUUAUAUCAUCUGAACCC 6207
    1363 1295 UUUAGGACUUCACCUGACA UGUCAGGUGAAGUCCUAAA 6208
     391 1296 CACAGCUCCUUCUCUGAGU ACUCAGAGAAGGAGCUGUG 6209
    1392 1297 AACGUCUUGUUCAGAACUG CAGIICIGAACAAGACGUU 6210
    1935 1298 CACAGCAGCAAUUUGUGGA UCCACAAAUUGCUGCUGUG 6211
    1872 1299 GACUAGUUCAGUUGCUUGU ACAAGCAACUGAACUAGUC 6212
    1159 1300 GACAGACUGCCUUCAAAUU AAUUUGAAGGCAGUCUGUC 6213
    2308 1301 CUCUCUCUUCAGAACAGAG CUCUGUUCUGAAGAGAGAG 6214
     632 1302 GUCCAGCGUUUGGCUGAAC GUUCAGCCAAACGCUGGAC 6215
    1564 1303 UAAGAACAAGAUGAUGGUC GACCAUCAUCUUGUUCUUA 6216
    1384 1304 UCCAAGUCAACGUCUUGUU AACAAGACGUUGACUUGGA 6217
    1690 1305 ACACCAAGAAGCAGAGAUG CAUCUCUGCUUCUUGGUGU 6218
    1421 1306 CUCAGGAAUCUUUCAGAUG CAUCUGAAAGAUUCCUGAG 6219
    1141 1307 UAAAUUCUUGGCUAUUACG CGUAAUAGCCAAGAAUUUA 6220
    1732 1308 CUAUGGACUACCAGUUGUG CACAACUGGUAGUCCAUAG 6221
     634 1309 CCAGCGUUUGGCUGAACCA UGGUUCAGCCAAACGCUGG 6222
     932 1310 UCCCAUCAUCGUGAGGGCU AGCCCUCACGAUGAUGGGA 6223
    1366 1311 AGGACUUCACCUGACAGAU AUCUGUCAGGUGAAGUCCU 6224
    1608 1312 UUGUGCGUACUGUCCUUCG CGAAGGACAGUACGCACAA 6225
    1923 1313 CCAUGGGUGGGACACAGCA UGCUGUGUCCCACCCAUGG 6226
    1458 1314 GGAUGGAAGGUCUCCUUGG CCAAGGAGACCUUCCAUCC 6227
    1908 1315 CCCAGCGCCGUACGUCCAU AUGGACGUACGGCGCUGGG 6228
     539 1316 GCUCAGAGGGUACGAGCUG CAGCUCGUACCCUCUGAGC 6229
    2016 1317 AUGUUCACAACCGAAUUGU ACAAUUCGGUUGUGAACAU 6230
    1884 1318 UGCUUGUUCGUGCACAUCA UGAUGUGCACGAACAAGCA 6231
     560 1319 AUGUUCCCUGAGACAUUAG CUAAUGUCUCAGGGAACAU 6232
     411 1320 GUAAAGGCAAUCCUGAGGA UCCUCAGGAUUGCCUUUAC 6233
     338 1321 CACUGGCAGCAACAGUCUU AAGACUGUUGCUGCCAGUG 6234
     830 1322 AUCAUGCGUUCUCCUCAGA UCUGAGGAGAACGCAUGAU 6235
    3086 1323 UAUGUAUGGGUAGGGUAAA UUUACCCUACCCAUACAUA 6236
    3115 1324 GUGUUAUUUGGAACCUUGU ACAAGGUUCCAAAUAACAC 6237
    2177 1325 ACAGCUCCUCUGACAGAGU ACUCUGUCAGAGGAGCUGU 6238
    1733 1326 UAUGGACUACCAGUUGUGG CCACAACUGGUAGUCCAUA 6239
     375 1327 AUUCUGGUGCCACUACCAC GUGGUAGUGGCACCAGAAU 6240
    2565 1328 UGCCUCCAGGUGACAGCAA UUGCUGUCACCUGGAGGCA 6241
    442 1329 UACCUCCCAAGUCCUGUAU AUACAGGACUUGGGAGGUA 6242
     819 1330 CCAGACACGCUAUCAUGCG CGCAUGAUAGCGUGUCUGG 6243
     700 1331 UGAUGCAGAACUUGCCACA UGUGGCAAGUUCUGCAUCA 6244
    1089 1332 GUUUAGCUGGUGGGCUGCA UGCAGCCCACCAGCUAAAC 6245
    1580 1333 GUCUGCCAAGUGGGUGGUA UACCACCCACUUGGCAGAC 6246
    1982 1334 GGUUGUACCGGAGCCCUUC GAAGGGCUCCGGUACAACC 6247
    1986 1335 GUACCGGAGCCCUUCACAU AUGUGAAGGGCUCCGGUAC 6248
     418 1336 CAAUCCUGAGGAAGAGGAU AUCCUCUUCCUCAGGAUUG 6249
    1306 1337 GCUAUCUGUCUGCUCUAGU ACUAGAGCAGACAGAUAGC 6250
    1377 1338 UGACAGAUCCAAGUCAACG CGUUGACUUGGAUCUGUCA 6251
    2467 1339 CAUGAUGGAACAUGAGAUG CAUCUCAUGUUCCAUCAUG 6252
    1414 1340 UUGGACUCUCAGGAAUCUU AAGAUUCCUGAGAGUCCAA 6253
    1668 1341 CUCUUCGUCAUCUGACCAG CUGGUCAGAUGACGAAGAG 6254
    1818 1342 UUGCCCUUUGUCCCGCAAA UUUGCGGGACAAAGGGCAA 6255
    1697 1343 GAAGCAGAGAUGGCCCAGA UCUGGGCCAUCUCUGCUUC 6256
     918 1344 CCUUGCAUAACCUUUCCCA UGGGAAAGGUUAUGCAAGG 6257
     605 1345 CAGUUUGAUGCUGCUCAUC GAUGAGCAGCAUCAAACUG 6258
    1374 1346 ACCUGACAGAUCCAAGUCA UGACUUGGAUCUGUCAGGU 6259
    1430 1347 CUUUCAGAUGCUGCAACUA UAGUUGCAGCAUCUGAAAG 6260
    3186 1348 GAUACGAUGCUUCAAGAGA UCUCUUGAAGCAUCGUAUC 6261
    1355 1349 AUGCAAGCUUUAGGACUUC GAAGUCCUAAAGCUUGCAU 6262
     433 1350 GGAUGUGGAUACCUCCCAA UUGGGAGGUAUCCACAUCC 6263
    1713 1351 AGAAUGCAGUUCGCCUUCA UGAAGGCGAACUGCAUUCU 6264
    1811 1352 CGAAAUCUUGCCCUUUGUC GACAAAGGGCAAGAUUUCG 6265
     491 1353 ACUCAAGAACAAGUAGCUG CAGCUACUUGUUCUUGAGU 6266
    2209 1354 GAAUGAAGGUGUGGCGACA UGUCGCCACACCUUCAUUC 6267
    1840 1355 UGCACCUUUGCGUGAGCAG CUGCUCACGCAAAGGUGCA 6268
     550 1356 ACGAGCUGCUAUGUUCCCU AGGGAACAUAGCAGCUCGU 6269
     429 1357 AAGAGGAUGUGGAUACCUC GAGGUAUCCACAUCCUCUU 6270
    2436 1358 GAUAUGGCCAGGAUGCCUU AAGGCAUCCUGGCCAUAUC 6271
    1597 1359 UAUAGAGGCUCUUGUGCGU ACGCACAAGAGCCUCUAUA 6272
    1496 1360 GGUUCAGAUGAUAUAAAUG CAUUUAUAUCAUCUGAACC 6273
    1456 1361 AGGGAUGGAAGGUCUCCUU AAGGAGACCUUCCAUCCCU 6274
    3159 1362 UAUCCCAAAGUUGUUGUAA UUACAACAACUUUGGGAUA 6275
    2309 1363 UCUCUCUUCAGAACAGAGC GCUCUGUUCUGAAGAGAGA 6276
    2300 1364 CUGACCAGCUCUCUCUUCA UGAAGAGAGAGCUGGUCAG 6277
    3177 1365 ACCUGCUGUGAUACGAUGC GCAUCGUAUCACAGCAGGU 6278
    1079 1366 AUGGCAGUGCGUUUAGCUG CAGCUAAACGCACUGCCAU 6279
    1383 1367 AUCCAAGUCAACGUCUUGU ACAAGACGUUGACUUGGAU 6280
    2563 1368 GCUGCCUCCAGGUGACAGC GCUGUCACCUGGAGGCAGC 6281
    1084 1369 AGUGCGUUUAGCUGGUGGG CCCACCAGCUAAACGCACU 6282
    1329 1370 AGCCGGCUAUUGUAGAAGC GCUUCUACAAUAGCCGGCU 6283
     573 1371 CAUUAGAUGAGGGCAUGCA UGCAUGCCCUCAUCUAAUG 6284
    2213 1372 GAAGGUGUGGCGACAUAUG CAUAUGUCGCCACACCUUC 6285
    1587 1373 AAGUGGGUGGUAUAGAGGC GCCUCUAUACCACCCACUU 6286
    2166 1374 CUGAGGGAGCCACAGCUCC GGAGCUGUGGCUCCCUCAG 2687
     637 1375 GCGUUUGGCUGAACCAUCA UGAUGGUUCAGCCAAACGC 6288
     397 1376 UCCUUCUCUGAGUGGUAAA UUUACCACUCAGAGAAGGA 6289
    1718 1377 GCAGUUCGCCUUCACUAUG CAUAGUGAAGGCGAACUGC 6290
    2357 1378 GGACUUGAUAUUGGUGCCC GGGCACCAAUAUCAAGUCC 6291
     639 1379 GUUUGGCUGAACCAUCACA UGUGAUGGUUCAGCCAAAC 6292
     585 1380 GCAUGCAGAUCCCAUCUAC GUAGAUGGGAUCUGCAUGC 6293
    2519 1381 GAUGGGCUGCCAGAUCUGG CCAGAUCUGGCAGCCCAUC 6294
    1367 1382 GGACUUCACCUGACAGAUC GAUCUGUCAGGUGAAGUCC 6295
    1391 1383 CAACGUCUUGUUCAGAACU AGUUCUGAACAAGACGUUG 6296
     509 1384 GAUAUUGAUGGACAGUAUG CAUACUGUCCAUCAAUAUC 6297
     303 1385 UGGCCAUGGAACCAGACAG CUGUCUGGUUCCAUGGCCA 6298
     494 1386 CAAGAACAAGUAGCUGAUA UAUCAGCUACUUGUUCUUG 6299
     328 1387 GGCUGUUAGUCACUGGCAG CUGCCAGUGACUAACAGCC 6300
    2058 1388 CAUUGUUUGUGCAGCUGCU AGCAGCUGCACAAACAAUG 6301
    1447 1389 UAAACAGGAAGGGAUGGAA UUCCAUCCCUUCCUGUUUA 6302
    1563 1390 AUAAGAACAAGAUGAUGGU ACCAUCAUCUUGUUCUUAU 6303
    1350 1391 GUGGAAUGCAAGCUUUAGG CCUAAAGCUUGCAUUCCAC 6304
    2208 1392 GGAAUGAAGGUGUGGCGAC GUCGCCACACCUUCAUUCC 6305
    1689 1393 GACACCAAGAAGCAGAGAU AUCUCUGCUUCUUGGUGUC 6306
    1407 1394 ACUGUCUUUGGACUCUCAG CUGAGAGUCCAAAGACAGU 6307
    2137 1395 GGACAAGGAAGCUGCAGAA UUCUGCAGCUUCCUUGUCC 6308
     854 1396 UCUGCUAUUGUACGUACCA UGGUACGUACAAUAGCAGA 6309
    2070 1397 AGCUGCUUUAUUCUCCCAU AUGGGAGAAUAAAGCAGCU 6310
     545 1398 AGGGUACGAGCUGCUAUGU ACAUAGCAGCUCGUACCCU 6311
    1640 1399 GAAGACAUCACUGAGCCUG CAGGCUCAGUGAUGUCUUC 6312
    2012 1400 CGGGAUGUUCACAACCGAA UUCGGUUGUGAACAUCCCG 6313
    1684 1401 CAGCCGACACCAAGAAGCA UGCUUCUUGGUGUCGGCUG 6314
    2017 1402 UGUUCACAACCGAAUUGUU AACAAUUCGGUUGUGAACA 6315
    2307 1403 GCUCUCUCUUCAGAACAGA UCUGUUCUGAAGAGAGAGC 6316
     844 1404 UCAGAUGGUGUCUGCUAUU AAUAGCAGACACCAUCUGA 6317
     405 1405 UGAGUGGUAAAGGCAAUCC GGAUUGCCUUUACCACUCA 6318
     379 1406 UGGUGCCACUACCACAGCU AGCUGUGGUAGUGGCACCA 6319
    1825 1407 UUGCUUUGCAAAUCAUGCA UGCAUGAUUUGCGGGACAA 6320
    2495 1408 CACCCUGGUGCUGACUAUC GAUAGUCAGCACCAGGGUG 6321
     629 1409 AAUGUCCAGCGUUUGGCUG CAGCCAAACGCUGGACAUU 6322
    2561 1410 GGGCUGCCUCCAGGUGACA UGUCACCUGGAGGCAGCCC 6323
    2192 1411 GAGUUACUUCACUCUAGGA UCCUAGAGUGAAGUAACUC 6324
    1809 1412 UUCGAAAUCUUGCCCUUUG CAAAGGGCAAGAUUUCGAA 6325
    1596 1413 GUAUAGAGGCUCUUGUGCG CGCACAAGAGCCUCUAUAC 6326
    2298 1414 AGCUGACCAGCUCUCUCUU AAGAGAGAGCUGGUCAGCU 6327
     858 1415 CUAUUGUACGUACCAUGCA UGCAUGGUACGUACAAUAG 6328
     524 1416 UAUGCAAUGACUCGAGCUC GAGCUCGAGUCAUUGCAUA 6329
    2542 1417 UGCCCAGGACCUCAUGGAU AUCCAUGAGGUCCUGGGCA 6330
    7498 1418 AACAAGUAGCUGAUAUUGA UCAAUAUCAGCUACUUGUU 6331
     414 1419 AAGGCAAUCCUGAGGAAGA UCUUCCUCAGGAUUGCCUU 6332
    1570 1420 CAAGAUGAUGGUCUGCCAA UUGGCAGACCAUCAUCUUG 6333
    1030 1421 UGCCAUUACAACUCUCCAC GUGGAGAGUUGUAAUGGCA 6334
    3087 1422 AUGUAUGGGUAGGGUAAAU AUUUACCCUACCCAUACAU 6335
    1664 1423 UGUGCUCUUCGUCAUCUGA UCAGAUGACGAAGAGCACA 6336
    1790 1424 AAGGCUACUGUUGGAUUGA UCAAUCCAACAGUAGCCUU 6337
    1615 1425 UACUGUCCUUCGGGCUGGU ACCAGCCCGAAGGACAGUA 6338
     774 1426 AUAAGGCUGCAGUUAUGGU ACCAUAACUGCAGCCUUAU 6339
    1672 1427 UCGUCAUCUGACCAGCCGA UCGGCUGGUCAGAUGACGA 6340
    3171 1428 GUUGUAACCUGCUGUGAUA UAUCACAGCAGGUUACAAC 6341
    2271 1429 AAGAUUACAAGAAACGGCU AGCCGUUUCUUGUAAUCUU 6342
    1183 1430 UUAUGGCAACCAAGAAAGC GCUUUCUUGGUUGCCAUAA 6343
    2512 1431 UCCAGUUGAUGGGCUGCCA UGGCAGCCCAUCAACUGGA 6344
    1931 1432 GGGACACAGCAGCAAUUUG CAAAUUGCUGCUGUGUCCC 6345
    2468 1433 AUGAUGGAACAUGAGAUGG CCAUCUCAUGUUCCAUCAU 6346
    3077 1434 UAUUUGGGAUAUGUAUGGG CCCAUACAUAUCCCAAAUA 6347
    2069 1435 CAGCUGCUUUAUUCUCCCA UGGGAGAAUAAAGCAGCUG 6348
    272 1436 GCUACUCAAGCUGAUUUGA UCAAAUCAGCUUGAGUAGC 6349
     564 1437 UCCCUGAGACAUUAGAUGA UCAUCUAAUGUCUCAGGGA 6350
     437 1438 GUGGAUACCUCCCAAGUCC GGACUUGGGAGGUAUCCAC 6351
    2206 1439 UAGGAAUGAAGGUGUGGCG CGCCACACCUUCAUUCCUA 6352
    2197 1440 UGACAGAGUUACUUCACUC GAGUGAAGUAACUCUGUCA 6353
     325 1441 AGCGGCUGUUAGUCACUGG CCAGUGACUAACAGCCGCU 6354
    3222 1442 AUGGUUCAGAAUUAAACUU AAGUUUAAUUCUGAACCAU 6355
    2024 1443 AACCGAAUUGUUAUCAGAG CUCUGAUAACAAUUCGGUU 6356
    1858 1444 GGGUGCCAUUCCACGACUA UAGUCGUGGAAUGGCACCC 6357
    1574 1445 AUGAUGGUCUGCCAAGUGG CCACUUGGCAGACCAUCAU 6358
    1896 1446 CACAUCAGGAUACCCAGCG CGCUGGGUAUCCUGAUGUG 6359
    2207 1447 AGGAAUGAAGGUGUGGCGA UCGCCACACCUUCAUUCCU 6360
    1300 1448 GAAGGUGCUAUCUGUCUGC UCGCCACACCUUCAUUCCU 6361
    1192 1449 CCAAGAAAGCAAGCUCAUC GAUGAGCUUGCUUUCUUGG 6362
     551 1450 CGAGCUGCUAUGUUCCCUG CAGGGAACAUAGCAGCUCG 6363
    2498 1451 CCUGGUGCUGACUAUCCAG CUGGAUAGUCAGCACCAGG 6364
    1305 1452 UGCUAUCUGUCUGCUCUAG CUAGAGCAGACAGAUAGCA 6365
    1337 1453 AUUGUAGAAGCUGGUGGAA UUCCACCAGCUUCUACAAU 6366
  • For each oligonucleotide of a target sequence, the two individual, complementary strands of the siNA were synthesized separately using solid phase synthesis, then purified separately by reversed phase solid phase extraction (SPE). The complementary strands were annealed to form the double strand (duplex) and delivered in the desired concentration and buffer of choice.
  • Briefly, the single strand oligonucleotides were synthesized using phosphoramidite chemistry on an automated solid-phase synthesizer, using procedures as are generally known in the art (see for example U.S. application Ser. No. 12/064,014). A synthesis column was packed with solid support derivatized with the first nucleoside residue (natural or chemically modified). Synthesis was initiated by detritylation of the acid labile 5′-O-dimethoxytrityl group to release the 5′-hydroxyl. A suitably protected phosphoramidite and a suitable activator in acetonitrile were delivered simultaneously to the synthesis column resulting in coupling of the amidite to the 5′-hydroxyl. The column was then washed with a solvent, such as acetonitrile. An oxidizing solution, such as an iodine solution was pumped through the column to oxidize the phosphite triester linkage P(III) to its phosphotriester P(V) analog. Unreacted 5′-hydroxyl groups were capped using reagents such as acetic anhydride in the presence of 2,6-lutidine and N-methylimidazole. The elongation cycle was resumed with the detritylation step for the next phosphoramidite incorporation. This process was repeated until the desired sequence was synthesized. The synthesis concluded with the final 5′-terminus protecting group (trityl or 5′-O-dimethoxytrityl).
  • Upon completion of the synthesis, the solid-support and associated oligonucleotide were dried under argon pressure or vacuum. Aqueous base was added and the mixture was heated to effect cleavage of the succinyl linkage, removal of the cyanoethyl phosphate protecting group, and deprotection of the exocyclic amine protection.
  • The following process was performed on single strands that do not contain ribonucleotides. After treating the solid support with the aqueous base, the mixture was filtered to separate the solid support from the deprotected crude synthesis material. The solid support was then rinsed with water, which is combined with the filtrate. The resultant basic solution allows for retention of the 5′-O-dimethoxytrityl group to remain on the 5′ terminal position (trityl-on).
  • For single strands that contain ribonucleotides, the following process was performed. After treating the solid support with the aqueous base, the mixture was filtered to separate the solid support from the deprotected crude synthesis material. The solid support was then rinsed with dimethylsulfoxide (DMSO), which was combined with the filtrate. Fluoride reagent, such as triethylamine trihydrofluoride, was added to the mixture, and the solution was heated. The reaction was quenched with suitable buffer to provide a solution of crude single strand with the 5′-O-dimethoxytrityl group on the final 5′ terminal position.
  • The trityl-on solution of each crude single strand was purified using chromatographic purification, such as SPE RPC purification. The hydrophobic nature of the trityl group permits stronger retention of the desired full-length oligo than the non-tritylated truncated failure sequences. The failure sequences were selectively washed from the resin with a suitable solvent, such as low percent acetonitrile. Retained oligonucleotides were then detritylated on-column with trifluoroacetic acid to remove the acid-labile trityl group. Residual acid was washed from the column, a salt exchange was performed, and a final desalting of the material commenced. The full-length oligo was recovered in a purified form with an aqueous-organic solvent. The final product was then analyzed for purity (HPLC), identity (Maldi-TOF MS), and yield (UV A260). The oligos were dried via lyophilization or vacuum condensation.
  • Annealing: Based on the analysis of the product, the dried oligos were dissolved in appropriate buffers followed by mixing equal molar amounts (calculated using the theoretical extinction coefficient) of the sense and antisense oligonucleotide strands. The solution was then analyzed for purity of duplex by chromatographic methods and desired final concentration. If the analysis indicated an excess of either strand, then the additional non-excess strand was titrated until duplexing was complete. When analysis indicated that the target product purity has been achieved the material was delivered and ready for use.
  • Below is a table showing various modified siNAs synthesized using this protocol or that can be synthesized using this protocol or using methods known in the art.
  • TABLE 1c
    CTNNB1 siNA Strands Synthesized (Antisense sequences are readily identified 
    as being complementary to the target sequence shown).
    Tar-
    get SEQ SEQ
    Site ID ID
    (hu- NO: NO:
    R Number man) 1 Target Sequence Modified Sequence 2
    R-008247452-000C  535    1 UCGAGCUCAGAGGGUACGA B ucGAGcucAGAGGGuAcGATT B 1454
    R-008247452-000C  535    1 UCGAGCUCAGAGGGUACGA UCGuAcccucuGAGcucGAUU 1455
    R-008247449-000W 1601    2 GAGGCUCUUGUGCGUACUG B GAGGcucuuGuGcGuAcuGTT B 1456
    R-008247449-000W 1601    2 GAGGCUCUUGUGCGUACUG CAGuAcGcAcAAGAGccucUU 1457
    R-008247575-000Y 1709    3 GCCCAGAAUGCAGUUCGCC B GcccAGAAuGcAGuucGccTT B 1458
    R-008247575-000Y 1709       3 GCCCAGAAUGCAGUUCGCC GGCGAAcuGcAuucuGGGcUU 1459
    R-008247572-000X  536    4 CGAGCUCAGAGGGUACGAG B cGAGcucAGAGGGuAcGAGTT B 1460
    R-008247572-000X  536    4 CGAGCUCAGAGGGUACGAG CUCGuAcccucuGAGcucGUU 1461
    R-008247569-000R 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGAAucAAuccAAcAGUU 1463
    R-008247569-000R 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAATT B 1462
    R-008247446-000V  853    6 GUCUGCUAUUGUACGUACC B GucuGcuAuuGuAcGuAccTT B 1464
    R-008247446-000V  853    6 GUCUGCUAUUGUACGUACC GGUAcGuAcAAuAGcAGAcUU 1465
    R-008247566-000P 1143    7 AAUUCUUGGCUAUUACGAC GUCGuAAuAGccAAGAAuuUU 1467
    R-008247566-000P 1143    7 AAUUCUUGGCUAUUACGAC B AAuucuuGGccAuuAcGAcTT B 1466
    R-008247563-000N 2014    8 GGAUGUUCACAACCGAAUU B GGAuGuucAcAAccGAAuuTT B 1468
    R-008247563-000N 2014    8 GGAUGUUCACAACCGAAUU AAUucGGuuGuGAAcAuccUU 1469
    R-008247560-000M  520    9 ACAGUAUGCAAUGACUCGA B AcAGuAuGcAAuGAcucGATT B 1470
    R-008247560-000M  520    9 ACAGUAUGCAAUGACUCGA UCGAGucAuuGcAuAcuGuUU 1471
    R-008247443-000U  814   10 AGCUUCCAGACACGCUAUC B AGcuuccAGAcAcGcuAucTT B 1472
    R-008247443-000U  814   10 AGCUUCCAGACACGCUAUC GAUAGcGuGucuGGAAGcuUU 1473
    R-008247440-000T  852   11 UGUCUGCUAUUGUACGUAC GUAcGuAcAAuAGcAGAcAUU 1475
    R-008247440-000T  852   11 UGUCUGCUAUUGUACGUAC B uGucuGcuAuuGuAcGuAcTT B 1474
    R-008247557-000F 1796   12 ACUGUUGGAUUGAUUCGAA UUCGAAucAAuccAAcAGuUU 1477
    R-008247557-000F 1796   12 ACUGUUGGAUUGAUUCGAA B AcuGuuGGAuuGAuucGAATT B 1476
    R-008247437-000L 1901   13 CAGGAUACCCAGCGCCGUA UACGGcGcuGGGuAuccuGUU 1479
    R-008247437-000L 1901   13 CAGGAUACCCAGCGCCGUA B cAGGAuAcccAGcGccGuATT B 1478
    R-008247554-000E  822   14 GACACGCUAUCAUGCGUUC B GAcAcGcuAucAuGcGuucTT B 1480
    R-008247554-000E  822   14 GACACGCUAUCAUGCGUUC GAAcGcAuGAuAGcGuGucUU 1481
    R-008247551-000D 1795   15 UACUGUUGGAUUGAUUCGA UCGAAucAAuccAAcAGuAUU 1483
    R-008247551-000D 1795   15 UACUGUUGGAUUGAUUCGA B uAcuGuuGGAuuGAuucGATT B 1482
    R-008247548-000X 1145   16 UUCUUGGCUAUUACGACAG B uucuuGGcuAuuAcGAcAGTT B 1484
    R-008247548-000X 1145   16 UUCUUGGCUAUUACGACAG CUGucGuAAuAGccAAGAAUU 1485
    R-008247545-000W  823   17 ACACGCUAUCAUGCGUUCU B AcAcGcuAucAuGcGuucuTT B 1486
    R-008247545-000W  823   17 ACACGCUAUCAUGCGUUCU AGAAcGcAuGAuAGcGuGuUU 1487
    R-008247434-000K  820   18 CAGACACGCUAUCAUGCGU B cAGAcAcGcuAucAuGcGuTT B 1488
    R-008247434-000K  820   18 CAGACACGCUAUCAUGCGU ACGcAuGAuAGcGuGucuGUU 1489
    R-008247431-000J 1798   19 UGUUGGAUUGAUUCGAAAU B uGuuGGAuuGAuucGAAAuTT B 1490
    R-008247431-000J 1798   19 UGUUGGAUUGAUUCGAAAU AUUucGAAucAAuccAAcAUU 1491
    R-008247428-000C 1380   20 CAGAUCCAAGUCAACGUCU B cAGAuccAAGucAAcGucuTT B 1492
    R-008247428-000C 1380   20 CAGAUCCAAGUCAACGUCU AGAcGuuGAcuuGGAucuGUU 1493
    R-008247542-000V 1602   21 AGGCUCUUGUGCGUACUGU B AGGcucuuGuGcGuAcuGuTT B 1494
    R-008247542-000V 1602   21 AGGCUCUUGUGCGUACUGU ACAGuAcGcAcAAGAGccuUU 1495
    R-008247539-000N 1612   22 GCGUACUGUCCUUCGGGCU B GcGuAcuGuccuucGGGcuTT B 1496
    R-008247539-000N 1612   22 GCGUACUGUCCUUCGGGCU AGCccGAAGGAcAGuAcGcUU 1497
    R-008247425-000B  626   23 ACUAAUGUCCAGCGUUUGG B AcuAAuGuccAGcGuuuGGTT B 1498
    R-008247425-000B  626   23 ACUAAUGUCCAGCGUUUGG CCAAAcGcuGGAcAuuAGuUU 1499
    R-008247536-000M 2000   24 CACAUCCUAGCUCGGGAUG B cAcAuccuAGcucGGGAuGTT B 1500
    R-008247536-000M 2000   24 CACAUCCUAGCUCGGGAUG CAUcccGAGcuAGGAuGuGUU 1501
    R-008247422-000A 2665   25 GUUGCUGAGAGGGCUCGAG B GuuGcuGAGAGGGcucGAGTT B 1502
    R-008247422-000A 2665   25 GUUGCUGAGAGGGCUCGAG CUCGAGcccucucAGcAAcUU 1503
    R-008247533-000L 1676   26 CAUCUGACCAGCCGACACC GGUGucGGcuGGucAGAuGUU 1505
    R-008247533-000L 1676   26 CAUCUGACCAGCCGACACC B cAucuGAccAGccGAcAccTT B 1504
    R-008247530-000K 1611   27 UGCGUACUGUCCUUCGGGC B uGcGuAcuGuccuucGGGcTT B 1506
    R-008247530-000K 1611   27 UGCGUACUGUCCUUCGGGC GCCcGAAGGAcAGuAcGcAUU 1507
    R-008247419-000U 2269   28 ACAAGAUUACAAGAAACGG B AcAAGAuuAcAAGAAAcGGTT B 1508
    R-008247419-000U 2269   28 ACAAGAUUACAAGAAACGG CCGuuucuuGuAAucuuGuUU 1509
    R-008247527-000D  674   29 GUUGUAAACUUGAUUAACU B GuuGuAAAcuuGAuuAAcuTT B 1510
    R-008247527-000D  674   29 GUUGUAAACUUGAUUAACU AGUuAAucAAGuuuAcAAcUU 1511
    R-008247602-000K  678   30 UAAACUUGAUUAACUAUCA B uAAAcuuGAuuAAcuAucATT B 1512
    R-008247602-000K  678   30 UAAACUUGAUUAACUAUCA UGAuAGuuAAucAAGuuuAUU 1513
    R-008247599-000T 1245   31 AUAUAAUGAGGACCUAUAC B AuAuAAuGAGGAccuAuAcTT B 1514
    R-008247599-000T 1245   31 AUAUAAUGAGGACCUAUAC GUAuAGGuccucAuuAuAuUU 1515
    R-008247596-000S  679   32 AAACUUGAUUAACUAUCAA B AAAcuuGAuuAAcuAucAATT B 1516
    R-008247596-000S  679   32 AAACUUGAUUAACUAUCAA UUGAuAGuuAAucAAGuuuUU 1517
    R-008247593-000R 1970   33 GAAAUAGUUGAAGGUUGUA B GAAAuAGuuGAAGGuuGuATT B 1518
    R-008247593-000R 1970   33 GAAAUAGUUGAAGGUUGUA UACAAccuucAAcuAuuucUU 1519
    R-008247590-000P 1247   34 AUAAUGAGGACCUAUACUU AAGuAuAGGuccucAuuAuUU 1521
    R-008247590-000P 1247   34 AUAAUGAGGACCUAUACUU B AuAAuGAGGAccuAuAcuuTT B 1520
    R-008247464-000M 1140   35 UUAAAUUCUUGGCUAUUAC B uuAAAuucuuGGcuAuuAcTT B 1522
    R-008247464-000M 1140   35 UUAAAUUCUUGGCUAUUAC GUAAuAGccAAGAAuuuAAUU 1523
    R-008247587-000H  676   36 UGUAAACUGGAUUAACUAU B uGuAAAcuuGAuuAAcuAuTT B 1524
    R-008247587-000H  676   36 UGUAAACUGGAUUAACUAU AUAGuuAAucAAGuuuAcAUU 1525
    R-008247461-000L  677   37 GUAAACUUGAUUAACUAUC GAUAGuuAAucAAGuuuAcUU 1527
    R-008247461-000L  677   37 GUAAACUUGAUUAACUAUC B GuAAAcuuGAuuAAcuAucTT B 1526
    R-008247458-000E  675   38 UUGUAAACUUGAUUAACUA B uuGuAAAcuuGAuuAAcuATT B 1528
    R-008247458-000E  675   38 UUGUAAACUUGAUUAACUA UAGuuAAucAAGuuuAcAAUU 1529
    R-008247584-000G 1235   39 GCUUUAGUAAAUAUAAUGA B GcuuuAGuAAAuAuAAuGATT B 1530
    R-008247584-000G 1235   39 GCUUUAGUAAAUAUAAUGA UCAuuAuAuuuAcuAAAGcUU 1531
    R-008247581-000F 2488   40 UGGCCACCACCCUGGUGCU B uGGccAccAcccuGGuGcuTT B 1532
    R-008247581-000F 2488   40 UGGCCACCACCCUGGUGCU AGCAccAGGGuGGuGGccAUU 1533
    R-008247578-000Z 1236   41 CUUUAGUAAAUAUAAUGAG B cuuuAGuAAAuAuAAuGAGTT B 1534
    R-008247578-000Z 1236   41 CUUUAGUAAAUAUAAUGAG CUCAuuAuAuuuAcuAAAGUU 1535
    R-008247455-000D 1237   42 UUUAGUAAAUAUAAUGAGG CCUcAuuAuAuuuAcuAAAUU 1537
    R-008247455-000D 1237   42 UUUAGUAAAUAUAAUGAGG B uuuAGuAAAuAuAAuGAGGTT B 1536
    R-008042883-001A 2555   43 GUAAAUCGUCCUUUAGGUA B GuAAAucGuccuuuAGGuATT B 1538
    R-008042883-001A 2555   43 GUAAAUCGUCCUUUAGGUA UACcuAAAGGAcGAuuuAcUU 1539
    R-008308583-000P 1545   44 ACCUCACUUGCAAUAAUUA B AccucAcuuGcAAuAAuuATT B 1540
    R-008308583-000P 1545   44 ACCUCACUUGCAAUAAUUA UAAuuAuuGcAAGuGAGGuUU 1541
    R-008308520-000J 2050   45 UACCAUUCCAUUGUUUGUG B uAccAuuccAuuGuuuGuGTT B 1542
    R-008308520-000J 2050   45 UACCAUUCCAUUGUUUGUG CACAAAcAAuGGAAuGGuAUU 1543
    R-008308622-000L 2097   46 UCCAAAGAGUAGCUGCAGG CCUGcAGcuAcucuuuGGAUU 1545
    R-008308622-000L 2097   46 UCCAAAGAGUAGCUGCAGG B uccAAAGAGuAGcuGcAGGTT B 1544
    R-008308652-000N 2510   47 UAUCCAGUUGAUGGGCUGC B uAuccAGuuGAuGGGcuGcTT B 1546
    R-008308652-000N 2510   47 UAUCCAGUUGAUGGGCUGC GCAGcccAucAAcuGGAuAUU 1547
    R-008308718-000F  871   48 CAUGCAGAAUACAAAUGAU AUCAuuuGuAuucuGcAuGUU 1549
    R-008308718-000F  871   48 CAUGCAGAAUACAAAUGAU B cAuGcAGAAuAcAAAuGAuTT B 1548
    R-008308694-000A 2098   49 CCAAAGAGUAGCUGCAGGG CCCuGcAGcuAcucuuuGGUU 1551
    R-008308694-000A 2098   49 CCAAAGAGUAGCUGCAGGG B ccAAAGAGuAGcuGcAGGGTT B 1550
    R-008308517-000C 1767   50 CACCAUCCCACUGGCCUCU B cAccAucccAcuGGccucuTT B 1552
    R-008308517-000C 1767   50 CACCAUCCCACUGGCCUCU AGAGGccAGuGGGAuGGuGUU 1553
    R-008308619-000E  869   51 ACCAUGCAGAAUACAAAUG B AccAuGcAGAAuAcAAAuGTT B 1554
    R-008308619-000E  869   51 ACCAUGCAGAAUACAAAUG CAUuuGuAuucuGcAuGGuUU 1555
    R-008308514-000B 1641   52 AAGACAUCACUGAGCCUGC B AAGAcAucAcuGAGccuGcTT B 1556
    R-008308514-000B 1641   52 AAGACAUCACUGAGCCUGC GCAGGcucAGuGAuGucuuUU 1557
    R-008308616-000D 2582   53 AAUCAGCUGGCCUGGUUUG B AAucAGcuGGccuGGuuuGTT B 1558
    R-008308616-000D 2582   53 AAUCAGCUGGCCUGGUUUG CAAAccAGGccAGcuGAuuUU 1559
    R-008308580-000N 1544   54 AACCUCACUUGCAAUAAUU AAUuAuuGcAAGuGAGGuu 1561
    R-008308580-000N 1544   54 AACCUCACUUGCAAUAAUU B AAccucAcuuGcAAuAAuuTT B 1560
    R-008308736-000Y 2550   55 ACCUCAUGGAUGGGCUGCC B AccucAuGGAuGGGcuGccTT B 1562
    R-008308736-000Y 2550   55 ACCUCAUGGAUGGGCUGCC GGCAGcccAuccAuGAGGuUU 1563
    R-008308613-000C 2051   56 ACCAUUCCAUUGUUUGUGC GCAcAAAcAAuGGAAuGGuUU 1565
    R-008308613-000C 2051   56 ACCAUUCCAUUGUUUGUGC B AccAuuccAuuGuuuGuGcTT B 1564
    R-008308577-000G  870   57 CCAUGCAGAAUACAAAUGA UCAuuuGuAuucuGcAuGGUU 1567
    R-008308577-000G  870   57 CCAUGCAGAAUACAAAUGA B ccAuGcAGAAuAcAAAuGATT B 1566
    R-008308691-000Z 1670   58 CUUCGUCAUCUGACCAGCC B cuucGucAucuGAccAGccTT B 1568
    R-008308691-000Z 1670   58 CUUCGUCAUCUGACCAGCC GGCuGGucAGAuGAcGAAGUU 1569
    R-008308649-000G 2122   59 CUGUGAACUUGCUCAGGAC B cuGuGAAcuuGcucAGGAcTT B 1570
    R-008308649-000G 2122   59 CUGUGAACUUGCUCAGGAC GUCcuGAGcAAGuucAcAGUU 1571
    R-008308553-000M 1642   60 AGACAUCACUGAGCCUGCC B AGAcAucAcuGAGccuGccTT B 1572
    R-008308553-000M 1642   60 AGACAUCACUGAGCCUGCC GGCAGGcucAGuGAuGucuUU 1573
    R-008308574-000F 2324   61 GAGCCAAUGGCUUGGAAUG B GAGccAAuGGcuuGGAAuGTT B 1574
    R-008308574-000F 2324   61 GAGCCAAUGGCUUGGAAUG CAUuccAAGccAuuGGcucUU 1575
    R-008308688-000T 1649   62 ACUGAGCCUGCCAUCUGUG B AcuGAGccuGccAucuGuGTT B 1576
    R-008308688-000T 1649   62 ACUGAGCCUGCCAUCUGUG CACAGAuGGcAGGcucAGuUU 1577
    R-008308550-000L 2159   63 AUUGAAGCUGAGGGAGCCA B AuuGAAGcuGAGGGAGccATT B 1578
    R-008308550-000L 2159   63 AUUGAAGCUGAGGGAGCCA UGGcucccucAGcuucAAuUU 1579
    R-008308511-000A  785   64 GUUAUGGUCCAUCAGCUUU B GuuAuGGuccAucAGcuuuTT B 1580
    R-008308511-000A  785   64 GUUAUGGUCCAUCAGCUUU AAAGcuGAuGGAccAuAAcUU 1581
    R-008308685-000S 1511   65 AAUGUGGUCACCUGUGCAG B AAuGuGGucAccuGuGcAGTT B 1582
    R-008308685-000S 1511   65 AAUGUGGUCACCUGUGCAG CUGcAcAGGuGAccAcAuuUU 1583
    R-008308610-000B 2586   66 AGCUGGCCUGGUUUGAUAC B AGcuGGccuGGuuuGAuAcTT B 1584
    R-008308610-000B 2586   66 AGCUGGCCUGGUUUGAUAC GUAucAAAccAGGccAGcuUU 1585
    R-008308571-000E  642   67 UGGCUGAACCAUCACAGAU B uGGcuGAAccAucAcAGAuTT B 1586
    R-008308571-000E  642   67 UGGCUGAACCAUCACAGAU AUCuGuGAuGGuucAGccAUU 1587
    R-008308715-000E 1763   68 CACCCACCAUCCCACUGGC B cAcccAccAucccAcuGGcTT B 1588
    R-008308715-000E 1763   68 CACCCACCAUCCCACUGGC GCCAGuGGGAuGGuGGGuGUU 1589
    R-008308682-000R 2328   69 CAAUGGCUUGGAAUGAGAC GUCucAuuccAAGccAuuGUU 1591
    R-008308682-000R 2328   69 CAAUGGCUUGGAAUGAGAC B cAAuGGcuuGGAAuGAGAcTT B 1590
    R-008308646-000F 1280   70 UGGACCACAAGCAGAGUGC GCAcucuGcuuGuGGuccAUU 1593
    R-008308646-000F 1280   70 UGGACCACAAGCAGAGUGC B uGGAccAcAAGcAGAGuGcTT B 1592
    R-008308508-000U 2052   71 CCAUUCCAUUGUUUGUGCA B ccAuuccAuuGuuuGuGcATT B 1594
    R-008308508-000U 2052   71 CCAUUCCAUUGUUUGUGCA UGCAcAAAcAAuGGAAuGGUU 1595
    R-008308547-000E 2546   72 CAGGACCUCAUGGAUGGGC GCCcAuccAuGAGGuccuGUU 1597
    R-008308547-000E 2546   72 CAGGACCUCAUGGAUGGGC B cAGGAccucAuGGAuGGGcTT B 1596
    R-008308505-000T 2124   73 GUGAACUUGCUCAGGACAA UUGuccuGAGcAAGuucAcUU 1599
    R-008308505-000T 2124   73 GUGAACUUGCUCAGGACAA B GuGAAcuuGcucAGGAcAATT B 1598
    R-008308733-000X 2545   74 CCAGGACCUCAUGGAUGGG CCCAuccAuGAGGuccuGGUU 1601
    R-008308733-000X 2545   74 CCAGGACCUCAUGGAUGGG B ccAGGAccucAuGGAuGGGTT B 1600
    R-008308544-000D  643   75 GGCUGAACCAUCACAGAUG B GGcuGAAccAucAcAGAuGTT B 1602
    R-008308544-000D  643   75 GGCUGAACCAUCACAGAUG CAUcuGuGAuGGuucAGccUU 1603
    R-008308643-000E 2501   76 GGUGCUGACUAUCCAGUUG B GGuGcuGAcuAuccAGuuGTT B 1604
    R-008308643-000E 2501   76 GGUGCUGACUAUCCAGUUG CAAcuGGAuAGucAGcAccUU 1605
    R-008308712-000D 2330   77 AUGGCUUGGAAUGAGACUG B AuGGcuuGGAAuGAGAcuGTT B 1606
    R-008308712-000D 2330   77 AUGGCUUGGAAUGAGACUG CAGucucAuuccAAGccAuUU 1607
    R-008308568-000Y 1638   78 GGGAAGACAUCACUGAGCC GGCucAGuGAuGucuucccUU 1609
    R-008308568-000Y 1638   78 GGGAAGACAUCACUGAGCC B GGGAAGAcAucAcuGAGccTT B 1608
    R-008308640-000D 1630   79 IGGUGACAGGGAAGACAUC B uGGuGAcAGGGAAGAcAucTT B 1610
    R-008308640-000D 1630   79 UGGUGACAGGGAAGACAUC GAUGucuucccuGucAccAUU 1611
    R-008308541-000C  616   80 UGCUCAUCCCACUAAUGUC GACAuuAGuGGGAuGAGcAUU 1613
    R-008308541-000C  616   80 UGCUCAUCCCACUAAUGUC B uGcucAucccAcuAAuGucTT B 1612
    R-008308679-000J 2509   81 CUAUCCAGUUGAUGGGCUG B cuAuccAGuuGAuGGGcuGTT B 1614
    R-008308679-000J 2509   81 CUAUCCAGUUGAUGGGCUG CAGcccAucAAcuGGAuAGUU 1615
    R-008308565-000X 2548   82 GGACCUCAUGGAUGGGCUG B GGAccucAuGGAuGGGcuGTT B 1616
    R-008308565-000X 2548   82 GGACCUCAUGGAUGGGCUG CAGcccAuccAuGAGGuccUU 1617
    R-008308538-000W 1773   83 CCCACUGGCCUCUGAUAAA UUUAucAGAGGccAGuGGGUU 1619
    R-008308538-000W 1773   83 CCCACUGGCCUCUGAUAAA B cccAcuGGccucuGAuAAATT B 1618
    R-008308535-000V 2247   84 UCCGAAUGUCUGAGGACAA UUGuccucAGAcAuucGGAUU 1621
    R-008308535-000V 2247   84 UCCGAAUGUCUGAGGACAA B uccGAAuGucuGAGGAcAATT B 1620
    R-008308637-000X 2331   85 UGGCUUGGAAUGAGACUGC B uGGcuuGGAAuGAGAcuGcTT B 1622
    R-008308637-000X 2331   85 UGGCUUGGAAUGAGACUGC GCAGucucAuuccAAGccAUU 1623
    R-008309111-000F 1498   86 UUCAGAUGAUAUAAAUGUG CACAuuuAuAucAucuGAAUU 1625
    R-008309111-000F 1498   86 UUCAGAUGAUAUAAAUGUG B uucAGAuGAuAuAAAuGuGTT B 1624
    R-008309108-000Z 2267   87 CCACAAGAUUACAAGAAAC B ccAcAAGAuuAcAAGAAAcTT B 1626
    R-008309108-000Z 2267   87 CCACAAGAUUACAAGAAAC GUUucuuGuAAucuuGuGGUU 1627
    R-008308994-000E 1547   88 CUCACUUGCAAUAAUUAUA UAUAAuuAuuGcAAGuGAGUU 1629
    R-008308994-000E 1547   88 CUCACUUGCAAUAAUUAUA B cucAcuuGcAAuAAuuAuATT B 1628
    R-008309075-000K 1549   89 CACUUGCAAUAAUUAUAAG CUUAuAAuuAuuGcAAGuGUU 1631
    R-008309075-000K 1549   89 CACUUGCAAUAAUUAUAAG B cAcuuGcAAuAAuuAuAAGTT B 1630
    R-008309045-000H  867   90 GUACCAUGCAGAAUACAAA UUUGuAuucuGcAuGGuAcUU 1633
    R-008309045-000H  867   90 GUACCAUGCAGAAUACAAA B GuAccAuGcAGAAuAcAAATT B 1632
    R-008309072-000J 1390   91 UCAACGUCUUGUUCAGAAC B ucAAcGucuuGuucAGAAcTT B 1634
    R-008309072-000J 1390   91 UCAACGUCUUGUUCAGAAC GUUcuGAAcAAGAcGuuGAUU 1635
    R-008309027-000R  593   92 AUCCCAUCUACACAGUUUG CAAAcuGuGuAGAuGGGAuUU 1637
    R-008309027-000R  593   92 AUCCCAUCUACACAGUUUG B AucccAucuAcAcAGuuuGTT B 1636
    R-008309009-000Y  274   93 UACUCAAGCUGAUUUGAUG CAUcAAAucAGcuuGAGuAUU 1639
    R-008309009-000Y  274   93 UACUCAAGCUGAUUUGAUG B uAcucAAGcuGAuuuGAuGTT B 1638
    R-008309024-000P  759   94 ACCAGGUGGUGGUUAAUAA B AccAGGuGGuGGuuAAuAATT B 1640
    R-008309024-000P  759   94 ACCAGGUGGUGGUUAAUAA UUAuuAAccAccAccuGGuUU 1641
    R-008309093-000C 1439   95 GCUGCAACUAAACAGGAAG B GcuGcAAcuAAAcAGGAAGTT B 1642
    R-008309093-000C 1439   95 GCUGCAACUAAACAGGAAG CUUccuGuuuAGuuGcAGcUU 1643
    R-008309069-000C 1801   96 UGGAUUGAUUCGAAAUCUU B uGGAuuGAuucGAAAucuuTT B 1644
    R-008309069-000C 1801   96 UGGAUUGAUUCGAAAUCUU AAGAuuucGAAucAAuccAUU 1645
    R-008309021-000N 1500   97 CAGAUGAUAUAAAUGUGGU B cAGAuGAuAuAAAuGuGGuTT B 1646
    R-008309021-000N 1500   97 CAGAUGAUAUAAAUGUGGU ACCAcAuuuAuAucAucuGUU 1647
    R-008309066-000B  848   98 AUGGUGUCUGCUAUUGUAC B AuGGuGucuGcuAuuGuAcTT B 1648
    R-008309066-000B  848   98 AUGGUGUCUGCUAUUGUAC GUAcAAuAGcAGAcAccAuUU 1649
    R-008309105-000Y 2268   99 CACAAGAUUACAAGAAACG CGUuucuuGuAAucuuGuGUU 1651
    R-008309105-000Y 2268   99 CACAAGAUUACAAGAAACG B cAcAAGAuuAcAAGAAAcGTT B 1650
    R-008309042-000G  882  100 CAAAUGAUGUAGAAACAGC GCUGuuucuAcAucAuuuGUU 1653
    R-008309042-000G  882  100 CAAAUGAUGUAGAAACAGC B cAAAuGAuGuAGAAAcAGcTT B 1652
    R-008309063-000A 2266  101 GCCACAAGAUUACAAGAAA UUUcuuGuAAucuuGuGGcUU 1655
    R-008309063-000A 2266  101 GCCACAAGAUUACAAGAAA B GccAcAAGAuuAcAAGAAATT B 1654
    R-008309018-000G  880  102 UACAAAUGAUGUAGAAACA B uAcAAAuGAuGuAGAAAcATT B 1656
    R-008309018-000G  880  102 UACAAAUGAUGUAGANACA UGUuucuAcAucAuuuGuAUU 1657
    R-008309039-000A 1810  103 UCGAAAUCUUGCCCUUUGU ACAAAGGGcAAGAuuucGAUU 1659
    R-008309039-000A 1810  103 UCGAAAUCUUGCCCUUUGU B ucGAAAucuuGcccuuuGuTT B 1658
    R-008309015-000F  685  104 GAUUAACUAUCAAGAUGAU B GAuuAAcuAucAAGAuGAuTT B 1660
    R-008309015-000F  685  104 GAUUAACUAUCAAGAUGAU AUCAucuuGAuAGuuAAucUU 1661
    R-008309060-000Z 1007  105 CCAGUGGAUUCUGUGUUGU ACAAcAcAGAAuccAcuGGUU 1663
    R-008309060-000Z 1007  105 CCAGUGGAUUCUGUGUUGU B ccAGuGGAuucuGuGuuGuTT B 1662
    R-008309057-000T 1789  106 AAAGGCUACUGUUGGAUUG B AAAGGcuAcuGuuGGAuuGTT B 1664
    R-008309057-000T 1789  106 AAAGGCUACUGUUGGAUUG CAAuccAAcAGuAGccuuuUU 1665
    R-008309054-000S  499  107 ACAAGUAGCUGAUAUUGAU AUCAAuAucAGcuAcuuGuUU 1667
    R-008309054-000S  499  107 ACAAGUAGCUGAUAUUGAU B AcAAGuAGcuGAuAuuGAuTT B 1666
    R-008309090-000B 2470  108 GAUGGAACAUGAGAUGGGU B GAuGGAAcAuGAGAuGGGuTT B 1668
    R-008309090-000B 2470  108 GAUGGAACAUGAGAUGGGU ACCcAucucAuGuuccAucUU 1669
    R-008309051-000R  694  109 UCAAGAUGAUGCAGAACUU B ucAAGAuGAuGcAGAAcuuTT B 1670
    R-008309051-000R  694  109 UCAAGAUGAUGCAGAACUU AAGuucuGcAucAucuuGAUU 1671
    R-008309036-000Z  278  110 CAAGCUGAUUUGAUGGAGU ACUccAucAAAucAGcuuGUU 1673
    R-008309036-000Z  278  110 CAAGCUGAUUUGAUGGAGU B cAAGcuGAuuuGAuGGAGuTT B 1672
    R-008309102-000X 1415  111 UGGACUCUCAGGAAUCUUU B uGGAcucucAGGAAucuuuTT B 1674
    R-008309102-000X 1415  111 UGGACUCUCAGGAAUCUUU AAAGAuuccuGAGAGuccAUU 1675
    R-008308991-000D 2046  112 UAAAUACCAUUCCAUUGUU AACAAuGGAAuGGuAuuuAUU 1677
    R-008308991-000D 2046  112 UAAAUACCAUUCCAUUGUU B uAAAuAccAuuccAuuGuuTT B 1676
    R-008309006-000X 1057  113 AUUACAUCAAGAAGGAGCU AGCuccuucuuGAuGuAAuUU 1679
    R-008309006-000X 1057  113 AUUACAUCAAGAAGGAGCU B AuuAcAucAAGAAGGAGcuTT B 1678
    R-008309087-000V 1422  114 UCAGGAAUCUUUCAGAUGC B ucAGGAAucuuucAGAuGcTT B 1680
    R-008309087-000V 1422  114 UCAGGAAUCUUUCAGAUGC GCAucuGAAAGAuuccuGAUU 1681
    R-008309084-000U  684  115 UGAUUAACUAUCAAGAUGA UCAucuuGAuAGuuAAucAUU 1683
    R-008309084-000U  684  115 UGAUUAACUAUCAAGAUGA B uGAuuAAcuAucAAGAuGATT B 1682
    R-008309099-000E 2197  116 ACUUCACUCUAGGAAUGAA B AcuucAcucuAGGAAuGAATT B 1684
    R-008309099-000E 2197  116 ACUUCACUCUAGGAAUGAA UUCAuuccuAGAGuGAAGuUU 1685
    R-008309003-000W  666  117 AACAUGCAGUUGUAAACUU B AAcAuGcAGuuGuAAAcuuTT B 1686
    R-008309003-000W  666  117 AACAUGCAGUUGUAAACUU AAGuuuAcAAcuGcAuGuuUU 1687
    R-008309012-000E  279  118 AAGCUGAUUUGAUGGAGUU AACuccAucAAAucAGcuuUU 1689
    R-008309012-000E  279  118 AAGCUGAUUUGAUGGAGUU B AAGcuGAuuuGAuGGAGuuTT B 1688
    R-008309033-000Y 1492  119 UCUGGGUUCAGAUGAUAUA B ucuGGGuucAGAuGAuAuATT B 1690
    R-008309033-000Y 1492  119 UCUGGGUUCAGAUGAUAUA UAUAucAucuGAAcccAGAUU 1691
    R-008309081-000T 2195  120 UUACUUCACUCUAGGAAUG CAUuccuAGAGuGAAGuAAUU 1693
    R-008309081-000T 2195  120 UUACUUCACUCUAGGAAUG B uuAcuucAcucuAGGAAuGTT B 1692
    R-008309048-000J 1424  121 AGGAAUCUUUCAGAUGCUG B AGGAAucuuucAGAuGcuGTT B 1694
    R-008309048-000J 1424  121 AGGAAUCUUUCAGAUGCUG CAGcAucuGAAAGAuuccuUU 1695
    R-008309000-000V  661  122 GCUGAAACAUGCAGUUGUA UACAAcuGcAuGuuucAGcUU 1697
    R-008309000-000V  661  122 GCUGAAACAUGCAGUUGUA B GcuGAAAcAuGcAGuuGuATT B 1696
    R-008309078-000L 1882  123 GUUGCUUGUUCGUGCACAU B GuuGcuuGuucGuGcAcAuTT B 1698
    R-008309078-000L 1882  123 GUUGCUUGUUCGUGCACAU AUGuGcAcGAAcAAGcAAcUU 1699
    R-008309096-000D 1966  124 GGAAGAAAUAGUUGAAGGU B GGAAGAAAuAGuuGAAGGuTT B 1700
    R-008309096-000D 1966  124 GGAAGAAAUAGUUGAAGGU ACCuucAAcuAuuucuuccUU 1701
    R-008308997-000F 2259  125 AGGACAAGCCACAAGAUUA B AGGAcAAGccAcAAGAuuATT B 1702
    R-008308997-000F 2259  125 AGGACAAGCCACAAGAUUA UAAucuuGuGGcuuGuccuUU 1703
    R-008309030-000X  832  126 CAUGCGUUCUCCUCAGAUG B cAuGcGuucuccucAGAuGTT B 1704
    R-008309030-000X  832  126 CAUGCGUUCUCCUCAGAUG CAUcuGAGGAGAAcGcAuGUU 1705
    R-008042849-001H 2346  127 GAUGAUCCCAGCUACCGUU AACGGuAGcuGGGAucAucUU 1707
    R-008042849-001H 2346  127 GAUGAUCCCAGCUACCGUU B GAuGAucccAGcuAccGuuTT B 1706
    R-008308601-000T 1653  128 AGCCUGCCAUCUGDGCUCU B AGccuGccAucuGuGcucuTT B 1708
    R-008308601-000T 1653  128 AGCCUGCCAUCUGDGCUCU AGAGcAcAGAuGGcAGGcuUU 1709
    R-008308562-000W 2389  129 UGGAUAUCGCCAGGAUGAU B uGGAuAucGccAGGAuGAuTT B 1710
    R-008308562-000W 2389  129 UGGAUAUCGCCAGGAUGAU AUCAuccuGGcGAuAuccAUU 1711
    R-008308709-000X 1669  130 UCUUCGUCAUCUGACCAGC B ucuucGucAucuGAccAGcTT B 1712
    R-008308709-000X 1669  130 UCUUCGUCAUCUGACCAGC GCUGGucAGAuGAcGAAGAUU 1713
    R-008308634-000W 2123  131 UGUGAACUUGCUCAGGACA B uGuGAAcuuGcucAGGAcATT B 1714
    R-008308634-000W 2123  131 UGUGAACUUGCUCAGGACA UGUccuGAGcAAGuucAcAUU 1715
    R-008308667-000Z 1521  132 CCUGUGCAGCUGGAAUUCU B ccuGuGcAGcuGGAAuucuTT B 1716
    R-008308667-000Z 1521  132 CCUGUGCAGCUGGAAUUCU AGAAuuccAGcuGcAcAGGUU 1717
    R-008308706-000W 2125  133 UGAACUUGCUCAGGACAAG CUUGuccuGAGcAAGuucAUU 1719
    R-008308706-000W 2125  133 UGAACUUGCUCAGGACAAG B uGAAcuuGcucAGGAcAAGTT B 1718
    R-008308724-000N 2503  134 UGCUGACUAUCCAGUUGAU B uGcuGAcuAuccAGuuGAuTT B 1720
    R-008308724-000N 2503  134 UGCUGACUAUCCAGUUGAU AUCAAcuGGAuAGucAGcAUU 1721
    R-008308703-000V 1502  135 GAUGAUAUAAAUGUGGUCA UGAccAcAuuuAuAucAucUU 1723
    R-008308703-000V 1502  135 GAUGAUAUAAAUGUGGUCA B GAuGAuAuAAAuGuGGucATT B 1722
    R-008308496-000Y 2502  136 GUGCUGACUAUCCAGUUGA UCAAcuGGAuAGucAGcAcUU 1725
    R-008308496-000Y 2502  136 GAUGAUAUAAAUGUGGUCA B GuGcuGAcuAuccAGuuGATT B 1724
    R-008308625-000M 2506  137 UGACUAUCCAGUUGAUGGG CCCAucAAcuGGAuAGucAUU 1727
    R-008308625-000M 2506  137 UGACUAUCCAGUUGAUGGG B uGAcuAuccAGuuGAuGGGTT B 1726
    R-008308589-000S 2127  138 AACUUGCUCAGGACAAGGA B AAcuuGcucAGGAcAAGGATT B 1728
    R-008308589-000S 2127  138 AACUUGCUCAGGACAAGGA UCCuuGuccuGAGcAAGuuUU 1729
    R-008308586-000R 2505  139 CUGACUAUCCAGUUGAUGG B cuGAcuAuccAGuuGAuGGTT B 1730
    R-008308586-000R 2505  139 CUGACUAUCCAGUUGAUGG CCAucAAcuGGAuAGucAGUU 1731
    R-008308493-000X  617  140 GCUCAUCCCACUAAUGUCC B GcucAucccAcuAAuGuccTT B 1732
    R-008308493-000X  617  140 CCUCAUCCCACUAAUGUCC GGAcAuuAGuGGGAuGAGcUU 1733
    R-008308697-000B 2504  141 GCUGACUAUCCAGUUGAUG B GcuGAcuAuccAGuuGAuGTT B 1734
    R-008308697-000B 2504  141 GCUGACUAUCCAGUUGAUG CAUcAAcuGGAuAGucAGcUU 1735
    R-008308661-000X 1503  142 AUGAUAUAAAUGUGGUCAC GUGAccAcAuuuAuAucAuUU 1737
    R-008308661-000X 1503  142 AUGAUAUAAAUGUGGUCAC B AuGAuAuAAAuGuGGucAcTT B 1736
    R-008308526-000L  618  143 CUCAUCCCACUAAUGUCCA UGGAcAuuAGuGGGAuGAGUU 1739
    R-008308526-000L  618  143 CUCAUCCCACUAAUGUCCA B cucAucccAcuAAuGuccATT B 1738
    R-008308556-000N 2074  144 GCUUUAUUCUCCCAUUGAA B GcuuuAuucucccAuuGAATT B 1740
    R-008308556-000N 2074  144 GCUUUAUUCUCCCAUUGAA UUCAAuGGGAGAAuAAAGcUU 1741
    R-008308523-000K 2499  145 CUGGUGCUGACUAUCCAGU B cuGGuGcuGAcuAuccAGuTT B 1742
    R-008308523-000K 2499  145 CUGGUGCUGACUAUCCAGU ACUGGAuAGucAGcAccAGUU 1743
    R-008362860-000A 1406  146 AACUGUCUUUGGACUCUCA B AAcuGucuuuGGAcucucATT B 1744
    R-008362860-000A 1406  146 AACUGUCUUUGGACUCUCA UGAGAGuccAAAGAcAGuuUU 1745
    R-008362809-000Z  582  147 AGGGCAUGCAGAUCCCAUC GAUGGGAucuGcAuGcccuUU 1747
    R-008362809-000Z  582  147 AGGGCAUGCAGAUCCCAUC B AGGGcAuGcAGAucccAucTT B 1746
    R-008362908-000A 1505  148 GAUAUAAAUGUGGUCACCU B GAuAuAAAuGuGGucAccuTT B 1748
    R-008362908-000A 1505  148 GAUAUAAAUGUGGUCACCU AGGuGAccAcAuuuAuAucUU 1749
    R-008362713-000E 1432  449 UUCAGAUGCUGCAACUAAA UUUAGuuGcAGcAucuGAAUU 1751
    R-008362713-000E 1432  149 UUCAGAUGCUGCAACUAAA B uucAGAuGcuGcAAcuAAATT B 1750
    R-008363073-000K 1968  150 AAGAAAUAGUUGAAGGUUG B AAGAAAuAGuuGAAGGuuGTT B 1752
    R-008363073-000K 1968  150 AAGAAAUAGUUGAAGGUUG CAAccuucAAcuAuuucuuUU 1753
    R-008362947-000L 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuTT B 1754
    R-008362947-000L 2398  151 CCAGGAUGAUCCUAGCUAU AUAGcuAGGAucAuccuGGUU 1755
    R-008363070-000J  954  152 UGGCCAUCUUUAAGUCUUG CCAGAcuuAAAGAuGGccAUU 1757
    R-008363070-000J  954  152 UGGCCAUCUUUAAGUCUGG B uGGccAucuuuAAGucuGGTT B 1756
    R-008362857-000U  505  153 AGCUGAUAUUGAUGGACAG B AGcuGAuAuuGAuGGAcAGTT B 1758
    R-008362857-000U  505  153 AGCUGAUAUUGAUGGACAG CUGuccAucAAuAucAGcuUU 1759
    R-008363067-000C 2011  154 UCGGGAUGUUCACAACCGA B ucGGGAuGuucAcAAccGATT B 1760
    R-008363067-000C 2011  154 UCGGGAUGUUCACAACCGA UCGGuuGuGAAcAucccGAUU 1761
    R-008362944-000K 1339  155 UGUAGAAGCUGGUGGAAUG B uGuAGAAGcuGGuGGAAuGTT B 1762
    R-008362944-000K 1339  155 UGUAGAAGCUGGUGGAAUG CAUuccAccAGcuucuAcAUU 1763
    R-008362761-000Z 1242  156 UAAAUAUAAUGAGGACCUA B uAAAuAuAAuGAGGAccuATT B 1764
    R-008362761-000Z 1242  156 UAAAUAUAAUGAGGACCUA UAGGuccucAuuAuAuuuAUU 1765
    R-008362758-000T  567  157 CUGAGACAUUAGAUGAGGG B cuGAGAcAuuAGAuGAGGGTT B 1766
    R-008362758-000T  567  157 CUGAGACAUUAGAUGAGGG CCCucAucuAAuGucucAGUU 1767
    R-008363007-000Y 1240  158 AGUAAAUAUAAUGAGGACC B AGuAAAuAuAAuGAGGAccTT B 1768
    R-008363007-000Y 1240  158 AGUAAAUAUAAUGAGGACC GGUccucAuuAuAuuuAcuUU 1769
    R-008362854-000T  438  159 UGGAUACCUCCCAAGUCCU B uGGAuAccucccAAGuccuTT B 1770
    R-008362854-000T  438  159 UGGAUACCUCCCAAGUCCU AGGAcuuGGGAGGuAuccAUU 1771
    R-008362755-000S 2445  160 AGGAUGCCUUGGGUAUGGA UCCAuAcccAAGGcAuccuUU 1773
    R-008362755-000S 2445  160 AGGAUGCCUUGGGUAUGGA B AGGAuGccuuGGGuAuGGATT B 1772
    R-008363064-000B  860  161 AUUGUACGUACCAUGCAGA B AuuGuAcGuAccAuGcAGATT B 1774
    R-008363064-000B  860  161 AUUGUACGUACCAUGGAGA UCUGcAuGGuAcGuAcAAuUU 1775
    R-008362752-000R 1413  162 UUUGGACUCUCAGGAAUCU B uuuGGAcucucAGGAAucuTT B 1776
    R-008362752-000R 1413  162 UUUGGACUCUCAGGAAUCU AGAuuccuGAGAGuccAAAUU 1777
    R-008363061-000A 1800  163 UUGGAUUGAUUCGAAAUCU AGAuuucGAAucAAuccAAUU 1779
    R-008363061-000A 1800  163 UUGGAUUGAUUCGAAAUCU B uuGGAuuGAuucGAAAucuTT B 1778
    R-008363004-000X 2037  164 UCAGAGGACUNAAUACCAU AUGGuAuuuAGuccucuGAUU 1781
    R-008363004-000X 2037  164 UCAGAGGACUAAAUACCAU B ucAGAGGAcuAAAuAccAuTT B 1780
    R-008362851-000S 2443  165 CCAGGAUGCCUUGGGUAUG B ccAGGAuGccuuGGGuAuGTT B 1782
    R-008362851-000S 2443  165 CCAGGAUGCCUUGGGUAUG CAUAcccAAGGcAuccuGGUU 1783
    R-008363001-000W 2471  166 AUGGAACAUGAGAUGGGUG B AuGGAAcAuGAGAuGGGuGTT B 1784
    R-008363001-000W 2471  166 AUGGAACAUGAGAUGGGUG CACccAucucAuGuuccAuUU 1785
    R-008362905-000Z 1792  167 GGCUACUGUUGGAUUGAUU B GGcuAcuGuuGGAuuGAuuTT B 1786
    R-008362905-000Z 1792  167 GGCUACUGUUGGAUUGAUU AAUcAAuccAAcAGuAGccUU 1787
    R-008362902-000Y 2547  168 AGGACCUCAUGGAUGGGCU B AGGAccucAuGGAuGGGcuTT B 1788
    R-008362902-000Y 2547  168 AGGACCUCAUGGAUGGGCU AGCccAuccAuGAGGuccuUU 1789
    R-008362998-000G 1662  169 UCUGUGCUCUUCGUCAUCU AGAuGAcGAAGAGcAcAGAUU 1791
    R-008362998-000G 1662  169 UCUGUGCUCUUCGUCAUCU B ucuGuGcucuucGucAucuTT B 1790
    R-008362848-000K  288  170 UGAUGGAGUUGGACAUGGC GCCAuGuccAAcuccAucAUU 1793
    R-008362848-000K  288  170 UGAUGGAGUUGGACAUGGC B uGAuGGAGuuGGAcAuGGcTT B 1792
    R-008362710-000D  579  171 AUGAGGGCAUGCAGAUCCC GGGAucuGcAuGcccucAuUU 1795
    R-008362710-000D  579  171 AUGAGGGCAUGCAGAUCCC B AuGAGGGcAuGcAGAucccTT B 1794
    R-008362707-000X 2508  172 ACUAUCCAGUUGAUGGGCU AGCccAucAAcuGGAuAGuUU 1797
    R-008362707-000X 2508  172 ACUAUCCAGUUGAUGGGCU B AcuauccAGuuGAuGGGcuTT B 1796
    R-008362806-000Y  580  173 UGAGGGCAUGCAGAUCCCA B uGAGGGcAuGcAGAucccATT B 1798
    R-008362806-000Y  580  173 UGAGGGCAUGGAGAUCCCA UGGGAucuGcAuGcccucAUU 1799
    R-008362803-000X 2388  174 UUGGAUAUCGCCAGGAUGA B uuGGAuAucGccAGGAuGATT B 1800
    R-008362803-000X 2388  174 UUGGAUAUCGCCAGGAUGA UCAuccuGGcGAuAuccAAUU 1801
    R-008362899-000F 2543  175 GCCCAGGACCUCAUGGAUG B GcccAGGAccucAuGGAuGTT B 1802
    R-008362899-000F 2543  175 GCCCAGGACCUCAUGGAUG CAUccAuGAGGuccuGGGcUU 1803
    R-008362749-000J  708  176 AACUUGCCACACGUGCAAU B AAcuuGccAcAcGuGcAAuTT B 1804
    R-008362749-000J  708  176 AACUUGCCACACGUGCAAU AUUGcAcGuGuGGcAAGuuUU 1805
    R-008362845-000J  447  177 CCCAAGUCCUGUAUGAGUG B cccAAGuccuGuAuGAGuGTT B 1806
    R-008362845-000J  447  177 CCCAAGUCCUGUAUGAGUG CACucAuAcAGGAcuuGGGUU 1807
    R-008362842-000H  654  178 CACAGAUGCUGAAACAUGC GCAuGuuucAGcAucuGuGUU 1809
    R-008362842-000H  654  178 CACAGAUGCUGAAACAUGC B cAcAGAuGcuGAAAcAuGcTT B 1808
    R-008362896-000E  912  179 CUGGGACCUUGCAUAACCU B cuGGGAccuuGcAuAAccuTT B 1810
    R-008362896-000E  912  179 CUGGGACCUUGCAUAACCU AGGuuAuGcAAGGucccAGUU 1811
    R-008363058-000U 1009  180 AGUGGAUUCUGUGUUGUUU AAAcAAcAcAGAAuccAcuUU 1813
    R-008363058-000U 1009  180 AGUGGAUUCUGUGUUGUUU B AGuGGAuucuGuGuuGuuuTT B 1812
    R-008362941-000J 1354  181 AAUGCAAGCUUUAGGACUU B AAuGcAAGcuuuAGGAcuuTT B 1814
    R-008362941-000J 1354  181 AAUGCAAGCUUUAGGACUU AAGuccuAAAGcuuGcAuuUU 1815
    R-008362839-000B 1969  182 AGAAAUAGUUGAAGGUUGU B AGAAAuAGuuGAAGGuuGuTT B 1816
    R-008362839-000B 1969  182 AGAAAUAGUUGAAGGUUGU ACAAccuucAAcuAuuucuUU 1817
    R-008363055-000T 1959  183 UCCGCAUGGAAGAAAUAGU ACUAuuucuuccAuGcGGAUU 1819
    R-008363055-000T 1959  183 UCCGCAUGGAAGAAAUAGU B uccGcAuGGAAGAAAuAGuTT B 1818
    R-008362836-000A  557  184 GCUAUGUUCCCUGAGACAU B GcuAuGuucccuGAGAcAuTT B 1820
    R-008362836-000A  557  184 GCUAUGUUCCCUGAGACAU AUGucucAGGGAAcAuAGcUU 1821
    R-008363052-000S  403  185 UCUGAGUGGUAAAGGCAAU AUUGccuuuAccAcucAGAUU 1823
    R-008363052-000S  403  185 UCUGAGUGGUAAAGGCAAU B ucuGAGuGGuAAAGGcAAuTT B 1822
    R-008363049-000K 1356  186 UGCAAGCUUUAGGACUUCA B uGcAAGcuuuAGGAcuucATT B 1824
    R-008363049-000K 1356  186 UGCAAGCUUUAGGACUUCA UGAAGuccuAAAGcuuGcAUU 1825
    R-008362893-000D  517  187 UGGACAGUAUGCAAUGACU B uGGAcAGuAuGcAAuGAcuTT B 1826
    R-008362893-000D  517  187 UGGACAGUAUGCAAUGACU AGUcAuuGcAuAcuGuccAUU 1827
    R-008362890-000C 1238  188 UUAGUAAAUAUAAUGAGGA UCCucAuuAuAuuuAcuAAUU 1829
    R-008362890-000C 1238  188 UUAGUAAAUAUAAUGAGGA B uuAGuAAAuAuAAuGAGGATT B 1828
    R-008362995-000F  843  189 CUCAGAUGGUGUCUGCUAU B cucAGAuGGuGucuGcuAuTT B 1830
    R-008362995-000F  843  189 CUCAGAUGGUGUCUGCUAU AUAGcAGAcAccAucuGAGUU 1831
    R-008362992-000E  496  190 AGAACAAGUAGCUGAUAUU B AGAAcAAGuAGcuGAuAuuTT B 1832
    R-008362992-000E  496  190 AGAACAAGUAGCUGAUAUU AAUAucAGcuAcuuGuucuUU 1833
    R-008363046-000J 2387  191 CUUGGAUAUCGCCAGGAUG B cuuGGAuAucGccAGGAuGTT B 1834
    R-008363046-000J 2387  191 CUUGGAUAUCGCCAGGAUG CAUccuGGcGAuAuccAAGUU 1835
    R-008362704-000W 1660  192 CAUCUGUGCUCUUCGUCAU AUGAcGAAGAGcAcAGAuGUU 1837
    R-008362704-000W 1660  192 CAUCUGUGCUCUUCGUCAU B cAucuGuGcucuucGucAuTT B 1836
    R-008362938-000C 2497  193 CCCUGGUGCUGACUAUCCA B cccuGGuGcuGAcuAuccATT B 1838
    R-008362938-000C 2497  193 CCCUGGUGCUGACUAUCCA UGGAuAGucAGcAccAGGGUU 1839
    R-008363043-000H 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuTT B 1840
    R-008363043-000H 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUU 1841
    R-008362746-000H 2353  195 UCUUGGACUUGAUAUUGGU B ucuuGGAcuuGAuAuuGGuTT B 1842
    R-008362746-000H 2353  195 UCUUGGACUUGAUAUUGGU ACCAAuAucAAGuccAAGAUU 1843
    R-008362743-000G 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuTT B 1844
    R-008362743-000G 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuAGcuAGGAucAuccUU 1845
    R-008362887-000W 1238  188 UUAGUAAAUAUAAUGAGGA B UUAGUAAAUAUAAUGAGGATT B 1846
    R-008362887-000W 1238  188 UUAGUAAAUAUAAUGAGGA UCCUCAUUAUAUUUACUAAUU 1847
    R-008363040-000G 2125  133 UGAACUUGCUCAGGACAAG B UGAACUUGCUCAGGACAAGTT B 1848
    R-008363040-000G 2125  133 UGAACUUGCUCAGGACAAG CUUGUCCUGAGCAAGUUCAUU 1849
    R-008362935-000B  843  189 CUCAGAUGGUGUCUGCUAU AUAGCAGACACCAUCUGAGUU 1851
    R-008362935-000B  843  189 CUCAGAUGGUGUCUGCUAU B CUCAGAUGGUGUCUGCUAUTT B 1850
    R-008362740-000F  496  190 AGAACAAGUAGCUGAUAUU AAUAUCAGCUACUUGUUCUUU 1853
    R-008362740-000F  496  190 AGAACAAGUAGCUGAUAUU B AGAACAAGUAGCUGAUAUUTT B 1852
    R-008362884-000V 2074  144 GCUUUAUUCUCCCAUUGAA UUCAAUGGGAGAAUAAAGCUU 1855
    R-008362884-000V 2074  144 GCUUUAUUCUCCCAUUGAA B GCUUUAUUCUCCCAUUGAATT B 1854
    R-008362701-000V 2503  134 UGCUGACUAUCCAGUUGAU B UGCUGACUAUCCAGUUGAUTT B 1856
    R-008362701-000V 2503  134 UGCUGACUAUCCAGUUGAU AUCAACUGGAUAGUCAGCAUU 1857
    R-008362698-000C 2387  191 CUUGGAUAUCGCCAGGAUG B CUUGGAUAUCGCCAGGAUGTT B 1858
    R-008362698-000C 2387  191 CUUGGAUAUCGCCAGGAUG CAUCCUGGCGAUAUCCAAGUU 1859
    R-008362800-000W 1660  192 CAUCUGUGCUCUUCGUCAU AUGACGAAGAGCACAGAUGUU 1861
    R-008362800-000W 1660  192 CAUCUGUGCUCUUCGUCAU B CAuCUGUGCUCUUCGUCAUTT B 1860
    R-008362737-000Z 2497  193 CCCUGGUGCUGACUAUCCA B CCCUGGUGCUGACUAUCCATT B 1862
    R-008362737-000Z 2497  193 CCCUGGUGCUGACUAUCCA UGGAUAGUCAGCACCAGGGUU 1853
    R-008363037-000A 1503  142 AUGAUAUAAAUGUGGUCAC B AUGAUAUAAAUGUGGUCACTT B 1864
    R-008363037-000A 1503  142 AUGAUAUAAAUGUGGUCAC GUGACCACAUUUAUAUCAUUU 1855
    R-008362734-000Y 2506  137 UGACUAUCCAGUUGAUGGG CCCAUCAACUGGAUAGUCAUU 1867
    R-008362734-000Y 2506  137 UGACUAUCCAGUUGAUGGG B UGACUAUCCAGUUGAUGGGTT B 1866
    R-008362797-000D 2052   71 CCAUUCCAUUGUUUGUGCA UGCACAAACAAUGGAAUGGUU 1869
    R-008362797-000D 2052   71 CCAUUCCAUUGUUUGUGCA B CCAUUCCAUUGUUUGUGCATT B 1868
    R-008362731-000X 2389  129 UGGAUAUCGCCAGGAUGAU B UGGAUAUCGCCAGGAUGAUTT B 1870
    R-008362731-000X 2389  129 UGGAUAUCGCCAGGAUGAU AUCAUCCUGGCGAUAUCCAUU 1871
    R-008362794-000C 1406  146 AACUGUCUUUGGACUCUCA B AACUGUCUUUGGACUCUCATT B 1872
    R-008362794-000C 1406  146 AACUGUCUUUGGACUCUCA UGAGAGUCCAAAGACAGUUUU 1873
    R-008362833-000Z 1796   12 ACUGUUGGAUUGAUUCGAA B ACUGUUGGAUUGAUUCGAATT B 1874
    R-008362833-000Z 1796   12 ACUGUUGGAUUGAUUCGAA UUCGAAUCAAUCCAACAGUUU 1875
    R-008362989-000Y 2505  139 CUGACUAUCCAGUUGAUGG B CUGAGUAUCCAGUUGAUGGTT B 1876
    R-008362989-000Y 2505  139 CUGACUAUCCAGUUGAUGG CCAUCAACUGGAUAGUCAGUU 1877
    R-008362791-000B 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAATT B 1878
    R-008362791-000B 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAGUU 1879
    R-008362881-000U  643   75 GGCUGAACCAUCACAGAUG B GGCUGAACCAUCACAGAUGTT B 1880
    R-008362881-000U  643   75 GGCUGAACCAUCACAGAUG CAUCUGUGAUGGUUGAGCCUU 1881
    R-008363034-000Z  582  147 AGGGCAUGCAGAUCCCAUC GAUGGGAUCUGCAUGCCCUUU 1883
    R-008363034-000Z  582  147 AGGGCAUGCAGAUCCCAUC B AGGGCAUGCAGAUCCCAUCTT B 1882
    R-008362830-000Y 2502  136 GUGCUGACUAUCCAGUUGA B GUGCUGACUAUCCAGUUGATT B 1884
    R-008362830-000Y 2502  136 GUGCUGACUAUCCAGUUGA UCAACUGGAUAGUCAGCACUU 1885
    R-008362827-000S 1505  148 GAUAUAAAUGUGGUCACCU AGGUGACCACAUUUAUAUCUU 1887
    R-008362827-000S 1505  148 GAUAUAAAUGUGGUCACCU B GAUAUAAAUGUGGUCACCUTT B 1886
    R-008362728-000R 1432  149 UUCAGAUGCUGCAACUAAA B UUCAGAUGCUGCAACUAAATT B 1888
    R-008362728-000R 1432  149 UUCAGAUGCUGCAACUAAA UUUAGUUGCAGCAUCUGAAUU 1889
    R-008362986-000X 1968  150 AAGAAAUAGUUGAAGGUUG CAACCUUCAACUAUUUCUUUU 1891
    R-008362986-000X 1968  150 AAGAAAUAGUUGAAGGUUG B AAGAAAUAGUUGAAGGUUGTT B 1890
    R-008362878-000M  694  109 UCAAGAUGAUGCAGAACUU B UCAAGAUGAUGCAGAACUUTT B 1892
    R-008362878-000M  694  109 UCAAGAUGAUGCAGAACUU AAGUUCUGGAUCAUCUUGAUU 1893
    R-008362824-000R 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGGUU 1895
    R-008362824-000R 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUTT B 1894
    R-008362932-000A 2259  125 AGGACAAGCCACAAGAUUA UAAUCUUGUGGCUUGUCCUUU 1897
    R-008362932-000A 2259  125 AGGACAAGCCACAAGAUUA B AGGACAAGCCACAAGAUUATT B 1896
    R-008362788-000V  954  152 UGGCCAUCUUUAAGUCUGG B UGGCCAUCUUUAAGUCUGGTT B 1898
    R-008362788-000V  954  152 UGGCCAUCUUUAAGUCUGG CCAGACUUAAAGAUGGCCAUU 1899
    R-008362983-000W 2197  116 ACUUCACUCUAGGAAUGAA B ACUUCACUCUAGGAAUGAATT B 1900
    R-008362983-000W 2197  116 ACUUCACUCUAGGAAUGAA UUCAUUCCUAGAGUGAAGUUU 1901
    R-008362929-000U  505  153 AGCUGAUAUUGAUGGACAG B AGCUGAUAUUGAUGGACAGTT B 1902
    R-008362929-000U  505  153 AGCUGAUAUUGAUGGACAG CUGUCCAUCAAUAUCAGCUUU 1903
    R-008362926-000T 2011  154 UCGGGAUGUUCACAACCGA B UCGGGAUGUUCACAACCGATT B 1904
    R-008362926-000T 2011  154 UCGGGAUGUUCACAACCGA UCGGUUGUGAACAUCCCGAUU 1905
    R-008362923-000S 1339  155 UGUAGAAGCUGGUGGAAUG B UGUAGAAGCUGGUGGAAUGTT B 1906
    R-008362923-000S 1339  155 UGUAGAAGCUGGUGGAAUG CAUUCCACCAGCUUCUACAUU 1907
    R-008362695-000B 1242  156 UAAAUAUAAUGAGGACCUA B UAAAUAUAAUGAGGACCUATT B 1908
    R-008362695-000B 1242  156 UAAAUAUAAUGAGGACCUA UAGGUCCUCALUAUAUUUAUU 1909
    R-008362692-000A  499  107 ACAAGUAGCUGAUAUUGAU B ACAAGUAGCUGAUAUUGAUTT B 1910
    R-008362692-000A  499  107 ACAAGUAGCUGAUAUUGAU AUCAAUAUCAGCUACUUGUUU 1911
    R-008362689-000U 1870  194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGUUU 1913
    R-008362689-000U 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUTT B 1912
    R-008362785-000U 2353  195 UCUUGGACUUGAUAUUGGU B UCUUGGACUUGAUAUUGGUTT B 1914
    R-008362785-000U 2353  195 UCUUGGACUUGAUAUUGGU ACCAAUAUCAAGUCCAAGAUU 1915
    R-008363031-000Y 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUU 1917
    R-008363031-000Y 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUTT B 1916
    R-008362920-000R  878  197 AAUACAAAUGAUGUAGAAA UUUCUACAUCAUUUGUAUUUU 1919
    R-008362920-000R  878  197 AAUACAAAUGAUGUAGAAA B AAUACAAAUGAUGUAGAAATT B 1918
    R-008362917-000J 2046  112 UAAAUACCAUUCCAUUGUU AACAAUGGAAUGGUAUUUAUU 1921
    R-008362917-000J 2046  112 UAAAUACCAUUCCAUUGUU B UAAAUACCAUUCCAUUGUUTT B 1920
    R-008362980-000V  647  198 GAACCAUCACAGAUGCUGA UCAGCAUCUGUGAUGGUUCUU 1923
    R-008362980-000V  647  198 GAACCAUCACAGAUGCUGA B GAACCAUCACAGAUGCUGATT B 1922
    R-008362725-000P 1998  199 UUCACAUCCUAGCUCGGGA B UUCACAUCCUAGCUCGGGATT B 1924
    R-008362725-000P 1998  199 UUCACAUCCUAGCUCGGGA UCCCGAGCUAGGAUGUGAAUU 1925
    R-008363028-000S  588  200 UGCAGAUCCCAUCUACACA UGUGUAGAUGGGAUCUGCAUU 1927
    R-008363028-000S  588  200 UGCAGAUCCCAUCUACACA B UGCAGAUCCCAUCUACACATT B 1926
    R-008362782-000T 2042  201 GGACUAAAUACCAUUCCAU AUGGAAUGGUAUUUAGUCCUU 1929
    R-008362782-000T 2042  201 GGACUAAAUACCAUUCCAU B GGACUAAAUACCAUUCCAUTT B 1928
    R-008362977-000N  855  202 CUGCUAUUGUACGUACCAU B CUGCUAUUGUACGUACCAUTT B 1930
    R-008362977-000N  855  202 CUGCUAUUGUACGUACCAU AUGGUACGUACAAUAGCAGUU 1931
    R-008362686-000T 2038  203 CAGAGGACUAAAUACCAUU AAUGGUAUUUAGUCCUCUGUU 1933
    R-008362686-000T 2038  203 CAGAGGACUAAAUACCAUU B CAGAGGACUAAAUACCAUUTT B 1932
    R-008362875-000L 1786  204 GAUAAAGGCUACUGUUGGA UCCAACAGUAGCCUUUAUCUU 1935
    R-008362875-000L 1786  204 GAUAAAGGCUACUGUUGGA B GAUAAAGGCUACUGUUGGATT B 1934
    R-008363025-000R 1501  205 AGAUGAUAUAAAUGUGGUC B AGAUGAUAUAAAUGUGGUCTT B 1936
    R-008363025-000R 1501  205 AGAUGAUAUAAAUGUGGUC GACCACAUUUAUAUCAUCUUU 1937
    R-008362914-000H 1834  206 AAAUCAUGCACCUUUGCGU ACGCAAAGGUGCAUGAUUUUU 1939
    R-008362914-000H 1834  206 AAAUCAUGCACCUUUGCGU B AAAUCAUGCACCUUUGCGUTT B 1938
    R-008362872-000K 1157  207 ACGACAGACUGCCUUCAAA B ACGACAGAGUGCCUUCAAATT B 1940
    R-008362872-000K 1157  207 ACGACAGACUGCCUUCAAA UUUGAAGGCAGUCUGUCGUUU 1941
    R-008362974-000M 1239  208 UAGUAAAUAUAAUGAGGAC B UAGUAAAUAUAAUGAGGACTT B 1942
    R-008362974-000M 1239  208 UAGUAAAUAUANUGAGGAC GUCCUCAUUAUAUUUACUAUU 1943
    R-008362821-000P 1248  209 UAAUGAGGACCUAUACUUA B UAAUGAGGACCUAUACUUATT B 1944
    R-008362821-000P 1248  209 UAAUGAGGACCUAUACUUA UAAGUAUAGGUCCUCAUUAUU 1945
    R-008362683-000S  660  210 UGCUGAAACAUGCAGUUGU B UGCUGAAACAUGCAGUUGUTT B 1946
    R-008362683-000S  660  210 UGCUGAAACAUGCAGUUGU ACAACUGCAUGUUUCAGCAUU 1947
    R-008363022-000P  285  211 AUUUGAUGGAGUUGGACAU B AUUUGAUGGAGUUGGACAUTT B 1948
    R-008363022-000P  285  211 AUUUGAUGGAGUUGGACAU AUGUCCAACUCCAUCAAAUUU 1949
    R-008362779-000L 1582  212 CUGCCAAGUGGGUGGUAUA B CUGCCAAGUGGGUGGUAUATT B 1950
    R-008362779-000L 1582  212 CUGCCAAGUGGGUGGUAUA UAUACCACCCACUUGGCAGUU 1951
    R-008363019-000H 1735  213 UGGACUACCAGUUGUGGUU AACCACAACUGGUAGUCCAUU 1953
    R-008363019-000H 1735  213 UGGACUACCAGUUGUGGUU B UGGACUACCAGUUGUGGUUTT B 1952
    R-008362776-000K  771  214 UUAAUAAGGCUGCAGUUAU AUAACUGCAGCCUUAUUAAUU 1955
    R-008362776-000K  771  214 UUAAUAAGGCUGCAGUUAU B UUAAUAAGGCUGCAGUUAUTT B 1954
    R-008363016-000G 1060  215 ACAUCAAGAAGGAGCUAAA B ACAUCAAGAAGGAGCUAAATT B 1956
    R-008363016-000G 1060  215 ACAUCAAGAAGGAGCUAAA UUUAGCUCCUUCUUGAUGUUU 1957
    R-008362773-000J 2390  216 GGAUAUCGCCAGGAUGAUC GAUCAUCCUGGCGAUAUCCUU 1959
    R-008362773-000J 2390  216 GGAUAUCGCCAGGAUGAUC B GGAUAUCGCCAGGAUGAUCTT B 1958
    R-008362971-000L 2509   81 CUAUCCAGUUGAUGGGCUG CAGCCCAUCAACUGGAUAGUU 1961
    R-008362971-000L 2509   81 CUAUCCAGUUGAUGGGCUG B CUAUCCAGUUGAUGGGCUGTT B 1960
    R-008362722-000N 2186  217 CUGACAGAGUUACUUCACU B CUGACAGAGUUACUUCACUTT B 1961
    R-008362722-000N 2186  217 CUGACAGAGUUACUUCACU AGUGAAGUAACUCUGUCAGUU 1963
    R-008363013-000F 1632  218 GUGACAGGGAAGACAUCAC B GUGACAGGGAAGACAUCACTT B 1964
    R-008363013-000F 1632  218 GUGACAGGGAAGACAUCAC GUGAUGUCUUCCCUGUCACUU 1965
    R-008362818-000H  619  219 UCAUCCCACUAAUGUCCAG CUGGACAUUAGUGGGAUGAUU 1967
    R-008362818-000H  619  219 UCAUCCCACUAAUGUCCAG B UCAUCCCACUAAUGUCCAGTT B 1966
    R-008362968-000E 1656  220 CUGCCAUCUGUGCUCUUCG B CUGCCAUCUGUGCUCUUCGTT B 1968
    R-008362968-000E 1656  220 CUGCCAUCUGUGCUCUUCG CGAAGAGCACAGAUGGCAGUU 1969
    R-008362815-000G 1506  221 AUAUAAAUGUGGUCACCUG B AUAUAAAUGUGGUCACCUGTT B 1970
    R-008362815-000G 1506  221 AUAUAAAUGUGGUCACCUG CAGGUGACCACAUUUAUAUUU 1971
    R-008362869-000D 2501   76 GGUGCUGACUAUCCAGUUG B GGUGCUGACUAUCCAGUUGTT B 1972
    R-008362869-000D 2501   76 GGUGCUGACUAUCCAGUUG CAACUGGAUAGUCAGCACCUU 1973
    R-008362719-000G 2494  222 CCACCCUGGUGCUGACUAU AUAGUCAGCACCAGGGUGGUU 1975
    R-008362719-000G 2494  222 CCACCCUGGUGCUGACUAU B CCACCCUGGUGCUGACUAUTT B 1974
    R-008362770-000H 1666  223 UGCUCUUCGUCAUCUGACC GGUCAGAUGACGAAGAGCAUU 1977
    R-008362770-000H 1666  223 UGCUCUTCGUCAUCUGACC B UGCUCUUCGUCAUCUGACCTT B 1976
    R-008362680-000R 1635  224 ACAGGGAAGACAUCACUGA B ACAGGGAAGACAUCACUGATT B 1978
    R-008362680-000R 1635  224 ACAGGGAAGACAUCACUGA UCAGUGAUGUCUUCCCUGUUU 1979
    R-008362866-000C  294  225 AGUUGGACAUGGCCAUGGA UCCAUGGCCAUGUCCAACUUU 1981
    R-008362866-000C  294  225 AGUUGGACAUGGCCAUGGA B AGUUGGACAUGGCCAUGGATT B 1980
    R-008362863-000B  641  226 UUGGCUGAACCAUCACAGA B UUGGCUGAACCAUCACAGATT B 1982
    R-008362863-000B  641  226 UUGGCUGAACCAUCACAGA UCUGUGAUGGUUCAGCCAAUU 1983
    R-008362965-000D  576  227 UAGAUGAGGGCAUGCAGAU AUCUGCAUGCCCUCAUGUAUU 1985
    R-008362965-000D  576  227 UAGAUGAGGGCAUGCAGAU B UAGAUGAGGGCALGCAGAUTT B 1984
    R-008362911-000G  577  228 AGAUGAGGGCAUGCAGAUC B AGAUGAGGGCAUGCAGAUCTT B 1986
    R-008362911-000G  577  228 AGAUGAGGGCAUGCAGAUC GAUCUGCAUGCCCUCAUCUUU 1987
    R-008362767-000B 1661  229 AUCUGUGCUCUUCGUCAUC GAUGACGAAGAGCACAGAUUU 1989
    R-008362767-000B 1661  229 AUCUGUGCUCUUCGUCAUC B AUCUGUGCUCUUCGUCAUCTT B 1988
    R-008362962-000C  707  230 GAACUUGCCACACGUGCAA B GAACUUGCCACACGUGCAATT B 1990
    R-008362962-000C  707  230 GAACUUGCCACACGUGCAA UUGCACGUGUGGCAAGUUCUU 1991
    R-008362677-000J 1659  231 CCAUCuGUGCUCUUCGUCA B CCAUCUGUGCUCUUCGUCATT B 1992
    R-008362677-000J 1659  231 CCAUCUGUGCUCUUCGUCA UGACGAAGAGCACAGAUGGUU 1993
    R-008362674-000H 1547   88 CUCACUUGCAAUANUUAUA UAUAAUUAUUGCAAGUGAGUU 1995
    R-008362674-000H 1547   88 CUCACUUGCAAUANUUAUA B CUCACUUGCAAUAAUUAUATT B 1994
    R-008362959-000W  867   90 GUACCAUGCAGAAUACAAA UUUGUAUUCUGCAUGGUACUU 1997
    R-008362959-000W  867   90 GUACCAUGCAGAAUACAAA B GUACCAUGCAGAAUACAAATT B 1996
    R-008362956-000V 1185  232 AUGGCAACCAAGAAAGCAA UUGCUUUCUUGGUUGCCAUUU 1999
    R-008362956-000V 1185  232 AUGGCAACCAAGAAAGCAA B AUGGCAACCAAGAAAGCAATT B 1998
    R-008362764-000A  664  233 GAAACAUGCAGUUGUAAAC GUUUACAACUGCAUGUUUCUU 2001
    R-008362764-000A  664  233 GAAACAUGCAGUUGUAAAC B GAAACAUGCAGUUGUAAACTT B 2000
    R-008362716-000F  820   18 CAGACACGCUAUCAUGCGU B CAGACACGCUAUCAUGCGUTT B 2002
    R-008362716-000F  820   18 CAGACACGCUAUCAUGCGU ACGCAUGAUAGCGUGUCUCUU 2003
    R-008362812-000F 2266  101 GCCACAAGAUUACAAGAAA UUUCUUGUAAUCUUGUGGCUU 2005
    R-008362812-000F 2266  101 GCCACAAGAUUACAAGAAA B GCCACAAGAUUACAAGAAATT B 2004
    R-008362671-000G 1749  234 UGGUUAAGCUCUUACACCC GGGUGUAAGAGUTUAACCAUU 2007
    R-008362671-000G 1749  234 UGGUUAAGCUCUUACACCC B UGGUUAAGCUCUUACACCCTT B 2006
    R-008362953-000U 1234  235 AGCUUUAGUAAAUAUAAUG B AGCUUUAGUAAAUAUAAUGTT B 2008
    R-008362953-000U 1234  235 AGCUUUAGUAAAUAUAAUG CAUUAUAUUUACUAAAGCUUU 2009
    R-008362950-000T  691  236 CUAUCAAGAUGAUGCAGAA B CUAUCAAGAUGAUGCAGAATT B 2010
    R-008362950-000T  691  236 CUAUCAAGAUGAUGCAGAA UUCUGCAUCAUCUUGAUAGUU 2011
    R-008363010-000E 1387  237 AAGUCAACGUCUUGUUCAG B AAGUCAACGUCUUGUUCAGTT B 2012
    R-008363010-000E 1387  237 AAGUCAACGUCUUGUUCAG CUGAACAAGACGUUGACUUUU 2013
    R-008381224-000R 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAGUsU 2015
    R-008381224-000R 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2014
    R-008381214-000X 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAAUsU B 2017
    R-008381211-000X 1797    5 CUGUUGGAUUGAUUCGAAA uuucGAAucAAuccAAcAGUsU 2016
    R-008381038-000Y 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGAAucAAuccAAcAGUsU 2019
    R-008381038-000Y 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAA UsU B 2018
    R-008381052-000F 1797    5 CUGUUGGAUUGAUUCGAAA uuucGAAucAAuccAAcAGUsU 2016
    R-008381052-000F 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2020
    R-008381158-000T 1797    5 CUGUUGGAUUGAUUCGAAA uuucGAAucAAuccAAcAGUsU 2016
    R-008381158-000T 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2021
    R-008381341-000J 1797    5 CUGUUGGAUUGAUUCGAAA uuucGAAucAAuccAAcAGUsU 2016
    R-008381341-000J 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAAUsU B 2022
    R-008381109-000P 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2020
    R-008381109-000P 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgaaUCaaUCCaaCagUsU 2023
    R-008380818-000X 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2021
    R-008380818-000X 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgaaUCaaUCCaaCagUsU 2023
    R-008381199-000W 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgaaUCaaUCCaaCagUsU 2023
    R-008381199-000W 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAAUsU B 2022
    R-008381296-000E 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAGUsU 2024
    R-008381296-000E 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2020
    R-008381042-000N 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAGUsU 2024
    R-008381042-000N 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2021
    R-008380923-000F 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAAUsU B 2022
    R-008380923-000F 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAGUsU 2024
    R-008381104-000W 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAGUsU 2025
    R-008381104-000W 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2020
    R-008381098-000C 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAGUsU 2025
    R-008381098-000C 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2021
    R-008380916-000P 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAAUsU B 2022
    R-008380916-000P 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAGUsU 2025
    R-008380906-000X 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2020
    R-008380906-000X 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGAAucAAuccAAcAGUsU 2019
    R-008381291-000L 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGAAucAAuccAAcAGUsU 2019
    R-008381291-000L 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2021
    R-008381334-000T 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGAAucAAuccAAcAGUsU 2019
    R-008381334-000T 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAAUsU B 2022
    R-008381330-000H 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2020
    R-008381330-000H 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgaaUCaaUCCaaCagUsU 2026
    R-008381036-000F 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgaaUCaaUCCaaCagUsU 2026
    R-008381036-000F 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2021
    R-008381287-000W 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAAUsU B 2022
    R-008381287-000W 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgaaUCaaUCCaaCagUsU 2026
    R-008381027-000X 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2027
    R-008381027-000X 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGGUsU 2028
    R-008380896-000U 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuUsU B 2029
    R-008380896-000U 2398  151 CCAGGAUGAUCCUAGCUAU AuAGcuAGGAucAuccuGGUsU 2030
    R-008381153-000Z 2398  151 CCAGGAUGAUCCUAGCUAU AUAGcuAGGAucAuccuGGUsU 2032
    R-008381153-000Z 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcAAuUsU B 2031
    R-008381323-000S 2398  151 CCAGGAUGAUCCUAGCUAU AuAGcuAGGAucAuccuGGUsU 2030
    R-008381323-000S 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2033
    R-008381315-000S 2398  151 CCAGGAUGAUCCUAGCUAU AuAGcuAGGAucAuccuGGUsU 2030
    R-008381315-000S 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2034
    R-008380888-000U 2398  151 CCAGGAUGAUCCUAGCUAU AuAGcuAGGAucAuccuGGUsU 2030
    R-008380888-000U 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuUsU B 2035
    R-008381013-000V 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2033
    R-008381013-000V 2398  151 CCAGGAUGAUCCUAGCUAU AUAgCUaggaUCaUCCUggUsU 2036
    R-008381007-000M 2398  151 CCAGGAUGAUCCUAGCUAU AUAgCUaggaUCaUCCUggUsU 2036
    R-008381007-000M 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2034
    R-008380995-000V 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuUsU B 2035
    R-008380995-000V 2398  151 CCAGGAUGAUCCUAGCUAU AUAgCUaggaUCaUCCUggUsU 2036
    R-008380878-000B 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGGUsU 2037
    R-008380878-000B 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2033
    R-008381143-000G 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGGUsU 2037
    R-008381143-000G 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2034
    R-008381282-000C 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuUsU B 2035
    R-008381282-000C 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGGUsU 2037
    R-008380985-000C 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGGUsU 2038
    R-008380985-000C 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2033
    R-008381278-000M 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGGUsU 2038
    R-008381278-000M 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2034
    R-008381139-000S 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGGUsU 2038
    R-008381139-000S 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuUsU B 2035
    R-008380871-000R 2398  151 CCAGGAUGAUCCUAGCUAU AUAGcuAGGAucAuccuGGUsU 2032
    R-008380871-000R 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2033
    R-008381272-000K 2398  151 CCAGGAUGAUCCUAGCUAU AUAGcuAGGAucAuccuGGUsU 2032
    R-008381272-000K 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2034
    R-008381268-000V 2398  151 CCAGGAUGAUCCUAGCUAU AUAGcuAGGAucAuccuGGUsU 2032
    R-008381268-000V 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuUsU B 2035
    R-008381133-000P 2398  151 CCAGGAUGAUCCUAGCUAU AUAgCUaggaUCaUCCUggUsU 2039
    R-008381133-000P 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2033
    R-008381261-000J 2398  151 CCAGGAUGAUCCUAGCUAU AUAgCUaggaUCaUCCUggUsU 2039
    R-008381261-000J 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2034
    R-008381091-000S 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuUsU B 2035
    R-008381091-000S 2398  151 CCAGGAUGAUCCUAGCUAU AUAgCUaggaUCaUCCUggUsU 2039
    R-008380861-000Y 1870  194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGUUsU 2041
    R-008380861-000Y 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2040
    R-008380853-000Y 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUsU 2043
    R-008380853-000Y 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuUsU B 2042
    R-008380811-000L 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuUsU B 2044
    R-008380811-000L 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUsU 2045
    R-008380974-000B 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUsU 2043
    R-008380974-000B 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2046
    R-008380966-000B 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUsU 2043
    R-008380966-000B 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2047
    R-008381310-000Y 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUsU 2043
    R-008381310-000Y 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuUsU B 2048
    R-008381194-000C 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2046
    R-008381194-000C 1870  194 ACGACUAGUUCAGUUGCUU AAGCaaCUgaaCUagUCgUUsU 2049
    R-008380833-000N 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2047
    R-008380833-000N 1870  194 ACGACUAGUUCAGUUGCUU AAGCaaCUgaaCUagUCgUUsU 2049
    R-008381115-000X 1870  194 ACGACUAGUUCAGUUGCUU AAGCaaCUgaaCUagUCgUUsU 2049
    R-008381115-000X 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuUsU B 2048
    R-008381242-000H 1870  194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGUUsU 2050
    R-008381242-000H 1870  194 ACGACUAGUUCAGUCGCUU B ACGACUAGUUCAGUUGCUUUsU B 2046
    R-008381235-000S 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2047
    R-008381235-000S 1870  194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGUUsU 2050
    R-008381231-000G 1870  194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGUUsU 2050
    R-008381231-000G 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuUsU B 2048
    R-008381304-000R 1870  194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGUUsU 2051
    R-008381304-000R 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2046
    R-008380828-000P 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2047
    R-008380828-000P 1870  194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGUUsU 2051
    R-008380926-000G 1870  194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGUUsU 2051
    R-008380926-000G 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuUsU B 2048
    R-008381350-000T 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUsU 2045
    R-008381350-000T 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2046
    R-008381162-000H 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2047
    R-008381162-000H 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUsU 2045
    R-008380823-000W 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUsU 2045
    R-008380823-000W 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuUsU B 2048
    R-008381068-000A 1870  194 ACGACUAGUUCAGUUGCUU AAGCaaCUgaaCUagUCgUUsU 2052
    R-008381068-000A 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2046
    R-008381190-000T 1870  194 ACGACUAGUUCAGUUGCUU AAGCaaCUgaaCUagUCgUUsU 2052
    R-008381190-000T 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2047
    R-008380959-000K 1870  194 ACGACUAGUUCAGUUGCUU AAGCaaCUgaaCUagUCgUUsU 2052
    R-008380959-000K 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuUsU B 2048
    R-008381084-000A 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUsU 2054
    R-008381084-000A 2401  196 GGAUGAUCCLAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2053
    R-008380848-000Z 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuUsU B 2055
    R-008380848-000Z 2401  196 GGAUGAUCCUAGCUAUCGU AcGAuAGcuAGGAucAuccUsU 2056
    R-008380807-000W 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuUsU B 2057
    R-008380807-000W 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuAGcuAGGAucAuccUsU 2058
    R-008380843-000F 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2059
    R-008380843-000F 2401  196 GGAUGAUCCUAGCUAUCGU AcGAuAGcuAGGAucAuccUsU 2056
    R-008381185-000U 2401  196 GGAUGAUCCUAGCUAUCCU B GGAUGAUCCUAGCUAUCGUUsU B 2060
    R-008381185-000U 2401  196 GGAUGAUCCUAGCUAUCGU AcGAuAGcuAGGAucAuccUsU 2056
    R-008380951-000R 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuUsU B 2061
    R-008380951-000R 2401  196 GGAUGAUCCUAGCUAUCGU AcGAuAGcuAGGAucAuccUsU 2056
    R-008380804-000V 2401  196 GGAUGAUCCUAGCUAUCCU B GGAUGAUCCUAGCUAUCGUUsU B 2059
    R-008380804-000V 2401  196 GGAUGAUCCUAGCUAUCGU ACGaUagCUaggaUCaUCCUsU 2062
    R-008381179-000L 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2060
    R-008381179-000L 2401  196 GGAUGAUCCUAGCUAUCGU ACGaUagCUaggaUCaUCCUsU 2062
    R-008381127-000G 2401  196 GGAUGAUCCUAGCUAUCGU ACGaUagCUaggaUCaUCCUsU 2062
    R-008381127-000G 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuUsU B 2061
    R-008380945-000H 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2059
    R-008380945-000H 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUsU 2063
    R-008381071-000G 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2060
    R-008381071-000G 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUsU 2063
    R-008381173-000J 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuUsU B 2061
    R-008381173-000J 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUsU 2063
    R-008381122-000N 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2059
    R-008381122-000N 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUsU 2064
    R-008380801-000U 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2060
    R-008380801-000U 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUsU 2064
    R-008380839-000R 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuUsU B 2061
    R-008380839-000R 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUsU 2064
    R-008380835-000F 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuAGcuAGGAucAuccUsU 2058
    R-008380835-000F 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2059
    R-008381258-000C 2401  196 GGAUGAUCCUGGCUAUCGU ACGAuAGcuAGGAucAuccUsU 2058
    R-008381258-000C 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2060
    R-008381169-000U 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuAGcuAGGAucAuccUsU 2058
    R-008381169-000U 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuUsU B 2061
    R-008380937-000H 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2059
    R-008380937-000H 2401  196 GGAUGAUCCUAGCUAUCGU ACGaUagCUaggaUCaUCCUsU 2065
    R-008381251-000S 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2060
    R-008381251-000S 2401  196 GGAUGAUCCUAGCUAUCGU ACGaUagCUaggaUCaUCCUsU 2065
    R-008380933-000Y 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuUsU B 2061
    R-008380933-000Y 2401  196 GGAUGAUCCUAGCUAUCGU ACGaUagCUaggaUCaUCCUsU 2065
    R-008381748-000J 1797    5 CUGUUGGAUUGAUUCGAAA B CUgUu G GAUU GAUUCGaAAUsU B 2066
    R-008381748-000J 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGaAUCAauccaACAGUsU 2067
    R-008381708-000P 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUuGGaUUGaUUCGAAaUsU B 2069
    R-008381708-000P 1797    5 CUGUUGGAUUGAUUCGAAA uuucGAauCaAUCcAaCaGUsU 2068
    R-008381704-000E 1797    5 CUGUUGGAUUGAUUCGAAA uUUcgAaUCaAuCCAACAGUsU 2070
    R-008381704-000E 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUuGgaUUG AUuCGaA A UsU B 2071
    R-008381746-000S 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGaaUCAAUCcAacaGUsU 2073
    R-008381746-000S 1797    5 CUGUUGGAUUGAUUCGAAA B C UgUUGgaUUGaUUCgA A A UsU B 2072
    R-008381728-000Z 1797    5 CUGUUGGAUUGAUUCGAAA B CUgU UGG A UUG AUuCgA AAUsU B 2074
    R-008381728-000Z 1797    5 CUGUUGGAUUGAUUCGAAA UUucGaAUCAAUCcAAcagUsU 2075
    R-008381686-000B 1797    5 CUGUUGGAUUGAUUCGAAA uuUCGAAUcaaUCCAAcAgUsU 2076
    R-008381686-000B 1797    5 CUGUUGGAUUGAUUCGAAA B CuG U UGgaUUgAuUCG AaaUsU B 2077
    R-008381726-000G 1797    5 CUGUUGGAUUGAUUCGAAA uuUcGAAUCaaUcCAACaGUsU 2078
    R-008381726-000G 1797    5 CUGUUGGAUUGAUUCGAAA B C UgUUgGaUU G AU UCGaaA UsU B 2079
    R-008381629-000Y 1797    5 CUGUUGGAUUGAUUCGAAA UUucGAAuCaaUCCAacAGUsU 2081
    R-008381629-000Y 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGG AU U GaUU C GAaAUsU B 2080
    R-008381724-000P 1797    5 CUGUUGGAUUGAUUCGAAA B CUgU U GgA UugAUUCgAAaUsU B 2083
    R-008381724-000P 1797    5 CUGUUGGAUUGAUUCGAAA uuuCgaAUCAAUCcAACagUsU 2082
    R-008381670-000G 1797    5 CUGUUGGAUUGAUUCGAAA B CugUUGGA UUGaUUcgaaaUsU B 2084
    R-008381670-000G 1797    5 CUGUUGGAUUGAUUCGAAA UuuCgAAUCAAUCcaACAGUsU 2085
    R-008381666-000S 1797    5 CUGUUGGAUUGAUUCGAAA UuuCGaauCAaUccaACAGUsU 2087
    R-008381666-000S 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUgGaUugAUuCGaAAUsU B 2086
    R-008381722-000X 1797    5 CUGUUGGAUUGAUUCGAAA B CUG U UgGAU UG A UUCgA A AUsU B 2088
    R-008381722-000X 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgAauCAAUCcAAcagUsU 2089
    R-008381700-000V 1797    5 CUGUUGGAUUGAUUCGAAA uUuCGAAUCAaUCcaaCAGUsU 2090
    R-008381700-000V 1797    5 CUGUUGGAUUGAUUCGAAA B CUgU UggAUUgaUUCGaAA UsU B 2091
    R-008381650-000X 1797    5 CUGUUGGAUUGAUUCGAAA UuUCGAAUcaauCCaACaGUsU 2093
    R-008381650-000X 1797    5 CUGUUGGAUUGAUUCGAAA B CU GUUG GaUUGaU UCgAAA UsU B 2092
    R-008381647-000R 1797    5 CUGUUGGAUUGAUUCGAAA B CUGU UGGaU UgaU UCgAaaUsU B 2094
    R-008381647-000R 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgAAuCAauCcaaCAgUsU 2095
    R-008381624-000E 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGaAUCAauCCAaCAGUsU 2097
    R-008381624-000E 1797    5 CUGUUGGAUUGAUUCGAAA B CuGuUgGAUUgaU UCGAaAUsU B 2096
    R-008381682-000S 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGgAUUGAU UCGaaaUsU B 2098
    R-008381682-000S 1797    5 CUGUUGGAUUGAUUCGAAA UUUcgaAUcAAUcCAACagUsU 2099
    R-008381622-000M 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGAaUcaAUCcaACAgUsU 2101
    R-008381622-000M 1797    5 CUGUUGGAUUGAUUCGAAA B CUgUUggaUUgaUUCgaaaUsU B 2100
    R-008381680-000Z 2398  151 CCAGGAUGAUCCUAGCUAU AuaGCUAggAUCAuCCuGGUsU 2103
    R-008381680-000Z 2398  151 CCAGGAUGAUCCUAGCUAU B C C A GGA UgaUcCUaGCUAU UsU B 2102
    R-008381606-000M 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGgaU GaUCCU AgCUA UUsU B 2104
    R-008381606-000M 2398  151 CCAGGAUGAUCCUAGCUAU AUAgcuaGgaUCAuCcUGgUsU 2105
    R-008381714-000X 2398  151 CCAGGAUGAUCCUAGCUAU aUagCUAGGaUCauccUGgUsU 2106
    R-008381714-000X 2398  151 CCAGGAUGAUCCUAGCUAU B CCagG AUgAU CC UAGCUaUUsU B 2107
    R-008381642-000X 2398  151 CCAGGAUGAUCCUAGCUAU B CCAG GAUG AU CCUA G C UaUUsU B 2109
    R-008381692-000X 2398  151 CCAGGAUGAUCCUAGCUAU aUagCuagGAUCAucCugGUsU 2108
    R-008381662-000G 2398  151 CCAGGAUGAUCCUAGCUAU AUAGcUAgGAuCauCCUggUsU 2111
    R-008381662-000G 2398  151 CCAGGAUGAUCCUAGCUAU B cC AGgAUGaUCCUagCUA UUsU B 2110
    R-008381618-000X 2398  151 CCAGGAUGAUCCUAGCUAU auAgCUaGGAuCauCCUGGUsU 2112
    R-008381618-000X 2398  151 CCAGGAUGAUCCUAGCUAU B CCA GGAUGAUC C U A GCU AUUsU B 2113
    R-008381698-000L 2398  151 CCAGGAUGAUCCUAGCUAU aUaGCuaggAUcaUcCUGGUsU 2114
    R-008381698-000L 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGG A UGAUC C UagC UaUUsU B 2115
    R-008381742-000G 2398  151 CCAGGAUGAUCCUAGCUAU B CCAgGAUgaU C CUaGCU A U UsU B 2117
    R-008381742-000G 2398  151 CCAGGAUGAUCCUAGCUAU aUagCUAggAuCAuCCuGgUsU 2116
    R-008381738-000S 2398  151 CCAGGAUGAUCCUAGCUAU B CCaggaUgaUCCUagCUaU UsU B 2118
    R-008381738-000S 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUaGGAUcauCCUgGUsU 2119
    R-008381660-000P 2398  151 CCAGGAUGAUCCUAGCUAU B C C AgGAUG AU CCUAGcUA UUsU B 2121
    R-008381660-000P 2398  151 CCAGGAUGAUCCUAGCUAU aUagcUAGGAUcaUCCugGUsU 2120
    R-008381696-000U 2398  151 CCAGGAUGAUCCUAGCUAU B CCaGGaUG A U CCUA G C U AU UsU B 2123
    R-008381696-000U 2398  151 CCAGGAUGAUCCUAGCUAU auAGcUaggauCAUCCuGGUsU 2122
    R-008381636-000P 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGgaUCauCcuGGUsU 2125
    R-008381636-000P 2398  151 CCAGGAUGAUCCUAGCUAU B CC AGGaUGaUC CuAgCUA UUsU B 2124
    R-008381634-000X 2398  151 CCAGGAUGAUCCUAGGUAU AUaGCUagGAucAuCCUgGUsU 2127
    R-008381634-000X 2398  151 CCAGGAUGAUCCUAGCUAU B cCAGGaU G AuCCU aGCUaU UsU B 2126
    R-008381632-000E 2398  151 CCAGGAUGAUCCUAGCUAU B CCaGgAUgAuCCU AGcU AUUsU B 2129
    R-008381632-000E 2398  151 CCAGGAUGAUCCUAGCUAU aUAGCuAGGAUCAUCcUggUsU 2128
    R-008381736-000Z 2398  151 CCAGGAUGAUCCUAGCUAU AUaGCuAGGaUcAUcCUggUsU 2131
    R-008381736-000Z 2398  151 CCAGGAUGAUCCUAGCUAU B CcaggAugaUC CU AG CUaU UsU B 2130
    R-008381600-000K 2398  151 CCAGGAUGAUCCUAGCUAU aUaGcUaggAUCAucCUGGUsU 2132
    R-008381600-000K 2398  151 CCAGGAUGAUCCUAGCUAU B CCAgGaU GAUcCUaGC UA U UsU B 2133
    R-008381732-000P 2398  151 CCAGGAUGAUCCUAGCUAU aUagCuAGGaUCAuCcUgGUsU 2134
    R-008381732-000P 2398  151 CCAGGAUGAUCCUAGCUAU B CCAggaUGAUC C UAgCU AuUsU B 2135
    R-008381656-000Z 2398  151 CCAGGAUGAUCCUAGCUAU B C CAGgAUgAU CCUAGcuaUUsU B 2136
    R-008381656-000Z 2398  151 CCAGGAUGAUCCUAGCUAU AuagCUAgGauCAUcCUGGUsU 2137
    R-008381750-000G 1870  194 ACGACUAGUUCAGUUGCUU aagCAaCUGaAcuAGUCgUUsU 2138
    R-008381750-000G 1870  194 ACGACUAGUUCAGUUGCUU B ACgACuAgUUcAGU U GCUU UsU B 2139
    R-008381690-000S 1870  194 ACGACUAGUUCAGUUGCUU aAGcAACUgAaCUaGUCguUsU 2140
    R-008381690-000S 1870  194 ACGACUAGUUCAGUUGCUU B aC G ACUAGuUCAgUugcUUUsU B 2141
    R-008381616-000E 1870  194 ACGACUAGUUCAGUUGCUU AAGcaACuGaaCUaGuCGUUsU 2143
    R-008381616-000E 1870  194 ACGACUAGUUCAGUUGCUU B aCGACUagUU CaGUUgCUU UsU B 2142
    R-008381688-000U 1870  194 ACGACUAGUUCAGUUGCUU aAgCaAcUGAACUAgUcGUUsU 2144
    R-008381688-000U 1870  194 ACGACUAGUUCAGUUGCUU B aCgaCuAGUuCAgU UgcUUUsU B 2145
    R-008381614-000M 1870  194 ACGACUAGUUCAGUUGCUU B aCgaC UAguUCAGUUGCU U UsU B 2147
    R-008381614-000M 1870  194 ACGACUAGUUCAGUUGCUU aaGCAAcUgAaCuagUcGUUsU 2146
    R-008381706-000X 1870  194 ACGACUAGUUCAGUUGCUU B ACGaCUA GUU CAGUU GCuU U sU B 2148
    R-008381706-000X 1870  194 ACGACUAGUUCAGUUGCUU AAgCAAcUGaACUaGUcgUUsU 2149
    R-008381672-000Z 1870  194 ACGACUAGUUCAGUUGCUU AAgCAacugAAcUagUCGUUsU 2151
    R-008381672-000Z 1870  194 ACGACUAGUUCAGUUGCUU B ACgAC UAGUUCaGU UGcU UUsU B 2150
    R-008381730-000X 1870  194 ACGACUAGUUCAGUUGCUU AagcAaCUgaaCUAGucgUUsU 2153
    R-008381730-000X 1870  194 ACGACUAGUUCAGUUGCUU B acG A CUagUUCagUuGCuU UsU B 2152
    R-008381612-000V 1870  194 ACGACUAGUUCAGUUGCUU B aCGAcU A GUU CA GUUgCUUUsU B 2154
    R-008381612-000V 1870  194 ACGACUAGUUCAGUUGCUU AaGCaAcUGAacUaGUcGUUsU 2155
    R-008381702-000M 1870  194 ACGACUAGUUCAGUUGCUU AAgcaaCUGAACuaGUCGUUsU 2157
    R-008381702-000M 1870  194 ACGACUAGUUCAGUUGCUU B AC GA C UaGUUCaGUUgCUU UsU B 2156
    R-008381744-000Z 1870  194 ACGACUAGUUCAGUUGCUU B A CGaCUaGU U CA G U U GcUU UsU B 2158
    R-008381744-000Z 1870  194 ACGACUAGUUCAGUUGCUU AaGCAACUgaACUAGuCGUUsU 2159
    R-008381610-000C 1870  194 ACGACUAGUUCAGUUGCUU aAgCAACUGAacUaGuCgUUsU 2160
    R-008381610-000C 1870  194 ACGACUAGUUCAGUUGCUU B ACgACU AgUUCAgUUgCUUUsU B 2161
    R-008381608-000E 1870  194 ACGACUAGUUCAGUUGCUU B ACGaCUaGuUCagUUGCUUUsU B 2162
    R-008381608-000E 1870  194 ACGACUAGUUCAGUUGCUU AAgCAACUGaACUaGUCguUsU 2163
    R-008381654-000G 1870  194 ACGACUAGUUCAGUUGCUU aAgCAaCuGaAcuaGUCgUUsU 2164
    R-008381654-000G 1870  194 ACGACUAGUUCAGUUGCUU B A C GaCUaG UUCaguUgCUuUsU B 2165
    R-008381668-000J 1870  194 ACGACUAGUUCAGUUGCUU B A CGAC U AG UUCAGUU G CUU UsU B 2167
    R-008381668-000J 1870  194 ACGACUAGUUCAGUUGCUU aAgCAACugAACuaguCgUUsU 2166
    R-008381627-000F 1870  194 ACGACUAGUUCAGUUGCUU B aCgaCUAG UUCaGUUG C UUUsU B 2169
    R-008381627-000F 1870  194 ACGACUAGUUCAGUUGCUU aAGCAacUgaACUaGUcGUUsU 2168
    R-008381719-000R 1870  194 ACGACUAGUUCAGUUGCUU B ACgAcU AgUuC AgUUGCUU UsU B 2170
    R-008381719-000R 1870  194 ACGACUAGUUCAGUUGCUU AAGCAAcUGAaCUaGUCGuUsU 2171
    R-008381717-000Y 1870  194 ACGACUAGUUCAGUUGCUU B aCgaCUagUUCagUUgCUU UsU B 2173
    R-008381717-000Y 1870  194 ACGACUAGUUCAGUUGCUU aaGCAACuGaACuagUcGuUsU 2172
    R-008381652-000P 2401  196 GGAUGAUCCUAGCUAUCGU ACgaUAGcuAGgauCAUCcUsU 2175
    R-008381652-000P 2401  196 GGAUGAUCCUAGCUAUCGU B gGaugaUcCUaGCuAUCgU UsU B 2174
    R-008381684-000J 2401  196 GGAUGAUCCUAGCUAUCGU B GgAUGaUCCuagcUAUCgUUsU B 2177
    R-008381684-000J 2401  196 GGAUGAUCCUAGCUAUCGU aCgAUagcuaGGAUcAUCCUsU 2176
    R-008381664-000Z 2401  196 GGAUGAUCCUAGCUAUCGU B gGA UgAUC CU A GCuaUC GUUsU B 2179
    R-008381664-000Z 2401  196 GGAUGAUCCUAGCUAUCGU aCGauAGCuAgGaUcauCCUsU 2178
    R-008381645-000Y 2401  196 GGAUGAUCCUAGCUAUCGU acgAUAGCUaGgAUCAuCCUsU 2180
    R-008381645-000Y 2401  196 GGAUGAUCCUAGCUAUCGU B gG A U GAUCCUAgC UauCGUUsU B 2181
    R-008381678-000B 2401  196 GGAUGAUCCUAGCUAUCGU ACgaUAgCUaGGAuCAUCcUsU 2183
    R-008381678-000B 2401  196 GGAUGAUCCUAGCUAUCGU B ggaUgaUCCUagCUaUCgU UsU B 2182
    R-008381620-000V 2401  196 GGAUGAUCCUAGCUAUCGU aCgauAgCUAggAucaUcCUsU 2184
    R-008381620-000V 2401  196 GGAUGAUCCUAGCUAUCGU B G GaUGAUCCUAG CUaU CgU UsU B 2185
    R-008381712-000E 2401  196 GGAUGAUCCUAGCUAUCGU aCGAuaGCuAGGAuCaUCCUsU 2186
    R-008381712-000E 2401  196 GGAUGAUCCUAGCUAUCGU B GGaU G A U C C UaGCUAUCgUUsU B 2187
    R-008381710-000M 2401  196 GGAUGAUCCUAGCUAUCGU B gGaUgAU CC UaGCUAUCG UUsU B 2188
    R-008381710-000M 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuAgcUaGGAUCauCCUsU 2189
    R-008381676-000J 2401  196 GGAUGAUCCUAGCUAUCGU aCGAuaGCUAGgAUCaUccUsU 2190
    R-008381676-000J 2401  196 GGAUGAUCCUAGCUAUCGU B GgAUGauC CUAGCUAU CguUsU B 2191
    R-008381604-000V 2401  196 GGAUGAUCCUAGCUAUCGU B GgaUgAUCcUagCUaUCGuUsU B 2192
    R-008381604-000V 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuAgCUagGAuCAUCcUsU 2193
    R-008381640-000E 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGaU C CUaGCUaUcgU UsU B 2194
    R-008381640-000E 2401  196 GGAUGAUCCUAGCUAUCGU AcGAUAGCUAGgaucaUCCUsU 2195
    R-008381740-000P 2401  196 GGAUGAUCCUAGCUAUCGU acgAuaGCUagGauCAUcCUsU 2196
    R-008381740-000P 2401  196 GGAUGAUCCUAGCUAUCGU B GgAUGA UCCUagCU A UC G U UsU B 2197
    R-008381674-000S 2401  196 GGAUGAUCCUAGCUAUCGU B G GAUG AuC CUaG CUAU C GU UsU B 2199
    R-008381674-000S 2401  196 GGAUGAUCCUAGCUAUCGU aCgAUagcUAGGAuCAuCCUsU 2198
    R-008381694-000B 2401  196 GGAUGAUCCUAGCUAUCGU B GgaU GaUCCUAgCUAUCGUUsU B 2201
    R-008381694-000B 2401  196 GGAUGAUCCUAGCUAUCGU aCGAUaGCuAGGauCauCCUsU 2200
    R-008381638-000G 2401  196 GGAUGAUCCUAGCUAUCGU B G GA UgA UCC U AgcUAU CgUUsU B 2203
    R-008381638-000G 2401  196 GGAUGAUCCUAGCUAUCGU aCGaUagcUAgGAUcAuCcUsU 2202
    R-008381602-000C 2401  196 GGAUGAUCCUAGCUAUCGU B GGaugaU CCuAG CuA UCGU UsU B 2204
    R-008381602-000C 2401  196 GGAUGAUCCUAGCUAUCGU AcGAUaGCUaGGauCAUccUsU 2205
    R-008381692-000J 2401  196 GGAUGAUCCUAGCUAUCGU AcgaUagCUAGGAUcAuCcUsU 2207
    R-008381692-000J 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUagCUAuCGU UsU B 2206
    R-008381658-000S 2401  196 GGAUGAUCCUAGCUAUCGU B gGAUgaUCCUAGCUaU C GU UsU B 2208
    R-008381658-000S 2401  196 GGAUGAUCCUAGCUAUCGU ACGaUAGcuaggAuCAUcCUsU 2209
    R-008381178-000C 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2020
    R-008381178-000C 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGaAUCAauccaACAGUsU 2067
    R-008380929-000H 1797    5 CUGUUGGAUUGAUUCGAAA uuucGAauCaAUCcAaCaGUsU 2068
    R-008380929-000H 1797       5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2021
    R-008381019-000X 1797    5 CUGUUGGAUUGAUUCGAAA uUUcgAaUCaAuCCAACAGUsU 2070
    R-008381019-000X 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAAUsU B 2022
    R-008381256-000K 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2020
    R-008381256-000K 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGaaUCAAUCcAacaGUsU 2073
    R-008381552-000E 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2021
    R-008381552-000E 1797    5 CUGUUGGAUUGAUUCGAAA UUucGaAUCAAUCcAAcagUsU 2075
    R-008381002-000U 1797    5 CUGUUGGAUUGAUUCGAAA uuUCGAAUcaaUCCAAcAgUsU 2076
    R-008381002-000U 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAAUsU B 2022
    R-008381394-000X 1797    5 CUGUUGGAUUGAUUCGAAA uuUcGAAUCaaUcCAACaGUsU 2078
    R-008381394-000X 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2020
    R-008381383-000W 1797    5 CUGUUGGAUUGAUUCGAAA UUucGAAuCaaUCCAacAGUsU 2081
    R-008381383-000W 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2021
    R-008381093-000J 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAAUsU B 2022
    R-008381093-000J 1797    5 CUGUUGGAUUGAUUCGAAA uuuCgaAUCAAUCcAACagUsU 2082
    R-008381375-000W 1797    5 CUGUUGGAUUGAUUCGAAA UuuCgAAUCAAUCcaACAGUsU 2085
    R-008381375-000W 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2020
    R-008381543-000W 1797    5 CUGUUGGAUUGAUUCGAAA UuuCGaauCAaUccaACAGUsU 2087
    R-008381543-000W 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2021
    R-008381535-000W 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgAauCAAUCcAAcagUsU 2089
    R-008381535-000W 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAAUsU B 2022
    R-008381528-000E 1797    5 CUGUUGGAUUGAUUCGAAA uUuCGAAUCAaUCcaaCAGUsU 2090
    R-008381528-000E 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2020
    R-008381365-000D 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2021
    R-008381365-000D 1797    5 CUGUUGGAUUGAUUCGAAA UuUCGAAUcaauCCaACaGUsU 2093
    R-008381520-000K 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgAAuCAauCcaaCAgUsU 2095
    R-008381520-000K 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAAUsU B 2022
    R-008380915-000F 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2020
    R-008380915-000F 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGaAUCAauCCAaCAGUsU 2097
    R-008381359-000W 1797    5 CUGUUGGAUUGAUUCGAAA UUUcgaAUcAAUcCAACagUsU 2099
    R-008381359-000W 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUsU B 2021
    R-008381249-000U 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAAUsU B 2022
    R-008381249-000U 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGAaUcaAUCcaACAgUsU 2101
    R-008381082-000H 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2033
    R-008381082-000H 2398  151 CCAGGAUGAUCCUAGCUAU AuaGCUAggAUCAuCCuGGUsU 2103
    R-008381240-000R 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2034
    R-008381290-000R 2398  151 CCAGGAUGAUCCUAGCUAU AUAgcuaGgaUCAuCcUGgUsU 2105
    R-008380907-000F 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuUsU B 2035
    R-008380907-000F 2398  151 CCAGGAUGAUCCUAGCUAU aUagCUAGGaUCauccUGgUsU 2106
    R-008381164-000A 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2033
    R-008381164-000A 2398  151 CCAGGAUGAUCCUAUCUAU aUagCuagGAUCAucCugGUsU 2108
    R-008381072-000R 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2034
    R-008381072-000R 2398  151 CCAGGAUGAUCCUAGCUAU AUAGcUAgGAuCauCCUggUsU 2111
    R-008381450-000C 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuUsU B 2035
    R-008381450-000C 2398  151 CCAGGAUGAUCCUAUCUAU auAgCUaGGAuCauCCUGGUsU 2112
    R-008381059-000S 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2033
    R-008381059-000S 2398  151 CCAGGAUGAUCCUAGCUAU aUaGCuaggAUcaUcCUGGUsU 2114
    R-008381154-000H 2398  151 CCAGGAUGAUCCUAGCUAU aUagCUAggAuCAuCCuGgUsU 2116
    R-008381154-000H 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2034
    R-008389143-000L 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUaGGAUcauCCUgGUsU 2119
    R-008381493-000L 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuUsU B 2035
    R-008381049-000Z 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2033
    R-008381099-000Z 2398  151 CCAGGAUGAUCCUAGCUAU aUagcUAGGAUcaUCCugGUsU 2120
    R-008381292-000V 2398  151 CCAGGAUGAUCCUAGCUAU auAGcUaggauCAUCCuGGUsU 2122
    R-008381292-000V 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2034
    R-008381010-000U 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGgaUCauCcuGGUsU 2125
    R-008381010-000U 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuUsU B 2035
    R-008381284-000V 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2033
    R-008381284-000V 2398  151 CCAGGAUGAUCCUAGCUAU AUaGCUagGAucAuCCUgGUsU 2127
    R-008381917-000U 2398  151 CCAGGAUGAUCCUAGCUAU aUAGCuAGGAUCAUCcUggUsU 2128
    R-008381417-000U 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2034
    R-008381265-000U 2398  151 CCAGGAUGAUCCUAGCUAU AUaGCuAGGaUcAUcCUggUsU 2131
    R-008381265-000U 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuUsU B 2035
    R-008381464-000E 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2033
    R-008381464-000E 2398  151 CCAGGAUGAUCCUAGCUAU aUaGcUaggAUCAucCUGGUsU 2132
    R-008381170-000H 2398  151 CCAGGAUGAUCCUAGCUAU aUagCuAGGaUCAuCcUgGUsU 2134
    R-008381170-000H 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2034
    R-008381408-000K 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuUsU B 2035
    R-008381408-000K 2398  151 CCAGGAUGAUCCUAGCUAU AuagCUAgGauCAUcCUGGUsU 2137
    R-008381110-000D 1870  194 ACGACUAGUUCAGUUGCUU aagCAaCUGaAcuAGUCgUUsU 2138
    R-008381110-000D 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2046
    R-008381558-000G 1870  194 ACGACUAGUUCAGUUGCUU aAGcAACUgAaCUaGUCguUsU 2140
    R-008381558-000G 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2047
    R-008381456-000E 1870  194 ACGACUAGUUCAGUUGCUU AAGcaACuGaaCUaGuCGUUsU 2143
    R-008381456-000E 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuUsU B 2048
    R-008381401-000Z 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2046
    R-008381401-000Z 1870  194 ACGACUAGUUCAGUUGCUU aAgCaAcUGAACUAgUcGUUsU 2144
    R-008380922-000X 1870  194 ACGACUAGUUCAGUUGCUU aaGCAAcUgAaCuagUcGUUsU 2146
    R-008380922-000X 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2047
    R-008381101-000V 1870  194 ACGACUAGUUCAGUUGCUU AAgCAAcUGaACUaGUcgUUsU 2149
    R-008381101-000V 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuUsU B 2048
    R-008381556-000P 1870  194 ACGACUAGUUCAGUUGCUU AAgCAacugAAcUagUCGUUsU 2151
    R-008381556-000P 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2046
    R-008381426-000C 1870  194 ACGACUAGUUCAGUUGCUU AagcAaCUgaaCUAGucgUUsU 2153
    R-008381126-000C 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2047
    R-008380979-000V 1870  194 ACGACUAGUUCAGUUGCUU AaGCaAcUGAacUaGUcGUUsU 2155
    R-008380979-000V 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuUsU B 2048
    R-008380882-000S 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2046
    R-008380882-000S 1870  194 ACGACUAGUUCAGUUGCUU AAgcaaCUGAACuaGUCGCUsU 2157
    R-008381204-000F 1870  194 ACGACUAGUUCAGUUGCUU AaGCAACUgaACUAGuCGUUsU 2159
    R-008381204-000F 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2047
    R-008381471-000W 1870  194 ACGACUAGUUCAGUUGCUU aAgCAACUGAacUaGuCgUUsU 2160
    R-008381471-000W 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuUsU B 2048
    R-008381197-000D 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2046
    R-008381197-000D 1870  194 ACGACUAGUUCAGUUGCUU AAgCAACUGaACUaGUCguUsU 2163
    R-008380970-000S 1870  194 ACGACUAGUUCAGUUGCUU aAgCAaCuGaAcuaGUCgUUsU 2164
    R-008380970-000S 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2047
    R-008381511-000B 1870  194 ACGACUAGUUCAGUUGCUU aAgCAACugAACuaguCgUUsU 2166
    R-008381511-000B 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuUsU B 2048
    R-008380992-000U 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2046
    R-008380992-000U 1870  194 ACGACUAGUUCAGUUGCUU aAGCAacUgaACUaGUcGUUsU 2168
    R-008381233-000Z 1870  194 ACGACUAGUUCAGUUGCUU AAGCAAcUGAaCUaGUCGuUsU 2171
    R-008381233-000Z 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2047
    R-008381352-000K 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuUsU B 2048
    R-008381352-000K 1870  194 ACGACUAGUUCAGUUGCUU aaGCAACuGaACUagUcGuUsU 2172
    R-008380987-000V 2401  196 GGAUGAUCCUAGCUAUCGU ACgaUAGcuAGgauCAUICUsU 2175
    R-008380987-000V 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2059
    R-008381345-000U 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2060
    R-008381345-004U 2401  196 GGAUGAUCCUAGCUAUCGU aCgAUagcuaGGAUcAUCCUsU 2176
    R-008381146-000H 2401  196 GGAUGAUCCUAGCUAUCGU aCGauAGCuAgGaUcauCCUsU 2178
    R-008381146-000H 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuUsU B 2061
    R-008381503-000B 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2059
    R-008381503-000B 2401  196 GGAUGAUCCUAGCUAUCGU acgAUAGCUaGgAUCAuCCUsU 2180
    R-008381137-000Z 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2060
    R-008381137-000Z 2401  196 GGAUGAUCCUAGCUAUCGU ACgaUAgCUaGGAuCAUCcUsU 2183
    R-008381337-000U 2401  196 GGAUGAUCCUAGCUAUCGU aCgauAgCUAggAucaUcCUsU 2184
    R-008381337-000U 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuUsU B 2061
    R-008380900-000V 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2059
    R-008380900-000V 2401  196 GGAUGAUCCUAGCUAUCGU aCGAuaGCuAGGAuCaUCCUsU 2186
    R-008381328-000K 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2060
    R-008381328-000K 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuAgcUaGGAUCauCCUsU 2189
    R-008381222-000Y 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuUsU B 2061
    R-008381222-000Y 2401  196 GGAUGAUCCUAGCUAUCGU aCGAuaGCUAGgAUCaUccUsU 2190
    R-008381494-000G 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuAgCUagGAuCAUCcUsU 2193
    R-008381494-000G 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2059
    R-008381212-000F 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2060
    R-008381212-000F 2401  196 GGAUGAUCCUAGCUAUCGU AcGAUAGCUAGgaucaUCCUsU 2195
    R-008381434-000C 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuUsU B 2061
    R-008381434-000C 2401  196 GGAUGAUCCUAGCUAUCGU acgAuaGCUagGauCAUcCUsU 2196
    R-008380895-000K 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2059
    R-008380895-000K 2401  196 GGAUGAUCCUAGCUAUCGU aCgAUagcUAGGAuCAuCCUsU 2198
    R-008381488-000Z 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2060
    R-008381488-000Z 2101  196 GGAUGAUCCUAGCUAUCGU aCGAUaGCuAGGauCauCCUsU 2200
    R-008381126-000Y 2401  196 GGAUGAUCCUAGCUAUCGU aCGaUagcUAgGAUcAuCcUsU 2202
    R-008381126-000Y 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuUsU B 2061
    R-008381479-000R 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2059
    R-008381479-000R 2401  196 GGAUGAUCCUAGCUAUCGU AcGAUaGCUaGGauCAUccUsU 2205
    R-008381319-000B 2401  196 GGAUGAUCCUAGCUAUCGU AcgaUagCUAGGAUcAucCUsU 2207
    R-008381319-000B 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUAGCUAUCGUUsU B 2060
    R-008380889-000C 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuUsU B 2061
    R-008380889-000C 2401  196 GGAUGAUCCUAGCUAUCGU ACGaUAGcuaggAuCAUcCUsU 2209
    R-008381831-000R 1797    5 CUGUUGGAUUGAUUCGAAA B CUgUuGGAUUGAUUCGaAAUsU B 2066
    R-008381831-000R 1797    5 CUGUUGGAUUGAUUCGAAA uuucGAAucAAuccAAcAGUsU 2016
    R-008381842-000S 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUuGGaUUGaUUCGAAaUsU B 2069
    R-008381842-000S 1797    5 CUGUUGGAUUGAUUCGAAA uuucGAAucAAuccAAcAGUsU 2016
    R-008381850-000S 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUuGgaUUGAUuCGaAAUsU B 2071
    R-008381850-000S 1797    5 CUGUUGGAUUGAUUCGAAA uuucGAAucAAuccAAcAGUsU 2016
    R-008381815-000R 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgaaUCaauCCaaCagUsU 2023
    R-008381815-000R 1797    5 CUGUUGGAUUGAUUCGAAA B CUgUUGgaUUGaUUCgAAAUsU B 2072
    R-008381783-000K 1797    5 CUGUUGGAUUGAUUCGAAA B CUgUUGGAUUGAUuCgAAAUsU B 2074
    R-008381783-000K 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgaaUCaauCCaaCagUsU 2023
    R-008381799-000E 1797    5 CUGUUGGAUUGAUUCGAAA B CuGUUGgaUUgAuUCGAaaUsU B 2077
    R-008381799-000E 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgaaUCaauCCaaCagUsU 2023
    R-008381814-000G 1797    5 CUGUUGGAUUGAUUCGAAA B CUgUUgGaUUGAUUCGaaAUsU B 2079
    R-008381814-000G 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAGUsU 2024
    R-008381780-000J 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAGUsU 2024
    R-008381780-000J 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGaUUCGAaAUsU B 2080
    R-008381841-000H 1797    5 CUGUUGGAUUGAUUCGAAA B CUgUUGgAUugAUUCgAAaUsU B 2083
    R-008381841-000H 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAGUsU 2024
    R-008381791-000K 1797    5 CUGUUGGAUUGAUUCGAAA B CugUUGGAUUGaUUcgaaaUsU B 2084
    R-008381791-000K 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAGUsU 2025
    R-008381839-000K 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAGUsU 2025
    R-008381839-000K 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUgGaUugAUuCGaAAUsU B 2086
    R-008381796-000D 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUgGAUUGAUUCgAAAUsU B 2088
    R-008381796-000D 1797    5 CUGUUGGAUUGAUUCGAAA UUUCGAAUCAAUCCAACAGUsU 2025
    R-008381838-000B 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGAAucAAuccAAcAGUsU 2019
    R-008381838-000B 1797    5 CUGUUGGAUUGAUUCGAAA B CUgUUggAUUgaUUCGaAAUsU B 2091
    R-008381790-000B 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGaUUGaUUCgAAAUsU B 2092
    R-008381790-000B 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGAAucAAuccAAcAGUsU 2019
    R-008381825-000H 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGaUUgaUUCgAaaUsU B 2094
    R-008381825-000H 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGAAucAAuccAAcAGUsU 2019
    R-008381789-000M 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgaaUCaaUCCaaCagUsU 2026
    R-008381789-000M 1797    5 CUGUUGGAUUGAUUCGAAA B CuGuUgGAUUgaUUCGAaAUsU B 2096
    R-008381805-000Y 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgaaUCaaUCCaaCagUsU 2026
    R-008381805-000Y 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGgAUUGAUUCGaaaUsU B 2098
    R-008381788-000D 1797    5 CUGUUGGAUUGAUUCGAAA UUUCgaaUCaaUCCaaCagUsU 2026
    R-008381788-000D 1797    5 CUGUUGGAUUGAUUCGAAA B CUgUUggaUUgaUUCgaaaUsU B 2100
    R-008381847-000K 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUgaUcCUaGCUAUUsU B 2102
    R-008381847-000K 2398  151 CCAGGAUGAUCCUAGCUAU AuAGcuAGGAucAuccuGGUsU 2030
    R-008381837-000T 2398  151 CCAGGAUGAUCCUAGCUAU AuAGcuAGGAucAuccuGGUsU 2030
    R-008381837-000T 2398  151 CCAGGAUGAUCCUAGCUAU B CCSGgaUGaUCCUAgCUAUUsU B 2104
    R-008381824-000Z 2398  151 CCAGGAUGAUCCUAGCUAU B CCagGAUgAUCCUAGCUaUUsU B 2107
    R-008381824-000Z 2398  151 CCAGGAUGAUCCUAGCUAU AuAGcuAGGAucAuccuGGUsU 2030
    R-008381810-000X 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUaUUsU B 2109
    R-008381810-000X 2398  151 CCAGGAUGAUCCUAGCUAU AUAgCUaggaUCaUCCUggUsU 2036
    R-008381802-000X 2398  151 CCAGGAUGAUCCUAGCUAU B cCAGgAUGaUCCUagCUAUUsU B 2110
    R-008381802-000X 2398  151 CCAGGAUGAUCCUAGCUAU AUAgCUaggaUCaUCCUggUsU 2036
    R-008381820-000P 2398  151 CCAGGAUGAUCCUAGCUAU AUAgCUaggaUCaUCCUggUsU 2036
    R-008381820-000P 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUAGCUAUUsU B 2113
    R-008381819-000A 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGGUsU 2037
    R-008381819-000A 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGAUGAUCCUagCUaUUsU B 2115
    R-008381787-000V 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGGUsU 2037
    R-008381787-000V 2398  151 CCAGGAUGAUCCUAGGUAU B CCAgGAUgaUCCUaGCUAUUsU B 2117
    R-008381835-000A 2398  151 CCAGGAUGAUCCUAGCUAU B CCaggaUgaUCCUagCUaUUsU B 2118
    R-008381835-000A 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGGUsU 2037
    R-008381844-000J 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGGUsU 2038
    R-008381844-000J 2398  151 CCAGGAUGAUCCUAGCUAU B CCAgGAUGAUCCUAGcUAUUsU B 2121
    R-008381853-000T 2398  151 CCAGGAUGAUCCUAGCUAU B CCaGGaUGAUCCUAGCUAUUsU B 2123
    R-008381853-000T 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGGUsU 2038
    R-008381833-000H 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGGaUGaUCCuAgCUAUUsU B 2124
    R-008381833-000H 2398  151 CCAGGAUGAUCCUAGCUAU AUAGCUAGGAUCAUCCUGGUsU 2038
    R-008381817-000H 2398  151 CCAGGAUGAUCCUAGCUAU AUAucuAGGAucAuccuGGUsU 2032
    R-008381817-000H 2398  151 CCAGGAUGAUCCUAGCUAU B cCAGGaUGAuCCUaGCUaUUsU B 2126
    R-008381786-000L 2398  151 CCAGGAUGAUCCUAGCUAU AUAGcuAGGAucAuccuGGUsU 2032
    R-008381786-000L 2398  151 CCAGGAUGAUCCUAGCUAU B CCaGgAUgAuCCUAGcUAUUsU B 2129
    R-008381851-000A 2398  151 CCAGGAUGAUCCUAGCUAU AUAGcuAGGAucAuccuGGUsU 2032
    R-008381851-000A 2398  151 CCAGGAUGAUCCUAGCUAU B CcaggAugaUCCUAGCUaUUsU B 2130
    R-008381809-000H 2398  151 CCAGGAUGAUCCUAGCUAU AUAgCUaggaUCaUCCUggUsU 2039
    R-008381809-000H 2398  151 CCAGGAUGAUCCUAGCUAU B CCAgGaUGAUcCUaGCUAUUsU B 2133
    R-008381808-000Z 2398  151 CCAGGAUGAUCCUAGCUAU B CCAggaUGAUCCUAgCUAuUsU B 2135
    R-008381808-000Z 2398  151 CCAGGAUGAUCCUAGCUAU AUAgCUaggaUCaUCCUggUsU 2039
    R-008381784-000U 2398  151 CCAGGAUGAUCCUAGCUAU AUAgCUaggaUCaUCCUggUsU 2039
    R-008381784-000U 2398  151 CCAGGAUGAUCCUAGCUAU B CCAGgAUgAUCCUAGcuaUUsU B 2136
    R-008381793-000C 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUsU 2043
    R-008381793-000C 1870  194 ACGACUAGUUCAGUUGCUU B ACgACuAgUUcAGUUGCUUUsU B 2139
    R-008381807-000R 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUsU 2043
    R-008381807-000R 1870  194 ACGACUAGUUCAGUUGCUU B aCGACUAGuUCAgUugcUUUsU B 2141
    R-008381816-000Z 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUsU 2043
    R-008381816-000Z 1870  194 ACGACUAGUUCAGUUGCUU B aCGACUagUUCaGUUgCUUUsU B 2142
    R-008381830-000G 1870  194 ACGACUAGUUCAGUUGCUU AAGCaaCugaaCUagUCgUUsU 2049
    R-008381830-000G 1870  194 ACGACUAGUUCAGUUGCUU B aCgaCuAGUuCAgUUgcUUUsU B 2145
    R-008381782-000B 1870  194 ACGACUAGUUCAGUUGCUU B aCgaCUAguUCAGUUGCUUUsU B 2147
    R-008381782-000B 1870  194 ACGACUAGUUCAGUUGCUU AAGCaaCugaaCUagUCgUUsU 2049
    R-008381849-000C 1870  194 ACGACUAGUUCAGUUGCUU B ACGaCUAGUUCAGUUGCuUUsU B 2148
    R-008381849-000C 1870  194 ACGACUAGUUCAGUUGCUU AAGCaaCugaaCUagUCgUUsU 2049
    R-008381781-000T 1870  194 ACGACUAGUUCAGUUGCUU B ACgACUAGUUCaGUUGcUUUsU B 2150
    R-008381781-000T 1870  194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGUUsU 2050
    R-008381829-000T 1870  194 ACGACUAGUUCAGUUGCUU B acGACUagUUCagUuGCuUUsU B 2152
    R-008381829-000T 1870  194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGUUsU 2050
    R-008381792-000U 1870  194 ACGACUAGUUCAGUUGCUU B aCGScUAGUUCAGUUgCUUUsU B 2154
    R-008381792-000U 1870  194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGUUsU 2050
    R-008381798-000W 1870  194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGUUsU 2051
    R-008381798-000W 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUaGUUCaGUUgCUUUsU B 2156
    R-008381828-000J 1870  194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGUUsU 2051
    R-008381828-000J 1870  194 ACGACUAGUUCAGUUGCUU B ACGaCUaGUUCAGUUGcUUUsU B 2158
    R-008381840-000Z 1870  194 ACGACUAGUUCAGUUGCUU AAGCAACUGAACUAGUCGUUsU 2051
    R-008381840-000Z 1870  194 ACGACUAGUUCAGUUGCUU B ACgACUAgUUCAgUUgCUUUsU B 2161
    R-008381797-000M 1870  194 ACGACUAGUUCAGUUGCUU B ACGaCUaGuUCagUUGCUUUsU B 2162
    R-008381797-000M 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUsU 2045
    R-008381813-000Y 1870  194 ACGACUAGUUCAGUUGCUU B ACGaCUaGUUCaguUgCUuUsU B 2165
    R-008381813-000Y 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUsU 2045
    R-008381827-000A 1870  194 ACGACUAGUUCAGUUGCUU B ACGACUAGUUCAGUUGCUUUsU B 2167
    R-008381827-000A 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUsU 2045
    R-008381812-000P 1870  194 ACGACUAGUUCAGUUGCUU B aCgaCUAGUUCaGUUGCUUUsU B 2169
    R-008381812-000P 1870  194 ACGACUAGUUCAGUUGCUU AAGCaaCUgaaCUagUCgUUsU 2052
    R-008381848-000U 1870  194 ACGACUAGUUCAGUUGCUU B ACgAcUAgUuCAgUUGGUUUsU B 2170
    R-008381848-000U 1870  194 ACGACUAGUUCAGUUGCUU AAGCaaCUgaaCUagUCgUUsU 2052
    R-008381779-000V 1870  194 ACGACUAGUUCAGUUGCUU B aCgaCUagUUCagUUgCUUUsU B 2173
    R-008381779-000V 1870  194 ACGACUAGUUCAGUUGCUU AAGCaaCUgaaCUagUCgUUsU 2052
    R-008381846-000B 2401  196 GGAUGAUCCUAGCUAUCGU AcGAuAGcuAGGAucAuccUsU 2056
    R-008381846-000B 2401  196 GGAUGAUCCUAGCUAUCGU B gGaugaUcCUaGCuAUCgUUsU B 2174
    R-008381811-000F 2401  196 GGAUGAUCCUAGCUAUCGU B GgAUGaUCCuagcUAUCgUUsU B 2177
    R-008381811-000F 2401  196 GGAUGAUCCUAGCUAUCGU AcGAuAGcuAGGAucAuccUsU 2056
    R-008381845-000T 2401  196 GGAUGAUCCUAGCUAUCGU B gGAUgAUCCUAGCuaUCGUUsU B 2179
    R-008381845-000T 2401  196 GGAUGAUCCUAGCUAUCGU AcGAuAGcuAGGAucAuccUsU 2056
    R-008381795-000V 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUsU 2062
    R-008381795-000V 2401  196 GGAUGAUCCUAGCUAUCGU B gGAUGAUCCUAgCUauCGUUsU B 2181
    R-008381823-000R 2401  196 GGAUGAUCCUAGCUAUCGU ACGaUagCUaggaUCaUCCUsU 2062
    R-008381823-000R 2401  196 GGAUGAUCCUAGCUAUCGU B ggaUgaUCCUagCUaUCgUUsU B 2182
    R-008381803-000F 2401  196 GGAUGAUCCUAGCUAUCGU ACGaUagCUaggaUCaUCCUsU 2062
    R-008381803-000F 2401  196 GGAUGAUCCUAGCUAUCGU B GGaUGAUCCUAGCUaUCgUUsU B 2185
    R-008381822-000G 2401  196 GGAUGAUCCUAGCUAUCGU B GGaUGAUCCUaGCUAUCgUUsU B 2187
    R-008381822-000G 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUsU 2063
    R-008381836-000J 2401  196 GGAUGAUCCUAGCUAUCUU B gGaUgAUCCUaGCUAUCGUUsU B 2188
    R-008381836-000J 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUsU 2063
    R-008381854-000B 2401  196 GGAUGAUCCUAGCUAUCGU B GgAUGauCCUAGCUAUCguUsU B 2191
    R-008381854-000B 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUsU 2063
    R-008381801-000N 2401  196 GGAUGAUCCUAGCUAUCUU B GgaUgAUCcUagCUaUCGuUsU B 2192
    R-008381801-000N 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUsU 2064
    R-008381800-000E 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGaUCCUsGCUaUchUsU B 2194
    R-008381800-000E 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUsU 2064
    R-008381834-000S 2401  196 GGAUGAUCCUAGCUAUCGU B GgSUGSUCCUagCUAUCGUUsU B 2197
    R-008381834-000S 2401  196 GGAUGAUCCUAGCUAUCGU ACGAUAGCUAGGAUCAUCCUsU 2064
    R-008381852-000J 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuAGcuAGGAucAuccUsU 2058
    R-008381852-000J 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAuCCUaGCUAUCGUUsU B 2199
    R-008381843-000A 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuAGcuAGGAucAuccUsU 2058
    R-008381843-000A 2401  196 GGAUGAUCCUAGCUAUCGU B GgaUGaUCCUAgCUAUCGUUsU B 2201
    R-008381832-000Z 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuAGcuAGGAucAuccUsU 2058
    R-008381832-000Z 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUgAUCCUAgcUAUCgUUsU B 2203
    R-008381818-000S 2401  196 GGAUGAUCCUAGCUAUCGU B GGaUgaUCCuAGCuAUCGUUsU B 2204
    R-008381818-000S 2401  196 GGAUGAUCCUAGCUAUCGU A CGaUagCUaggaUCaUCCUsU 2065
    R-008381785-000C 2401  196 GGAUGAUCCUAGCUAUCGU B GGAUGAUCCUagCUAuCGUUsU B 2206
    R-008381785-000C 2401  196 GGAUGAUCCUAGCUAUCGU A CGaUagCUaggaUCaUCCUsU 2065
    R-008381794-000L 2401  196 GGAUGAUCCUAGCUAUCGU A CGaUagCUaggaUCaUCCUsU 2065
    R-008381794-000L 2401  196 GGAUGAUCCUAGCUAUCGU B gGAUgaUCCUAGCUaUCGUUsU B 2208
    R-008395187-000D 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAATT B 2210
    R-008395187-000D 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGAAucAAuccAAcAGUU 1463
    R-008395214-000T 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAATT B 2210
    R-008395244-000T 1797    5 CUGUUGGAUUGAUUCGAAA IUUcGAAucAAuccAAcAGUU 2211
    R-008395198-000E 1797    5 CUGUUGGAUUGAUUCGAAA UIUcGAAucAAuccAAcAGUU 2212
    R-008395198-000E 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAATT B 2210
    R-008395222-000R 1797    5 CUGUUGGAUUGAUUCGAAA UUIcGAAucAAuccAAcAGUU 2213
    R-008395222-000R 1797    5 CUOUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAATT B 2210
    R-008395155-000J 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAATT B 2210
    R-008395155-000J 1797    5 CUGUUGGAUUGAUUCGAAA UUUIGAAucAAuccAAcAGUU 2214
    R-008395242-000A 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAATT B 2210
    R-008395242-000A 1797    5 CUGUUGGAUUGAUUCGAAA UUUcIAAucAAuccAAcAGUU 2215
    R-008395267-000D 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAATT B 2210
    R-008395267-000D 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGIAucAAuccAAcAGUU 2216
    R-008395153-000S 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAATT B 2210
    R-008395153-000S 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGAUucAAuccAAcAGUU 2217
    R-008395286-000E 1797    5 CUGUUGGAUUGAUUCGAAA B cuGuuGGAuuGAuucGAAATT B 2210
    R-008395286-000E 1797    5 CUGUUGGAUUGAUUCGAAA UUUcGAAIcAAuccAAcAGUU 2218
    R-008395196-000M 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuTT B 2219
    R-008395196-000M 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcuGAAcuAGucGuUU 1841
    R-008395168-000C 1870  194 ACGACUAGUUCAGUUGCUU IAGcAAcuGAAcuAGucGuUU 2220
    R-008395168-000C 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuTT B 2219
    R-008395265-000L 1870  194 ACGACUAGUUCAGUUGCUU AIGcAAcuGAAcuAGucGuUU 2221
    R-008395265-000L 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuTT B 2219
    R-008395150-000R 1870  194 ACGACUAGUUCAGUUGCUU AAIcAAcuGAAcuAGucGuUU 2222
    R-008395150-000R 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuTT B 2219
    R-008395263-000U 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuTT B 2219
    R-008395263-000U 1870  194 ACGACUAGUUCAGUUGCUU AAGIAAcuGAAcuAGucGuUU 2223
    R-008395172-000T 1870  194 ACGACUAGUUCAGUUGCUU AAGcIAcuGAAcuAGucGuUU 2224
    R-008395172-000T 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuTT B 2219
    R-008395170-000A 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuTT B 2219
    R-008395170-000A 1870  194 ACGACUAGUUCAGUUGCUU AAGcAIcuGAAcuAGucGuUU 2225
    R-008395226-000A 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuTT B 2219
    R-008395226-000A 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAIuGAAcuAGucGuUU 2226
    R-008395207-000Z 1870  194 ACGACUAGUUCAGUUGCUU AAGcAAcIGAAcuAGucGuUU 2227
    R-008395207-000Z 1870  194 ACGACUAGUUCAGUUGCUU B AcGAcuAGuucAGuuGcuuTT B 2219
    R-008395205-000G 2398  151 CCAGGAUGAUCCUAGCUAU AUAGcuAGGAucAuccuGGUU 1755
    R-008395205-000G 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuTT B 2228
    R-008395250-000A 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuTT B 2228
    R-008395250-000A 2398  151 CCAGGAUGAUCCUAGCUAU IUAGcuAGGAucAuccuGGUU 2229
    R-008395248-000C 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuTT B 2228
    R-008395248-000C 2398  151 CCAGGAUGAUCCUAGCUAU AIAGcuAGGAucAuccuGGUU 2230
    R-008395275-000D 2398  151 CCAGGAUGAUCCUAGCUAU AUIGcuAGGAucAuccuGGUU 2231
    R-008395275-000D 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuTT B 2228
    R-008395163-000J 2398  151 CCAGGAUGAUCCUAGCUAU AUAIcuAGGAucAuccuGGUU 2232
    R-008395163-000J 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuTT B 2228
    R-008395224-000H 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuTT B 2228
    R-008395224-000H 2398  151 CCAGGAUGAUCCUAGCUAU AUAGIuAGGAucAuccuGGUU 2233
    R-008395161-000S 2398  151 CCAGGAUGAUCCUAGCUAU AUAGcIAGGAucAuccuGGUU 2234
    R-008395161-000S 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuTT B 2228
    R-008395290-000V 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuTT B 2228
    R-008395290-000V 2398  151 CCAGGAUGAUCCUAGCUAU AUAGcuIGGAucAuccuGGUU 2235
    R-008395273-000L 2398  151 CCAGGAUGAUCCUAGCUAU B ccAGGAuGAuccuAGcuAuTT B 2228
    R-008395273-000L 2398  151 CCAGGAUGAUCCUAGCUAU AUAGcuAIGAucAuccuGGUU 2236
    R-008395188-000M 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuAGcuAGGAucAuccUU 1845
    R-008395188-000M 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuTT B 2237
    R-008395204-000Y 2401  196 GGAUGAUCCUAGCUAUCGU ICGAuAGcuAGGAucAuccUU 2238
    R-008395204-000Y 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuTT B 2237
    R-008395202-000F 2401  196 GGAUGAUCCUAGCUAUCGU AIGAuAGcuAGGAucAuccUU 2239
    R-008395202-000F 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuTT B 2237
    R-008395158-000K 2401  196 GGAUGAUCCUAGCUAUCGU ACIAuAGcuAGGAucAuccUU 2240
    R-008395158-000K 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuTT B 2237
    R-008395296-000K 2401  196 GGAUGAUCCUAGCUAUCGU ACGIuAGcuAGGAucAuccUU 2241
    R-008395246-000K 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuTT B 2237
    R-008395271-000U 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuTT B 2237
    R-008395271-000U 2401  196 GGAUGAUCCUAGCUAUCGU ACGAIAGcuAGGAucAuccUU 2242
    R-008395200-000N 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuIGcuAGGAucAuccUU 2243
    R-008395200-000N 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuTT B 2237
    R-008395288-000X 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuTT B 2237
    R-008395288-000X 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuAIcuAGGAucAuccUU 2244
    R-008395269-000W 2401  196 GGAUGAUCCUAGCUAUCGU ACGAuAGIuAGGAucAuccUU 2245
    R-008395269-000W 2401  196 GGAUGAUCCUAGCUAUCGU B GGAuGAuccuAGcuAucGuTT B 2237
    R-008397891-000B 1382  238 GAUCCAAGUCAACGUCUUG B GAUCCAAGUCAACGUCUUGTT B 2246
    R-008397891-000B 1382  238 GAUCCAAGUCAACGUCUUG CAAGACGUUGACUUGGAUCUU 2247
    R-008397894-000C  828  239 CUAUCAUGCGUUCUCCUCA B CUAUCAUGCGUUCUCCUCATT B 2248
    R-008397894-000C  828  239 CUAUCAUGCGUUCUCCUCA UGAGGAGAACGCAUGAUAGUU 2249
    R-008396925-000E 1244  240 AAUAUAAUGAGGACCUAUA B ASUAUSAUGAGGACCUAUATT B 2250
    R-008396925-000E 1244  240 AAUAUAAUGAGGACCUAUA UAUAGGUCCUCAUUAUAUUUU 2251
    R-008395991-000K 1304  241 GUGCUAUCUGUCUGCUCUA B GUGCUAUGUGUCUGCUCUATT B 2252
    R-008395941-000K 1304  241 GUGCUAUCUGUCUGCUCUA UAGAGCAGACAGAUAGCACUU 2253
    R-008395944-000L  812  242 GAAGCUUCCAGACACGCUA B GAAGCUUCCAGACACGCUATT B 2254
    R-008395944-000L  812  242 GAAGCUUCCAGACACGCUA UAGCGUGUCUGGAAGCUUCUU 2255
    R-008397498-000Y 1558  243 UAAUUAUAAGAACAAGAUG B UAAUUAUAAGAACAAGAUGTT B 2256
    R-008397498-000Y 1558  243 UAAUUAUAAGAACAAGAUG CAUCUUGUUCUUAUAAUUAUU 2257
    R-008397501-000R  879  244 AUACAAAUGAUGUAGAAAC B AUACAAAUGAUGUAGAAACTT B 2258
    R-008397501-000R  879  244 AUACAAAUGAUGUAGAAAC GUUUCUACAUCAUUUGUAUUU 2259
    R-008396451-000Y 1311  245 CUGUCUGCUCUAGUAAUAA UUAUUACUAGAGCAGACAGUU 2261
    R-008396451-000Y 1311  245 CUGUCUGCUCUAGUAAUAA B CUGUCUGCUCUAGUAAUAATT B 2260
    R-008397504-000S  856  246 UGCUAUUGUACGUACCAUG B UGCUAUUGUACGUACCAUGTT B 2262
    R-008397504-000S  856  246 UGCUAUUGUACGUACCAUG CAUGGUACGUACAAUAGCAUU 2263
    R-008396961-000P 1296  247 UGCUGAAGGUGCUAUCUGU B UGCUGAAGGUGCUAUCUGUTT B 2264
    R-008396961-000P 1296  247 UGCUGAAGGUGCUAUCUGU ACAGAUAGCACCUUCAGCAUU 2265
    R-008396967-000S 1235   39 GCUUUAGUAAAUAUAAUGA B GCUUUAGUAAAUAUAAUGATT B 2266
    R-008396967-000S 1235   39 GCUUUAGUAAAUAUAAUGA UCAUUAUAUUUACUAAAGCUU 2267
    R-008396463-000H  960  248 UCUUUAAGUCUGGAGGCAU AUGCCUCCAGACUUAAAGAUU 2269
    R-008396463-000H  960  248 UCUUUAAGUCUGGAGGCAU B UCUUUAAGUCUGGAGGCAUTT B 2268
    R-008398998-000S 2099  249 AUACCAUUCCAUUGUUUGU B AUACCAUUCCAUUGUUUGUTT B 2270
    R-008398998-000S 2049  249 AUACCAUUCCAUUGUUUGU ACAAACAAUGGAAUGGUAUUU 2271
    R-008398515-000M 1791  250 AGGCUACUGUUGGAUUGAU AUCAAUCCAACAGUAGCCUUU 2273
    R-008398515-000M 1791  250 AGGCUACUGUUGGAUUGAU B AGGCUACUGUUGGAUUGAUTT B 2272
    R-008395947-000M  783  251 CAGUUAUGGUCCAUCAGCU B CAGUUAUGGUCCAUCAGCUTT B 2274
    R-008395997-000M  783  251 CAGUUAUGGUCCAUCAGCU AGCUGAUGGACCAUAACUGUU 2275
    R-008396466-000J 1569  252 ACAAGAUGAUGGUCUGCCA B ACAAGAUGAUGGUCUGCCATT B 2276
    R-008396466-000J 1569  252 ACAAGAUGAUGGUCUGCCA UGGCAGACCAUCAUCUUGUUU 2277
    R-008396970-000Y 2224  253 GACAUAUGCAGCUGCUGUU AACAGCAGCUGCAUAUGUCUU 2279
    R-008396970-000Y 2224  253 GACAUAUGCAGCUGCUGUU B GACAUAUGCAGGUGCUGUUTT B 2278
    R-008395989-000Z 1882  123 GUUGCUUGUUCGUGCACAU B GUUGCUUGUUCGUGCACAUTT B 2280
    R-008395989-000Z 1882  123 GUUGCUUGUUCGUGCACAU AUGUGCACGAACAAGCAACUU 2281
    R-008398626-000Y  934  254 CCAUCAUCGUGAGGGCUUA B CCAUCAUCGUGAGGGCUUATT B 2282
    R-008398626-000Y  934  254 CCAUCAUCGUGAGGGCUUA UAAGCCCUCACGAUGAUGGUU 2283
    R-008396121-000S 1378  255 GACAGAUCCAAGUCAACGU B GACAGAUCCAAGUCAACGUTT B 2284
    R-008396121-000S 1378  255 GACAGAUCCAAGUCAACGU ACGUUGACUUGGAUCUGUCUU 2285
    R-008396001-000X  569  256 GAGACAUUAGAUGAGGGCA UGCCCUCAUCUAAUGUCUCUU 2287
    R-008396001-000X  569  256 GAGACAUUAGAUGAGGGCA B GAGACAUUAGAUGAGGGCATT B 2286
    R-008396007-000Z 1722  257 UUCGCCUUCACUAUGGACU B UUCGCCUUCACUAUGGACUTT B 2288
    R-008396007-000Z 1722  257 UUCGCCUUCACUAUGGACU AGUCCAUAGUGAAGGCGAAUU 2289
    R-008396547-000T 1483  258 UGUUCAGCUUCUGGGUUCA B UGUUCAGCUUCUGGGUUCATT B 2290
    R-008396547-000T 1483  258 UGUUCAGCUUCUGGGUUCA UGAACCCAGAAGCUGAACAUU 2291
    R-008399088-000F 2352  259 AUCUUGGACUUGAUAUUGG CCAAUAUCAAGUCCAAGAUUU 2293
    R-008399088-000F 2352  259 AUCUUGGACUUGAUAUUGG B AUCUUGGACUUGAUAUUGGTT B 2292
    R-008398596-000K  719  260 CGUGCAAUCCCUGAACUGA B CGUGCAAUCCCUGAACUGATT B 2294
    R-008398596-000K  719  260 CGUGCAAUCCCUGAACUGA UCAGUUCAGGGAUUGCACGUU 2295
    R-008399094-000N  762  261 AGGUGGUGGUUAAUAAGGC B AGGUGGUGGUUAAUAAGGCTT B 2296
    R-008399094-000N  762  261 AGGUGGUGGUUAAUAAGGC GCCUUAUUAACCACCACCUUU 2297
    R-008397585-000P  599  262 UCUACACAGUUUGAUGCUG B UCUACACAGUUUGAUGCUGTT B 2298
    R-008397585-000P  599  262 UCUACACAGUUUGAUGCUG CAGCAUCAAACUGUGUAGAUU 2299
    R-008396073-000L 1704  263 AGAUGGCCCAGAAUGCAGU B AGAUGGCCCAGAAUGCAGUTT B 2300
    R-008396073-000L 1704  263 AGAUGGCCCAGAAUGCAGU ACUGCAUUCUGGGCCAUCUUU 2301
    R-008398599-000L 2270  264 CAAGAUUACAAGAAACGGC GCCGUUUCUUGUAAUCUUGUU 2303
    R-008398599-000L 2270  264 CAAGAUUACAAGAAACGGC B CAAGADUACAAGAAACGGCTT B 2302
    R-008399532-000R 1810  103 UCGAAAUCUUGCCCUUUGU ACAAAGGGCAAGAUUUCGAUU 2305
    R-008399532-000R 1810  103 UCGAAAUCUUGCCCUUUGU B UCGAAAUCUUGCCCUUUGUTT B 2304
    R-008398602-000D  662  265 CUGAAACAUGCAGUUGUAA B CUGAAACAUGCAGUUGUAATT B 2306
    R-008398602-000D  662  265 CUGAAACAUGCAGUUGUAA UUACAACUGCAUGUUUCAGUU 2307
    R-008399106-000J  396  266 CUCCUUCUCUGAGUGGUAA UUACCACUCAGAGAAGGAGUU 2309
    R-008399106-000J  396  266 CUCCUUCUCUGAGUGGUAA B CUCCUUCUCUGAGUGGUAATT B 2308
    R-008398053-000R 1199  267 AGCAAGCUCAUCAUACUGG CCAGUAUGAUGAGCUUGCUUU 2311
    R-008398053-000R 1199  267 AGCAAGCUCAUCAUACUGG B AGCAAGCUCAUCAUACUGGTT B 2310
    R-008396583-000C 1560  268 AUUAUAAGAACAAGAUGAU B AUUAUAAGAACAAGAUGAUTT B 2312
    R-008396583-000C 1560  268 AUUAUAAGAACAAGAUGAU AUCAUCUUGUUCUUAUAAUUU 2313
    R-008399028-000B  593   92 AUCCCAUCUACACAGUUUG CAAACUGUGUAGAUGGGAUUU 2315
    R-008399028-000B  593   92 AUCCCAUCUACACAGUUUG B AUCCCAUCUACACAGUUUGTT B 2314
    R-008398104-000X 1310  269 UCUGUCUGCUCUAGUAAUA B UCUGUCUGCUCUAGUAAUATT B 2316
    R-008398104-000X 1310  269 UCUGUCUGCUCUAGUAAUA UAUUACUAGAGCAGACAGAUU 2317
    R-008398113-000F 1233  270 AAGCUUUAGUAAAUAUAAU B AAGCUUUAGUAAAUAUAAUTT B 2318
    R-008398113-000F 1233  270 AAGCUUUAGUAAAUAUAAU AUUAUAUUUACUAAAGCUUUU 2319
    R-008399622-000H 1330  271 GCCGGCUAUUGUAGAAGCU B GCCGGCUAUUGUAGAAGCUTT B 2320
    R-008399622-000H 1330  271 GCCGGCUAUUGUAGAAGCU AGCUUCUACAAUAGCCGGCUU 2321
    R-008399151-000C 1312  272 UGUCUGCUCUAGUAAUAAG B UGUCUGCUCUAGUAAUAAGTT B 2322
    R-008399151-000C 1312  272 UGUCUGCUCUAGUAAUAAG CUUAUUACUAGAGCAGACAUU 2323
    R-008396127-000U 1556  273 AAUAAUUAUAAGAACAAGA UCUUGUUCUUAUAAUUAUUUU 2325
    R-008396127-000U 1556  273 AAUAAUUAUAAGAACAAGA B AAUAAUUAUAAGAACAAGATT B 2324
    R-008395707-000Y 2438  274 UAUGGCCAGGAUGCCUUGG B UAUGGCCAGGAUGCCUUGGTT B 2326
    R-008395707-000Y 2438  274 UAUGGCCAGGAUGCCUUGG CCAAGGCAUCCUGGCCAUAUU 2327
    R-008395710-000E 1826  275 UGUCCCGCAAAUCAUGCAC GUGCAUGAUUUGCGGGACAUU 2329
    R-008395710-000E 1826  275 UGUCCCGCAAAUCAUGCAC B UGUCCCGCAAAUCAUGCACTT B 2328
    R-008395713-000F 1397  276 CUUGUUCAGAACUGUCUUU B CUUGUUCAGAACUGUCUUUTT B 2330
    R-008395713-000F 1397  276 CUUGUUCAGAACUGUCUUU AAAGACAGUUCUGAACAAGUU 2331
    R-008395716-000G 3181  277 GCUGUGAUACGAUGCUUCA UGAAGCAUCGUAUCACAGCUU 2333
    R-008395716-000G 3181  277 GCUGUGAUACGAUGCUUCA B GCUGUGAUACGAUGCUUCATT B 2332
    R-008395719-000H 1912  278 GCGCCGUACGUCCAUGGGU B GCGCCGUACGUCCAUGGGUTT B 2334
    R-008395719-000H 1912  278 GCGCCGUACGUCCAUGGGU ACCCAUGGACGUACGGCGCUU 2335
    R-008395722-000P  846  279 AGAUGGUGUCUGCUAUUGU B AGAUGGUGUCUGCUAUUGUTT B 2336
    R-008395722-000P  846  279 AGAUGGUGUCUGCUAUUGU ACAAUAGCAGACACCAUCUUU 2337
    R-008395725-000R 1404  280 AGAACUGUCUUUGGACUCU B AGAACUGUCUUUGGACUCUTT B 2338
    R-008395725-000R 1404  280 AGAACUGUCUUUGGACUCU AGAGUCCAAAGACAGUUCUUU 2339
    R-008395728-000S  586  281 CAUGCAGAUCCCAUCUACA UGUAGAUGGGAUCUGCAUGUU 2341
    R-008395728-000S  586  281 CAUGCAGAUCCCAUCUACA B CAUGCAGAUCCCAUCUACATT B 2340
    R-008395731-000Y 1469  282 CUCCUUGGGACUCUUGUUC GAACAAGAGUCCCAAGGAGUU 2343
    R-008395731-000Y 1469  282 CUCCUUGGGACUCUUGUUC B CUCCUUGGGACUCUUGUUCTT B 2342
    R-008395734-000Z  380  283 GGUGCCACUACCACAGCGC B GGUGCCACUACCACAGCUCTT B 2344
    R-008395734-000Z  380  283 GGUGCCACUACCACAGCGC GAGCUGUGGUAGUGGCACCUU 2345
    R-008395737-000A 1345  284 AGCUGGUGGAAUGCAAGCU B AGCUGGUGGAAUGCAAGCUTT B 2346
    R-008395737-000A 1345  284 AGCUGGUGGAAUGCAAGCU AGCUUGCAUUCCACCAGCUUU 2347
    R-008395740-000G 1863  285 CCAUUCCACGAGUAGUUCA B CCAUUCCACGACUAGUUCATT B 2348
    R-008395740-000G 1863  285 CCAUUCCACGAGUAGUUCA UGAACUAGUCGUGGAAUGGUU 2349
    R-008395743-000H  635  286 CAGCGUUUGGCUGAACCAU AUGGUUCAGCCAAACGCUGUU 2351
    R-008395743-000H  635  286 CAGCGUUUGGCUGAACCAU B CAGCGUUUGGCUGAACCAUTT B 2350
    R-008395746-000J  959  287 AUCUGUAAGUCUGGAGGCA UGCCUCCAGACUUAAAGAUUU 2353
    R-008395746-000J  959  287 AUGUUUAAGGCUGGAGGCA B AUCUUUAAGUCUGGAGGCATT B 2352
    R-008395749-000K 2440  288 UGGCCAGGAUGCCUUGGGU B UGGCCAGGAUGCCUUGGGUTT B 2354
    R-008395749-000K 2440  288 UGGCCAGGAUGCCUUGGGU ACCCAAGGCAUCCUGGCCAUU 2355
    R-008395752-000S  877  289 GAAUACAAAUGAUGUAGAA UUCUACAUCAUUUGUAUUCUU 2357
    R-008395752-000S  877  289 GAAUACAAAUGAUGUAGAA B GAAUACAAAUGAUGUAGAATT B 2356
    R-008395755-000T 2556  290 UGGAUGGGCUGCCUCCAGG CCUGGAGGCAGCCCAUCCAUU 2359
    R-008395755-000T 2556  290 UGGAUGGGCUGCCUCCAGG B UGGAUGGGCUGCCUCCAGGTT B 2358
    R-008395758-000U 1916  291 CGUACGUCCAUGGGUGGGA B CGUACGUCCAUGGGUGGGATT B 2360
    R-008395758-000U 1916  291 CGUACGUCCAUGGGUGGGA UCCCACCCAUGGACGUACGUU 2361
    R-008395761-000A  850  292 GGUGUCUGCUAUUGUACGU B GGUGUCUGGUAUUGUACGUTT B 2362
    R-008395761-000A  850  292 GGUGUCUGCUAUUGUACGU ACGUACAAUAGCAGACACCUU 2363
    R-008395764-000B 1303  293 GGUGCUAUCUGUCUGCUCU B GGUGCUAUCUGUCUGCUCUTT B 2364
    R-008395764-000B 1303  293 GGUGCUAUCUGUCUGCUCU AGAGCAGACAGAUAGCACCUU 2365
    R-008395767-000C 1726  294 CCUUCACUAUGGACUACCA UGGUAGUCCAUAGUGAAGGUU 2367
    R-008395767-000C 1726  294 CCUUCACUAUGGACUACCA B CCUUCACUAUGGACUACCATT B 2366
    R-008395770-000J 1477  295 GACUCUUGUUCAGCUUCUG CAGAAGCUGAACAAGAGUCUU 2369
    R-008395770-000J 1477  295 GACUCUUGUUCAGCUUCUG B GACUCUUGUUCAGCUUCUGTT B 2368
    R-008395773-000K  598  296 AUCUACACAGUUUGAUGCU B AUCUACACAGUUUGAUGCUTT B 2370
    R-008395773-000K  598  296 AUCUACACAGUUUGAUGCU AGCAUCAAACUGUGUAGAUUU 2371
    R-008395776-000L 2062  297 GUUUGUGCAGCUGCUUUAU B GUUUGUGCAGGUGCUUUAUTT B 2372
    R-008395776-000L 2062  297 GUUUGUGCAGCUGCUUUAU AUAAAGCAGCUGCACAAACUU 2373
    R-008395779-000M 2278  298 CAAGAAACGGCUUUCAGUU B CAAGAAACGGCUUUCAGUUTT B 2374
    R-008395779-000M 2278  298 CAAGAAACGGCUUUCAGUU AACUGAAAGCCGUUUCUUGUU 2375
    R-008395782-000U 1877  299 GUUCAGUUGCUUGUUCGUG CACGAACAAGCAACUGAACUU 2377
    R-008395782-000U 1877  299 GUUCAGUUGCUUGUUCGUG B GUUCAGUUGCUUGUUCGUGTT B 2376
    R-008395785-000V 1499  300 UCAGAUGAUAUAAAUGUGG B UCAGAUGAUAUAAAUGUGGTT B 2378
    R-008395785-000V 1499  300 UCAGAUGAUAUAAAUGUGG CCACAUUUAUAUCAUCUGAUU 2379
    R-008395788-000W 1136  301 AAUGUUAAAUUCUUGGCUA B AAUGUUAAAUUCUUGGGUATT B 2380
    R-008395788-000W 1136  301 AAUGUUAAAUUCUUGGCUA UAGCCAAGAAUUUAACAUUUU 2381
    R-008395791-000C 1494  302 UGGGUUCAGAUGAUAUAAA UUUAUAUCAUCUGAACCCAUU 2383
    R-008395791-000C 1494  302 UGGGUUCAGAUGAUAUAAA B UGGGIICAGAIGAIAIAAATT B 2382
    R-008395794-000D 1972  303 AAUAGUUGAAGGUUGUACC B AAUAGUUGAAGGUUGUACCTT B 2384
    R-008395794-000D 1972  303 AAUAGUUGAAGGUUGUACC GGUACAACCUUCAACUAUUUU 2385
    R-008395797-000E  668  304 CAUGCAGUUGUAAACUUGA UCAAGUUUACAACUGCAUGUU 2387
    R-008395797-000E  668  304 CAUGCAGUUGUAAACUUGA B CAUGCAGUUGUAAACUUGATT B 2386
    R-008395800-000X 2945  305 AAUCUGAAUAAAGUGUAAC GUUACACUUUAUUCAGAUUUU 2389
    R-008395800-000X 2945  305 AAUCUGAAUAAAGUGUAAC B AAUCUGAAUAAAGUGUAACTT B 2388
    R-008395803-000Y 2492  306 CACCACCCUGGUGCUGACU B CACCACCCUGGUGCUGACUTT B 2390
    R-008395803-000Y 2492  306 CACCACCCUGGUGCUGACU AGUCAGCACCAGGGUGGUGUU 2391
    R-008395806-000Z  293  307 GAGUUGGACAUGGCCAUGG B GAGUUGGACAUGGCCAUGGTT B 2392
    R-008395806-000Z  293  307 GAGUUGGACAUGGCCAUGG CCAUGGCCAUGUCCAACUCUU 2393
    R-008395809-000A 1905  308 AUACCCAGCGCCGUACGUC B AUACCCAGCGCCGUACGUCTT B 2394
    R-008395809-000A 1905  308 AUACCCAGCGCCGUACGUC GACGUACGGCGCUGGGUAUUU 2395
    R-008395812-000G  944  309 GAGGGCUUACUGGCCAUCU AGAUGGCCAGUAAGCCCUCUU 2397
    R-008395812-000G  944  309 GAGGGCUUACUGGCCAUCU B GAGGGCUUACUGGCCAUCUTT B 2396
    R-008395815-000H  581  310 GAGGGCAUGCAGAUCCCAU B GAGGGCAUGCAGAUCCCAUTT B 2398
    R-008395815-000H  581  310 GAGGGCAUGCAGAUCCCAU AUGGGAUCUGCAUGCCCUCUU 2399
    R-008395818-000J 1454  311 GAAGGGAUGGAAGGUCUCC B GAAGGGAUGGAAGGUCUCCTT B 2400
    R-008395818-000J 1454  311 GAAGGGAUGGAAGGUCUCC GGAGACCUUCCAUCCCUUCUU 2401
    R-008395821-000R 2254  312 GUCUGAGGACAAGCCACAA B GUCUGAGGACAAGCCACAATT B 2402
    R-008395821-000R 2254  312 GUCUGAGGACAAGCCACAA UUGUGGCUUGUCCUCAGACUU 2403
    R-008395824-000S 1837  313 UCAUGCACCUUUGCGUGAG CUCACGCAAAGGUGCAUGAUU 2405
    R-008395824-000S 1837  313 UCAUGCACCUUUGCGUGAG B UCAUGCACCUUUGCGUGAGTT B 2404
    R-008395827-000T 1425  314 GGAAUCUUUCAGAUGCUGC B GGAAUCUUUCAGAUGCUGCTT B 2406
    R-008395827-000T 1425  314 GGAAUCUUUCAGAUGCUGC GCAGCAUCUGAAAGAUUCCUU 2407
    R-008395830-000Z 1372  315 UCACCUGACAGAUCCAAGU ACUUGGAUCUGUCAGGUGAUU 2409
    R-008395830-000Z 1372  315 UCACCUGACAGAUCCAAGU B UCACCUGACAGAUCCAAGUTT B 2408
    R-008395833-000A 1298  316 CUGAAGGUGCUAUCUGUCU B CUGAAGGUGCUAUCUGUCUTT B 2410
    R-008395833-000A 1298  316 CUGAAGGUGCUAUCUGUCU AGACAGAUAGCACCUUCAGUU 2411
    R-008395836-000B 1674  317 GUCAUCUGACCAGCCGACA B GUCAUCUGACCAGCCGACATT B 2412
    R-008395836-000C 1674  317 GUCAUCUGACCAGCCGACA UGUCGGCUGGUCAGAUGACUU 2413
    R-008395839-000C 1864  318 CAUUCCACGACUAGUUCAG CUGAACUAGUCGUGGAAUGUU 2415
    R-008395839-000C 1864  318 CAUUCCACGACUAGUUCAG B CAUUCCACGACUAGUUCAGTT B 2414
    R-008395842-000J 2404  319 UGAUCCUAGCUAUCGUUCU AGAACGAUAGCUAGGAUCAUU 2417
    R-008395842-000J 2404  319 UGAUCCUAGCUAUCGUUCU B UGAUCCUAGCUAUCGUUCUTT B 2416
    R-008395845-000K 1992  320 GAGCCCUUCACAUCCUAGC GCUAGGAUGUGAAGGGCUCUU 2419
    R-008395845-000K 1992  320 GAGCCCUUCACAUCCUAGC B GAGCCCUUCACAUCCUAGCTT B 2418
    R-008395848-000L 2124   73 GUGAACUUGCUCAGGACAA UUGUCCUGAGCAAGUUCACUU 2421
    R-008395848-000L 2124   73 GUGAACUUGCUCAGGACAA B GUGAACUUGCUCAGGACAATT B 2420
    R-008395851-000T  578  321 GAUGAGGGCAUGCAGAUCC GGAUCUGCAUGCCCUCAUCUU 2423
    R-008395851-000T  578  321 GAUGAGGGCAUGCAGAUCC B GAUGAGGGCAUGCAGAUCCTT B 2422
    R-008395854-000U 3091  322 AUGGGUAGGGUAAAUCAGU B AUGGGUAGGGUAAAUCAGUTT B 2424
    R-008395854-000U 3091  322 AUGGGUAGGGUAAAUCAGU ACUGAUUUACCCUACCCAUUU 2425
    R-008395857-000V  720  323 GUGCAAUCCCUGAACUGAC B GUGCAAUCCCUGAACUGACTT B 2426
    R-008395857-000V  720  323 GUGCAAUCCCUGAACUGAC GUCAGUUCAGGGAUUGCACUU 2427
    R-008395860-000B 2054  324 AUUCCAUUGUUUGUGCAGC B AUUCCAUUGUUUGUGCAGCTT B 2428
    R-008395860-000B 2054  324 AUUCCAUUGUUUGUGCAGC GCUGCACAAACAAUGGAAUUU 2429
    R-008395863-000C 1237   42 UUUAGUAAAUAUAAUGAGG CCUCAUUAUAUUUACUAAAUU 2431
    R-008395863-000C 1237   42 UUUAGUAAAUAUAAUGAGG B UUUAGUAAAUAUAAUGAGGTT B 2430
    R-008395866-000D  374  325 CAUUCUGGUGCCACUACCA UGGUAGUGGCACCAGAAUGUU 2433
    R-008395866-000D  374  325 CAUUCUGGUGCCACUACCA B CAUUCUGGUGCCACUACCATT B 2432
    R-008395869-000E  868  326 UACCAUGCAGAAUACAAAU AUUUGUAUUCUGCAUGGUAUU 2435
    R-008395869-000E  868  326 UACCAUGCAGAAUACAAAU B UACCAUGCAGAAUACAAAUTT B 2434
    R-008395872-000L  626   23 ACUAAUGUCCAGCGUUUGG CCAAACGCUGGACAUUAGUUU 2437
    R-008395872-000L  626   23 ACUAAUGUCCAGCGUUUGG B ACUAAUGUCCAGCGUUUGGTT B 2436
    R-008395875-000M 1716  327 AUGCAGUUCGCCUUCACUA B AUGCAGUUCGCCUUCACUATT B 2438
    R-008395875-000M 1716  327 AUGCAGUUCGCCUUCACUA UAGUGAAGGCGAACUGCAUUU 2439
    R-008395878-000N  950  328 UUACUGGCCAUCUUUAAGU B UUACUGGCCAUCUUUAAGUTT B 2440
    R-008395878-000N  950  328 UUACUGGCCAUCUUUAAGU ACUUAAAGAUGGCCAGUAAUU 2441
    R-008395881-000V 1489  329 GCUUCUGGGUUCAGAUGAU B GCUUCUGGGUUCAGAUGAUTT B 2442
    R-008395881-000V 1489  329 GCUUCUGGGUUCAGAUGAU AUCAUCUGAACCCAGAAGCUU 2443
    R-008395884-000W 1451  330 CAGGAAGGGAUGGAAGGUC B CAGGAAGGGAUGGAAGGUCTT B 2444
    R-008395884-000W 1451  330 CAGGAAGGGAUGGAAGGUC GACCUUCCAUCCCUUCCUGUU 2445
    R-008395S87-000X  438  159 UGGAUACCUCCCAAGUCCU AGGACUUGGGAGGUAUCCAUU 2447
    R-008395887-000X  438  159 UGGAUACCUCCCAAGUCCU B UGGAUACCUCCCAAGUCCUTT B 2446
    R-008395890-000D 1181  331 GCUUAUGGCAACCAAGAAA UUUCUUGGUUGCCAUAAGCUU 2449
    R-008395890-000D 1181  331 GCUUAUGGCAACCAAGAAA B GCUUAUGGCAACCAAGAAATT B 2448
    R-008395893-000E 1633  332 UGACAGGGAAGACAUCACU AGUGAUGUCUUCCCUGUCAUU 2451
    R-008395893-000E 1633  332 UGACAGGGAAGACAUCACU B UGACAGGGAAGACAUCACUTT B 2450
    R-008395896-000F 2394  333 AUCGCCAGGAUGAUCCUAG CUAGGAUCAUCCUGGCGAUUU 2453
    R-008395896-000F 2394  333 AUCGCCAGGAUGAUCCUAG B AUCGCCAGGAUGAUCCUAGTT B 2452
    R-008395899-000G 1322  334 AGUAAUAAGCCGGCUAUUG B AGUAAUAAGCCGGGUAUUGTT B 2454
    R-008395899-000G 1322  334 AGUAAUAAGCCGGCUAUUG CAAUAGCCGGCUUAUUACUUU 2455
    R-008395902-000Z  884  335 AAUGAUGUAGAAACAGCUC GAGCUGUUUCUACAUCAUUUU 2457
    R-008395902-000Z  884  335 AAUGAUGUAGAAACAGCUC B AAUGAUGUAGAAACAGCUCTT B 2456
    R-008395905-000A 2255  336 UCUGAGGACAAGCCACAAG B UCUGAGGACAAGCCACAAGTT B 2458
    R-008395905-000A 2255  336 UCUGAGGACAAGCCACAAG CUUGUGGCUUGUCCUCAGAUU 2459
    R-008395908-000B 1466  337 GGUCUCCUUGGGACUCUUG CAAGAGUCCCAAGGAGACCUU 2461
    R-008395908-000B 1466  337 GGUCUCCUUGGGACUCUUG B GGUCUCCUUGGGACUCUUGTT B 2460
    R-008395911-000H 1399  338 UGUUCAGAACUGUCUUUGG CCAAAGACAGUUJUGAACAUU 2463
    R-008395911-000H 1399  338 UGUUCAGAACUGUCUUUGG B UGUUCAGAACUGUCUUUGGTT B 2462
    R-008395914-000J  378  339 CUGGUGCCACUACCACAGC B CUGGUGCCACUACCACAGCTT B 2464
    R-008395914-000J  378  339 CUGGUGCCACUACCACAGC GCUGUGGUAGUGGCACCAGUU 2465
    R-008395917-000K 1921  340 GUCCAUGGGUGGGACACAG CUGUGUCCCACCCAUGGACUU 2467
    R-008395917-000K 1921  340 GUCCAUGGGUGGGACACAG B GUCCAUGGGUGGGACACAGTT B 2466
    R-008395920-000S 1085  341 GUGCGUUUAGCUGGUGGGC B GUGCGUUUAGCUGGUGGGCTT B 2468
    R-008395920-000S 1085  341 GUGCGUUUAGCUGGUGGGC GCCCACCAGCUAAACGCACUU 2469
    R-008395923-000T  865  342 ACGUACCAUGCAGAAUACA B ACGUACCAUGCAGAAUACATT B 2470
    R-008395923-000T  865  342 ACGUACCAUGCAGAAUACA UGUAUUCUGCAUGGUACGUUU 2471
    R-008395926-000U 2015  343 GAUGUUCACAACCGAAUUG B GAUGUUCACAACCGAAUUGTT B 2472
    R-008395926-000U 2015  343 GAUGUUCACAACCGAAUUG CAAUUCGGUUGUGAACAUCUU 2473
    R-008395929-000V 1195  344 AGAAAGCAAGCUCAUCAUA B AGAAAGCAAGCUCAUCAUATT B 2474
    R-008395929-000V 1195  344 AGAAAGCAAGCUCAUCAUA UAUGAUGAGCUUGCUUUCUUU 2475
    R-008395932-000B 1484  345 GUUCAGCUUCUGGGUUCAG CUGAACCCAGAAGCUGAACUU 2477
    R-008395932-000B 1484  345 GUUCAGCUUCUGGGUUCAG B GUUCAGCUUCUGGGUUCAGTT B 2476
    R-008395935-000C 1855  346 GCAGGGUGCCAUUCCACGA B GCAGGGUGCCAUUCCACGATT B 2478
    R-008395935-000C 1855  346 GCAGGGUGCCAUUCCACGA UCGUGGAAUGGCACCCUGCUU 2479
    R-008395938-000D 1341  347 UAGAAGCUGGUGGAAUGCA B UAGAAGCUGGUGGAAUGCATT B 2480
    R-008395938-000D 1341  347 UAGAAGCUGGUGGAAUGCA UGCAUUCCACCAGCUUCUAUU 2481
    R-008395950-000U 1963  348 CAUGGAAGAAAUAGUUGAA UUCAACUAUUUCUUCCAUGUU 2483
    R-008395950-000U 1963  348 CAUGGAAGAAAUAGUUGAA B CAUGGAAGAAAUAGUUGAATT B 2482
    R-008395953-000V 2362  349 UGAUAUUGGUGCCCAGGGA B UGAUAUUGGUGCCCAGGGATT B 2484
    R-008395953-000V 2362  349 UGAUAUUGGUGCCCAGGGA UCCCUGGGCACCAAUAUCAUU 2485
    R-008395956-000W  584  350 GGCAUGCAGAUCCCAUCUA B GGCAUGCAGAUCCCAUCUATT B 2486
    R-008395956-000W  584  350 GGCAUGCAGAUCCCAUCUA UAGAUGGGAUCUGCAUGCCUU 2487
    R-008395959-000X 1613  351 CGUACUGUCCUUCGGGCUG B CGUACUGUCCUUCGGGCUGTT B 2488
    R-008395959-000X 1613  351 CGUACUGUCCUUCGGGCUG CAGCCCGAAGGACAGUACGUU 2489
    R-008395962-000D 1155  352 UUACGACAGACUGCCUUCA UGAAGGCAGUCUGUCGUAAUU 2491
    R-008395962-000D 1155  352 UUACGACAGACUGCCUUCA B UUACGACAGACUGCCUUCATT B 2490
    R-008395965-000E  334  353 UAGUCACUGGCAGCAACAG B UAGUCACUGGCAGCAACAGTT B 2492
    R-008395965-000E  334  353 UAGUCACUGGCAGCAACAG CUGUUGCUGCCAGUGACUAUU 2493
    R-008395968-000F 1031  354 GCCAUUACAACUCUCCACA B GCCAUUACAACUCUCCACATT B 2494
    R-008395968-000F 1031  354 GCCAUUACAACUCUCCACA UGUGGAGAGUUGUAAUGGCUU 2495
    R-008395971-000M 1725  355 GCCUUCACUAUGGACUACC B GCCUUCACUAUGGACUACCTT B 2496
    R-008395971-000M 1725  355 GCCUUCACUAUGGACUACC GGUAGUCCAUAGUGAAGGCUU 2497
    R-008395974-000N 2018  356 GUUCACAACCGAAUUGUUA B GUUCACAACCGAAUUGUUATT B 2498
    R-008395974-000N 2018  356 GUUCACAACCGAAUUGUUA UAACAAUUCGGUUGUGAACUU 2499
    R-008395977-000P  914  357 GGGACCUUGCAUAACCUUU AAAGGUUAUGCAAGGUCCCUU 2501
    R-008395977-000P  914  357 GGGACCUUGCAUAACCUUU B GGGACCUUGCAUAACCUUUTT B 2500
    R-008395980-000W 2264  358 AAGCCACAAGAUUACAAGA B AAGCCACAAGAUUACAAGATT B 2502
    R-008395980-000W 2264  358 AAGCCACAAGAUUACAAGA UCUUGUAAUCUUGUGGCUUUU 2503
    R-008395983-000X  343  359 GCAGCAACAGUCUUACCUG CAGGUAAGACUGUUGCUGCUU 2505
    R-008395983-000X  343  359 GCAGCAACAGUCUUACCUG B GCAGCAACAGUCUUACCUGTT B 2504
    R-008395986-000Y 1056  360 UAUUACAUCAAGAAGGAGC B UAUUACAUCAAGAAGGAGCTT B 2506
    R-008395986-000Y 1056  360 UAUUACAUCAAGAAGGAGC GCUCCUUCUUGAUGUAAUAUU 2507
    R-008395992-000F  772  361 UAAUAAGGCUGCAGUUAUG B UAAUAAGGCUGCAGUUAUGTT B 2508
    R-008395992-000F  772  361 UAAUAAGGCUGCAGUUAUG CAUAACUGCAGCCUUAUUAUU 2509
    R-008395995-000G 1390   91 UCAACGUCUUGUUCAGAAC GUUCUGAACAAGACGUUGAUU 2511
    R-008395995-000G 1390   91 UCAACGUCUUGUUCAGAAC B UCAACGUCUUGUUCAGAACTT B 2510
    R-008395998-000H 1959  183 UCCGCAUGGAAGAAAUAGU ACUAUUUCUUCCAUGCGGAUU 2513
    R-008395998-000H 1959  183 UCCGCAUGGAAGAAAUAGU B UCCGCAUGGAAGAAAUAGUTT B 2512
    R-008396004-000Y  763  362 GGUGGUGGUUAAUAAGGCU B GGUGGUGGUUAAUAAGGCUTT B 2514
    R-008396004-000Y  763  362 GGUGGUGGUUAAUAAGGCU AGCCUUAUUAACCACCACCUU 2515
    R-008396010-000F  628  363 UAAUGUCCAGCGUUUGGCU B UAAUGUCCAGCGUUUGGCUTT B 2516
    R-008396010-000F  628  363 UAAUGUCCAGCGUUUGGCU AGCCAAACGCUGGACAUUAUU 2517
    R-008396013-000G  399  364 CUUCUCUGAGUGGUAAAGG B CUUCUCUGAGUGGUAAAGGTT B 2518
    R-008396013-000G  399  364 CUUCUCUGAGUGGUAAAGG CCUUUACCACUCAGAGAAGUU 2519
    R-008396016-000H 1682  365 ACCAGCCGACACCAAGAAG CUUCUUGGUGUCGGCUGGUUU 2521
    R-008396016-000H 1682  365 ACCAGCCGACACCAAGAAG B ACCAGCCGACACCAAGAAGTT B 2520
    R-008396019-000J  441  366 AUACCUCCCAAGUCCUGUA B AUACCUCCCAAGUCCUGUATT B 2522
    R-008396019-000J  441  366 AUACCUCCCAAGUCCUGUA UACAGGACUUGGGAGGUAUUU 2523
    R-008396022-000R 1729  367 UCACUAUGGACUACCAGUU B UCACUAUGGACUACCAGUUTT B 2524
    R-008396022-000R 1729  367 UCACUAUGGACUACCAGUU AACUGGUAGUCCAUAGUGAUU 2525
    R-008396025-000S 1902  368 AGGAUACCCAGCGCCGUAC GUACGGCGCUGGGUAUCCUUU 2527
    R-008396025-000S 1902  368 AGGAUACCCAGCGCCGUAC B AGGAUACCCAGCGCCGUACTT B 2526
    R-008396028-000T 1637  369 AGGGAAGACAUCACUGAGC B AGGGAAGACAUCACUGAGCTT B 2528
    R-008396028-000T 1637  369 AGGGAAGACAUCACUGAGC GCUCAGUGAUGUCUUCCCUUU 2529
    R-008396031-000Z 2391  370 GAUAUCGCCAGGAUGAUCC B GAUAUCGCCAGGAUGAUCCTT B 2530
    R-008396031-000Z 2391  370 GAUAUCGCCAGGAUGAUCC GGAUCAUCCUGGCGAUAUCUU 2531
    R-008396034-000A  501  371 AAGUAGCUGAUAUUGAUGG B AAGUAGCUGAUAUUGAUGGTT B 2532
    R-008396034-000A  501  371 AAGUAGCUGAUAUUGAUGG CCAUCAAUAUCAGCUACUUUU 2533
    R-008396037-000B 1358  372 CAAGCUUUAGGACUUCACC B CAAGCUUUAGGACUUCACCTT B 2534
    R-008396037-000B 1358  372 CAAGCUUUAGGACUUCACC GGUGAAGUCCUAAAGCUUGUU 2535
    R-008396040-000H 1821  373 CCCUUUGUCCCGCAAAUCA B CCCUUUGUCCCGCAAAUCATT B 2536
    R-008396040-000H 1821  373 CCCUUUGUCCCGCAAAUCA UGAUUUGCGGGACAAAGGGUU 2537
    R-008396043-000J  575  374 UUAGAUGAGGGCAUGCAGA B UUAGAUGAGGGCAUGCAGATT B 2538
    R-008396043-000J  575  374 UUAGAUGAGGGCAUGCAGA UCUGCAUGCCCUCAUCUAAUU 2539
    R-008396046-000K  528  375 CAAUGACUCGAGCUCAGAG B CAAUGACUCGAGCUCAGAGTT B 2540
    R-008396046-000K  528  375 CAAUGACUCGAGCUCAGAG CUCUGAGCUCGAGUCAUUGUU 2541
    R-008396049-000L 2433  376 GUGGAUAUGGCCAGGAUGC B GUGGAUAUGGCCAGGAUGCTT B 2542
    R-008396049-000L 2433  376 GUGGAUAUGGCCAGGAUGC GCAUCCUGGCCAUAUCCACUU 2543
    R-008396052-000T 1497  377 GUUCAGAUGAUAUAAAUGU ACAUUUAUAUCAUCUGAACUU 2545
    R-008396052-000T 1497  377 GUUCAGAUGAUAUAAAUGU B GUUCAGAUGAUAUAAAUGUTT B 2544
    R-008396055-000U 2134  378 UCAGGACAAGGAAGCUGCA B UCAGGACAAGGAAGCUGCATT B 2546
    R-008396055-000U 2134  378 UCAGGACAAGGAAGCUGCA UGCAGCUUCCUUGUCCUGAUU 2547
    R-008396058-000V 2160  379 UUGAAGCUGAGGGAGCCAC GUGGCUCCCUCAGCUUCAAUU 2549
    R-008396058-000V 2160  379 UUGAAGCUGAGGGAGCCAC B UUGAAGCUGAGGGAGCCACTT B 2548
    R-008396061-000B  291  380 UGGAGUUGGACAUGGCCAU A UGGCCAUGUCCAACUCAUU 2551
    R-008396061-000B  291  380 UGGAGUUGGACAUGGCCAU B UGGAGUUGGACAUGGCCAUTT B 2550
    R-008396064-000C  657  381 AGAUGCUGAAACAUGCAGU B AGAUGCUGAAACAUGCAGUTT B 2552
    R-008396064-000C  657  381 AGAUGCUGAAACAUGCAGU ACUGCAUGUUUCAGCAUCUUU 2553
    R-008396067-000D 1575  382 UGAUGGUCUGCCAAGUGGG B UGAUGGUCUGCCAAGUGGGTT B 2554
    R-008396067-000D 1575  382 UGAUGGUCUGCCAAGUGGG CCCACUUGGCAGACCAUCAUU 2555
    R-008396070-000K  667  383 ACAUGCAGUUGUAAACUUG CAAGUUUACAACUGCAUGUUU 2557
    R-008396070-000K  667  383 ACAUGCAGIUGUAAACUUG B ACAUGCAGUUGUAAACUUGTT B 2556
    R-008396076-000M 2190  384 CAGAGUUACUUCACUCUAG B CAGAGUUACUUCACUCUAGTT B 2558
    R-008396076-000M 2190  384 CAGAGUUACUUCACUCUAG CUAGAGUGAAGUAACUCUGUU 2559
    R-008396079-000N  532  385 GACUCGAGCUCAGAGGGUA UACCCUCUGAGCUCGAGUCUU 2561
    R-008396079-000N  532  385 GACUCGAGCUCAGAGGGUA B GACUCGAGCUCAGAGGGUATT B 2560
    R-008396082-000V  953  386 CUGGCCAUCUUUAAGUCUG CAGACUUAAAGAUGGCCAGUU 2563
    R-008396082-000V  953  386 CUGGCCAUCUUUAAGUCUG B CUGGCCAUCUUUAAGUCUGTT B 2562
    R-008396085-000W 3188  387 UACGAUGCUUCAAGAGAAA UUUCUCUUGAAGCAUCGUAUU 2565
    R-008396085-000W 3188  387 UACGAUGCUUCAAGAGAAA B UACGAUGCUUCAAGAGAAATT B 2564
    R-008396088-000X 2301  388 UGACCAGCUCUCUCUUCAG B UGACCAGCUCUCUCUUCAGTT B 2566
    R-008396088-000X 2301  388 UGACCAGCUCUCUCUUCAG CUGAAGAGAGAGCUGGUCAUU 2567
    R-008396091-000D 2310  389 CUCUCUUCAGAACAGAGCC B CUCUCUUCAGAACAGAGCCTT B 2568
    R-008396091-000D 2310  389 CUCUCUUCAGAACAGAGCC GGCUCUGUUCUGAAGAGAGUU 2569
    R-008396094-000E 2287  390 GCUUUCAGUUGAGCUGACC B GCUUUCAGUUGAGCUGACCTT B 2570
    R-008396094-000E 2287  390 GCUUUCAGUUGAGCUGACC GGUCAGCUCAACUGAAAGCUU 2571
    R-008396097-000F 1927  391 GGGUGGGACACAGCAGCAA UUGCUGCUGUGUCCCACCCUU 2573
    R-008396097-000F 1927  391 GGGUGGGACACAGCAGCAA B GGGUGGGACACAGCAGCAATT B 2572
    R-008396100-000Y  712  392 UGCCACACGUGCAAUCCCU AGGGAUUGCACGUGUGGCAUU 2575
    R-008396100-000Y  712  392 UGCCACACGUGCAAUCCCU B UGCCACACGUGCAAUCCCUTT B 2574
    R-008396103-000Z 2121  393 UCUGUGAACUUGCUCAGGA B UCUGUGAACUUGCUCAGGATT B 2576
    R-008396103-000Z 2121  393 UCUGUGAACUUGCUCAGGA UCCUGAGCAAGUUCACAGAUU 2577
    R-008396106-000A 2898  394 UGAGUAAUGGUGUAGAACA B UGAGUAAUGGUGUAGAACATT B 2578
    R-008396106-000A 2898  394 UGAGUAAUGGUGUAGAACA UGUUCUACACCAUUACUCAUU 2579
    R-008396109-000B 1799  395 GUUGGAUUGAUUCGAAAUC B GUUGGAUUGAUUCGAAAUCTT B 2580
    R-008396109-000B 1799  395 GUUGGAUUGAUUCGAAAUC GAUUUCGAAUCAAUCCAACUU 2581
    R-008396112-000H 1036  396 UACAACUCUCCACAACCUU AAGGUUGUGGAGAGUUGUAUU 2583
    R-008396112-000H 1036  396 UACAACUCUCCACAACCUU B UACAACUCUCCACAACCUUTT B 2582
    R-008396115-000J  449  397 CAAGUCCUGUAUGAGUGGG CCCACUCAUACAGGACUUGUU 2585
    R-008396115-000J  499  397 CAAGUCCUGUAUGAGUGGG B CAAGUCCUGUAUGAGUGGGTT B 2584
    R-008396118-000K 1452  398 AGGAAGGGAUGGAAGGUCU B AGGAAGGGAUGGAAGGUCUTT B 2586
    R-008396118-000K 1452  398 AGGAAGGGAUGGAAGGUCU AGACCUUCCAUCCCUUCCUUU 2587
    R-008396124-000T 1203  399 AGCUCAUCAUACUGGCUAG B AGCUCAUCAUACUGGCUAGTT B 2588
    R-008396124-000T 1203  399 AGCUCAUCAUACUGGCUAG CUAGCCAGUAUGAUGAGCUUU 2589
    R-008396130-000A 1357  400 GCAAGCUUUAGGACUUCAC GUGAAGUCCUAAAGCUUGCUU 2591
    R-008396130-000A 1357  400 GCAAGCUUUAGGACUUCAC B GCAAGCUUUAGGAGUUCACTT B 2590
    R-008396133-000B 1512  401 AUGUGGUCACCUGUGCAGC GCUGCACAGGUGACCACAUUU 2593
    R-008396133-000B 1512  401 AUGUGGUCACCUGUGCAGC B AUGUGGUCACCUGUGCAGCTT B 2592
    R-008396136-000C  275  402 ACUCAAGCUGAUUUGAUGG B ACUCAAGCUGAUUUGAUGGTT B 2594
    R-008396136-000C  275  402 ACUCAAGCUGAUUUGAUGG CCAUCAAAUCAGCUUGAGUUU 2595
    R-008396139-000D  299  403 GACAUGGCCAUGGAACCAG CUGGUUCCAUGGCCAUGUCUU 2597
    R-008396139-000D  299  403 GACAUGGCCAUGGAACCAG B GACAUGGCCAUGGAACCAGTT B 2596
    R-008396192-000K 1241  404 GUAAAUAUAAUGAGGACCU B GUAAAUAUAAUGAGGACCUTT B 2598
    R-008396142-000K 1241  404 GUAAAUAUAAUGAGGACCU AGGUCCUCAUUAUAUUUACUU 2599
    R-008396195-000L 1961  405 CGCAUGGAAGAAAUAGUUG CAACUAUUUCUUCCAUGCGUU 2601
    R-008396145-000L 1961  405 CGCAUGGAAGAAAUAGUUG B CGCAUGGAAGAAAUAGUUGTT B 2600
    R-008396198-000M 1436  406 GAUGGUGCAACUAAACAGG B GAUGCUGCAACUAAACAGGTT B 2602
    R-008396148-000M 1436  406 GAUGGUGCAACUAAACAGG CCUGUUUAGUUGCAGCAUCUU 2603
    R-008396151-000U 2469  407 UGAUGGAACAUGAGAUGGG B UGAUGGAACAUGAGAUGGGTT B 2604
    R-008396151-000U 2469  407 UGAUGGAACAUGAGAUGGG CCCAUCUCAUGUUCCAUCAUU 2605
    R-008396154-000V  760  408 CCAGGUGGUGGUUAAUAAG B CCAGGUGGUGGUUAAUAAGTT B 2606
    R-008396154-000V  760  408 CCAGGUGGUGGUUAAUAAG CUUAUUAACCACCACCUGGUU 2607
    R-008396157-000W 2504  141 GCUGACUAUCCAGUUGAUG CAUCAACUGGAUAGUCAGCUU 2609
    R-008396157-000W 2504  141 GCUGACUAUCCAGUUGAUG B GCUGACUAUCCAGUUGAUGTT B 2608
    R-008396160-000C 2257  409 UGAGGAGAAGCCACAAGAU AUCUUGUGGCUUGUCCUCAUU 2611
    R-008396160-000C 2257  409 UGAGGAGAAGCCACAAGAU B UGAGGACAAGCCACAAGAUTT B 2610
    R-008396163-000D  952  410 ACUGGCCAUCUUUAAGUCU AGACUUAAAGAUGGCCAGUUU 2613
    R-008396163-000D  952  410 ACUGGCCAUCUUUAAGUCU B ACUGGCCAUCUUUAAGUCUTT B 2612
    R-008396166-000E 2283  411 AACGGCUUUCAGUUGAGCU B AACGGCUUUCAGUUGAGCUTT B 2614
    R-008396166-000E 2283  411 AACGGCUUUCAGUUGAGCU AGCUCAACUGAAAGCCGUUUU 2615
    R-008396169-000F 1649   62 ACUGAGCCUGCCAUCUGUG B ACUGAGCCUGCCAUCUGUGTT B 2616
    R-008396169-000F 1649   62 ACUGAGCCUGCCAUCUGUG CACAGAUGGCAGGCUCAGUUU 2617
    R-008396172-000M 2014    8 GGAUGUUCACAACCGAAUU AAUUCGGUUGUGAACAUCCUU 2619
    R-008396172-000M 2014       8 GGAUGUUCACAACCGAAUU B GGAUGUUCACAACCGAAUUTT B 2618
    R-008396175-000N 1794  412 CUACUGUUGGAUUGAUUCG CGAAUCAAUCCAACAGUAGUU 2621
    R-008396175-000N 1794  412 CUACUGUUGGAUUGAUUCG B CUACUGUUGGAUUGAUUCGTT B 2620
    R-008396178-000P 1745  413 GUUGUGGUUAAGCUCUUAC B GUUGUGGUUAAGCUCUUACTT B 2622
    R-008396178-000P 1745  413 GUUGUGGUUAAGCUCUUAC GUAAGAGCUUAACCACAACUU 2623
    R-008396181-000W 1211  414 AUACUGGCUAGUGGUGGAC GUCCACCACUAGCCAGUAUUU 2625
    R-008396181-000W 1211  414 AUACUGGCUAGUGGUGGAC B AUACUGGCUAGUGGUGGACTT B 2624
    R-008396184-000X 2549  415 GACCUCAUGGAUGGGCUGC B GACCUCAUGGAUGGGCUGGTT B 2626
    R-008396184-000X 2549  415 GACCUCAUGGAUGGGCUGC GCAGCCCAUCCAUGAGGUCUU 2627
    R-008396187-000Y 2007  416 UAGCUCGGGAUGUUCACAA UUGUGAACAUCCCGAGCUAUU 2629
    R-008396187-000Y 2007  416 UAGCUCGGGAUGUUCACAA B UAGCUCGGGAUGUUCACAATT B 2628
    R-008396190-000E 2474  417 GAACAUGAGAUGGGUGGCC B GAACAUGAGAUGGGUGGCCTT B 2630
    R-008396190-000E 2474  417 GAACAUGAGAUGGGUGGCC GGCCACCCAUCUCAUGUUCUU 2631
    R-008396193-000F 1712  418 CAGAAUGCAGUUCGCCUUC GAAGGCGAACUGCAUUCUGUU 2633
    R-008396193-000F 1712  418 CAGAAUGCAGUUCGCCUUC B CAGAAUGCAGUUCGCCUUCTT B 2632
    R-008396196-000G 1919  419 ACGUCCAUGGGUGGGACAC B ACGUCCAUGGGUGGGACACTT B 2634
    R-008396196-000G 1919  419 ACCUCCAUGGGUGGGACAC GUGUCCGACCCAUGGACGUUU 2635
    R-008396199-000H 1000  420 UGGUUCACCAGUGGAUUCU AGAAUCCACUGGUGAACCAUU 2637
    R-008396199-000H 1000  420 UGGUUCACCAGUGGAUUCU B UGGUUCACCAGUGGAUUCUTT B 2636
    R-008396202-000A 2392  421 AUAUCGCCAGGAUGAUCCU AGGAUCAUCCUGGCGAUAUUU 2639
    R-008396202-000A 2392  421 AUAUCGCCAGGAUGAUCCU B AUAUGGCCAGGAUGAUCCUTT B 2638
    R-008396205-000B 1449  422 AACAGGAAGGGAUGGAAGG B AACAGGAAGGGAUGGAAGGTT B 2640
    R-008396205-000B 1449  422 AACAGGAAGGGAUGGAAGG CCUUCCAUCCCUUCCUGUUUU 2641
    R-008396208-000C 2294  423 GUUGAGCUGACCAGCUCUC GAGAGCUGGUCAGCUCAACUU 2643
    R-008396208-000C 2294  423 GUUGAGCUGACCAGCUCUC B GUUGAGCUGACCAGCUCUCTT B 2642
    R-008396211-000J 1135  424 AAAUGUUAAAUUCUUGGCU B AAAUGUUAAAUUCUUGGCUTT B 2644
    R-008396211-000J 1135  424 AAAUGUUAAAUUCUUGGCU AGCCAAGAAUUUAACAUUUUU 2645
    R-008396214-000K  822   14 GACACGCUAUCAUGCGUUC B GACACGCUAUCAUGCGUUCTT B 2646
    R-008396214-000K  822   14 GACACGCUAUCAUGCGUUC GAACGCAUGAUAGCGUGUCUU 2647
    R-008396217-000L 1333  425 GGCUAUUGUAGAAGCUGGU ACCAGCUUCUACAAUAGCCUU 2649
    R-008396217-000L 1333  425 GGCUAUUGUAGAAGCUGGU B GGCUAUUGUAGAAGCUGGUTT B 2648
    R-008396220-000T 1743  426 CAGUUGUGGUUAAGCUCUU AAGAGCUUAACCACAACUGUU 2651
    R-008396220-000T 1743  426 CAGUUGUGGUUAAGCUCUU B CAGUUGUGGUUAAGCUCUUTT B 2650
    R-008396223-000U  600  427 CUACACAGUUUGAUGCUGC GCAGCAUCAAACUGUGUAGUU 2653
    R-008396223-000U  600  427 CUACACAGUUUGAUGCUGC B CUACACAGUUUGAUGCUGUTT B 2652
    R-008396226-000V  970  428 UGGAGGCAUUCCUGCCCUG CAGGGGAGGAAUGCCUCCAUU 2655
    R-008396226-000V  970  428 UGGAGGCAUUCCUGCCCUG B UGGAGGCAUUCCUGCCCUGTT B 2654
    R-008396229-000W 3137  429 GGACAGUUUACCAGUUGCC B GGACAGUUUACCAGUUGCCTT B 2656
    R-008396229-000W 3137  429 GGACAGUUUACCAGUUGCC GGCAACUGGUAAACUGUCCUU 2657
    R-008396232-000C  372  430 UCCAUUCUGGUGCCACUAC GUAGUGGCACCAGAAUGGAUU 2659
    R-008396232-000C  372  430 UCCAUUCUGGUGCCACUAC B UCCAUUCUGGUGCCACUACTT B 2658
    R-008396235-000D 1761  431 UACACCCACCAUCCCACUG B UACACCCACCAUCCCACUGTT B 2660
    R-008396235-000D 1761  431 UACACCCACCAUCCCACUG CAGUGGGAUGGUGGGUGUAUU 2661
    R-008396238-000E 1650  432 CUGAGCCUGCCAUCUGUGC GCACAGAUGGCAGGCUCAGUU 2663
    R-008396238-000E 1650  432 CUGAGCCUGCCAUCUGUGC B CUGAGCCUGCCAUCUGUGCTT B 2662
    R-008396241-000L  972  433 GAGGCAUUCCUGCCGUGGU B GAGGCAUUCCUGCCCUGGUTT B 2664
    R-008396241-000L  972  433 GAGGCAUUCCUGCCCUGGU ACCAGGGCAGGAAUGCCUCUU 2665
    R-008396244-000M 1147  434 CUUGGCUAUUACGACAGAC GUCUGUCGUAAUAGCCAAGUU 2667
    R-008396244-000M 1147  434 CUUGGCUAUUACGACAGAC B CUUGGCUAUUACGACAGACTT B 2666
    R-008396297-000N  565  435 CCCUGAGACAUUAGAUGAG B CCCUGAGACAUUAGAUGAGTT B 2668
    R-008396247-000N  565  435 CCCUGAGACAUUAGAUGAG CUCAUCUAAUGUCUCAGGGUU 2669
    R-008396250-000V  525  436 AUGCAAUGACUCGAGCUCA B AUGCAAUGACUCGAGCUCATT B 2670
    R-008396250-000V  525  436 AUGCAAUGACUCGAGCUCA UGAGCUCGAGUCAUUGCAUUU 2671
    R-008396253-000W 1599  437 UAGAGGCUCUUGUGCGUAC B UAGAGGCUCUUGUGCGUACTT B 2672
    R-008396253-000W 1599  437 UAGAGGCUCUUGUGCGUAC GUACGCACAAGAGCCUCUAUU 2673
    R-008396256-000X 2199  438 UUCACUCUAGGAAUGAAGG B UUCACUCUAGGAAUGAAGGTT B 2674
    R-008396256-000X 2199  438 UUCACUCUAGGAAUGAAGG CCUUCAUUCCUAGAGUGAAUU 2675
    R-008396259-000Y 2261  439 GACAAGCCACAAGAUUACA B GACAAGCCACAAGAUUACATT B 2676
    R-008396259-000Y 2261  439 GACAAGCCACAAGAUUACA UGUAAUCUUGUGGCUUGUCUU 2677
    R-008396262-000E  705  440 CAGAACUUGCCACACGUGC B CAGAACUUGCCACACGUGCTT B 2678
    R-008396262-000E  705  440 CAGAACUUGCCACACGUGC GCACGUGUGGCAAGUUCUGUU 2679
    R-008396265-000F  916  441 GACCUUGCAUAACCUUUCC B GACCUUGCAUAACCUUUCCTT B 2680
    R-008396265-000F  916  441 GACCUUGCAUAACCUUUCC GGAAAGGUUAUGCAAGGUCUU 2681
    R-008396268-000G  385  442 CACUACCACAGCUCCUUCU AGAAGGAGCUGUGGUAGUGUU 2683
    R-008396268-000G  385  442 CACUACCACAGCUCCUUCU B CACUACCACAGCUCCUUCUTT B 2682
    R-008396271-000N 3076  443 CUAUUUGGGAUAUGUAUGG B CUAUUUGGGAUAUGUAUGGTT B 2684
    R-008396271-000N 3076  443 CUAUUUGGGAUAUGUAUGG CCAUACAUAUCCCAAAUAGUU 2685
    R-008396274-000P 1396  444 UCUUGUUCAGAACUGUCUU B UCUUGUUCAGAACUGUCUUTT B 2686
    R-008396274-000P 1396  444 UCUUGUUCAGAACUGUCUU AAGACAGUUCUGAACAAGAUU 2687
    R-008396277-000R 2447  445 GAUGCCUUGGGUAUGGACC GGUCCAUACCCAAGGCAUCUU 2689
    R-008396277-000R 2447  445 GAUGCCUUGGGUAUGGACC B GAUGCCUUGGGUAUGGACCTT B 2688
    R-008396280-000X 1338  446 UUGUAGAAGCUGGUGGAAU B UUGUAGAAGCUGGUGGAAUTT B 2690
    R-008396280-000X 1338  446 UUGUAGAAGCUGGUGGAAU AUUCCACCAGCUUCUACAAUU 2691
    R-008396283-000Y 2215  447 AGGUGUGGCGACAUAUGCA UGCAUAUGUCGCCACACCUUU 2693
    R-008396283-000Y 2215  447 AGGUGUGGCGACAUAUGCA B AGGUGUGGCGACAUAUGCATT B 2692
    R-008396286-000Z  722  448 GCAAUCCCUGAACUGACAA B GCAAUCCCUGAACUGACAATT B 2694
    R-008396286-000Z  722  448 GCAAUCCCUGAACUGACAA UUGUCAGUUCAGGGAUUGCUU 2695
    R-008396289-000A 1316  449 UGCUCUAGUAAUAAGCCGG CCGGCUUAUUACUAGAGCAUU 2697
    R-008396289-000A 1316  449 UGCUCUAGUAAUAAGCCGG B UGCUCUAGUAAUAAGCCGGTT B 2696
    R-008396292-000G 1687  450 CCGACACCAAGAAGCAGAG B CCGACACCAAGAAGCAGAGTT B 2698
    R-008396292-000G 1687  450 CCGACACCAAGAAGCAGAG CUCUGCUUCUUGGUGUCGGUU 2699
    R-008396295-000H  697  451 AGAUGAUGCAGAACUUGCC B AGAUGAUGCAGAACUUGCCTT B 2700
    R-008396295-000H  697  451 AGAUGAUGCAGAACUUGCC GGCAAGUUCUGCAUCAUCUUU 2701
    R-008396298-000J 2517  452 UUGAUGGGCUGCCAGAUCU B UUGAUGGGCUGCCAGAUCUTT B 2702
    R-008396298-000J 2517  452 UUGAUGGGCUGCCAGAUCU AGAUCUGGCAGCCCAUCAAUU 2703
    R-008396301-000B 1685  453 AGCCGACACCAAGAAGCAG B AGCCGACACCAAGAAGCAGTT B 2704
    R-008396301-000B 1685  453 AGCCGACACCAAGAAGCAG CUGCUUCUUGGUGUCGGCUUU 2705
    R-008396304-000C 3090  454 UAUGGGUAGGGUAAAUCAG CUGAUUUACCCUACCCAUAUU 2707
    R-008396304-000C 3090  454 UAUGGGUAGGGUAAAUCAG B UAUGGGUAGGGUAAAUCAGTT B 2706
    R-008396307-000D 1205  455 CUCAUCAUACUGGCUAGUG B CUCAUCAUACUGGCUAGUGTT B 2708
    R-008396307-000D 1205  455 CUCAUCAUACUGGCUAGUG CACUAGCCAGUAUGAUGAGUU 2709
    R-008396310-000K 1153  456 UAUUACGACAGACUGCCUU B UAUUACGACAGACUGCCUUTT B 2710
    R-008396310-000K 1153  456 UAUUACGACAGACUGCCUU AAGGCAGUCUGUCGUAAUAUU 2711
    R-008396313-000L  723  457 CAAUCCCUGAACUGACAAA B CAAUCCCUGAACUGACAAATT B 2712
    R-008396313-000L  723  457 CAAUCCCUGAACUGACAAA UUUGUCAGUUCAGGGAUUGUU 2713
    R-008396316-000M 1468  458 UCUCCUUGGGACUCUUGUU AACAAGAGUCCCAAGGAGAUU 2715
    R-008396316-000M 1468  458 UCUCCUUGGGACUCUUGUU B UCUCCUUGGGACUCUUGUUTT B 2714
    R-008396319-000N 2480  459 GAGAUGGGUGGCCACCACC B GAGAUGUGUGGCCACCACCTT B 2716
    R-008396319-000N 2480  459 GAGAUGGGUGGCCACCACC GGUGGUGGCCACCCAUCUCUU 2717
    R-008396322-000V 1856  460 CAGGGUGCCAUUCCACGAC B CAGGGUGCCAUUCCACGACTT B 2718
    R-008396322-000V 1856  460 CAGGGUGCCAUUCCACGAC GUCGUGGAAUGGCACCCUGUU 2719
    R-008396325-000W 2193  461 AGUUACUUCACUCUAGGAA B AGUUACUUCACUCUAGGAATT B 2720
    R-008396325-000W 2193  461 AGUUACUUCACUCUAGGAA UUCCUAGAGUGAAGUAACUUU 2721
    R-008396328-000X 2355  462 UUGGACUUGAUAUUGGUGC B UUGGACUUGAUAUUGGUGCTT B 2722
    R-008396328-000X 2355  462 UUGGACUUGAUAUUGGUGC GCACCAAUAUCAAGUCCAAUU 2723
    R-008396331-000D 1995  463 CCCUUCACAUCCUAGCUCG CGAGCUAGGAUGUGAAGGGUU 2725
    R-008396331-000D 1995  463 CCCUUCACAUCCUAGCUCG B CCCUUCACAUCCUAGCUCGTT B 2724
    R-008396334-000E  821  464 AGACACGCUAUCAUGCGUU B AGACACGCUAUCAUGCGUUTT B 2726
    R-008396334-000E  821  464 AGACACGCUAUCAUGCGUU AACGCAUGAUAGCGUGUCUUU 2727
    R-008396337-000F 1715  465 AAUGCAGUUCGCCUUCACU B AAUGCAGUUCGCCUUCACUTT B 2728
    R-008396337-000F 1715  465 AAUGCAGUUCGCCUUCACU AGUGAAGGCGAACUGCAUUUU 2729
    R-008396390-000M 1182  466 CUUAUGUCAACCAAGAAAG CUUUCUUGGUUGCCAUAAGUU 2731
    R-008396340-000M 1182  466 CUUAUGUCAACCAAGAAAG B CUUAUGGCAACCAAGAAAGTT B 2730
    R-008396343-000N  445  467 CUCCCAAGUCCUGUAUGAG B CUCCCAAGUCCUGUAUGAGTT B 2732
    R-008396343-000N  445  467 CUCCCAAGUCCUGUAUGAG CUCAUACAGGACUUGGGAGUU 2733
    R-008396396-000P 1759  468 CUUACACCCACCAUCCCAC GUGGGAUGGUGGGUGUAAGUU 2735
    R-008396346-000P 1759  468 CUUACACCCACCAUCCCAC B CUUACACCCACCAUCCCACTT B 2734
    R-008396349-000R 1461  469 UGGAAGGUCUCCUUGGGAC B UGGAAGGUCUCCUUGGGACTT B 2736
    R-008396349-000R 1461  469 UGGAAGGUCUCCUUGGGAC GUCCCAAGGAGACCUUCCAUU 2737
    R-008396352-000X 1993  470 AGCCCUUCACAUCCUAGCU AGCUAGGAUGUGAAGGGCUUU 2739
    R-008396352-000X 1993  470 AGCCCUUCACAUCCUAGCU B AGCCCUUCACAUCCUAGCUTT B 2738
    R-008396355-000Y 2558  471 GAUGGGCUGCCUCCAGGUG B GAUGGGCUGCCUCCAGGUGTT B 2740
    R-008396355-000Y 2558  471 GAUGGGCUGCCUCCAGGUG CACCUGGAGGCAGCCCAUCUU 2741
    R-008396358-000Z 1488  472 AGCUUCUGGGUUCAGAUGA B AGCUUCUGGGUUCAGAUGATT B 2742
    R-008396358-000Z 1488  472 AGCUUCUGGGUUCAGAUGA UCAUCUGAACCCAGAAGCUUU 2743
    R-008396361-000F 1652  473 GAGCCUGCCAUCUGUGCUC B GAGCCUGCCAUCUGUGCUCTT B 2744
    R-008396361-000F 1652  473 GAGCCUGCCAUCUGUGCUC GAGCACAGAUGGCAGGCUCUU 2745
    R-008396364-000G  963  474 UUAAGUGUGGAGGCAUUCC B UUAAGUCUGGAGGCAUUCCTT B 2746
    R-008396364-000G  963  474 UUAAGUGUGGAGGCAUUCC GGAAUGCCUCCAGACUUAAUU 2747
    R-008396367-000H 1520  475 ACCUGUGGAGCUGGAAUUC B ACCUGUGCAGCUGGAAUUCTT B 2748
    R-008396367-000H 1520  475 ACCUGUGGAGCUGGAAUUC GAAUUCCAGCUGCACAGGUUU 2749
    R-008396370-000P 1828  476 UCCCGCAAAUCAUGCACCU AGGUGCAUGAUUUGCGGGAUU 2751
    R-008396370-000P 1828  476 UCCCGCAAAUCAUGCACCU B UCCCGCAAAUCAUGCACCUTT B 2750
    R-008396373-000R 2214  477 AAGGUGUGGCGACAUAUGC B AAGGUGUGGCGACAUAUGCTT B 2752
    R-008396373-000R 2214  477 AAGGUGUGGCGACAUAUGC GCAUAUGUCGCCACACCUUUU 2753
    R-008396376-000S 2155  478 AGCUAUUGAAGCUGAGGGA UCCCUCAGCUUCAAUAGCUUU 2755
    R-008396376-000S 2155  478 AGCUAUUGAAGCUGAGGGA B AGCUAUUGAAGCUGAGGGATT B 2754
    R-008396379-000T  332  479 GUUAGUCACUGGCAGCAAC GUUGCUGCCAGUGACUAACUU 2757
    R-008396379-000T  332  479 GUUAGUCACUGGCAGGAAC B GUUAGUCACUGGCAGCAACTT B 2756
    R-008396382-000Z 2545   74 CCAGGACCUCAUGGAUGGG CCCAUCCAUGAGGUCCUGGUU 2759
    R-008396382-000Z 2545   74 CCAGGACCUCAUGGAUGGG B CCAGGACCUCAUGGAUGGGTT B 2758
    R-008396385-000A 1878  480 UUCAGUUGCUUGUUCGUGC B UUCAGUUGCUUGUUCGUGCTT B 2760
    R-008396385-000A 1878  480 UUCAGUUGCUUGUUCGUGC GCACGAACAAGCAACUGAAUU 2761
    R-008396388-000B 1789  106 AAAGGCUACUGUUGGAUUG CAAUCCAACAGUAGCCUUUUU 2763
    R-008396388-000B 1789  106 AAAGGCUACUGUUGGAUUG B AAAGGCUACUGUUGGAUUGTT B 2762
    R-008396391-000H 2597  168 AGGACCUCAUGGAUGGGCU B AGGACCUCAUGGAUGGGCUTT B 2764
    R-008396391-000H 2547  168 AGGACCUCAUGGAUGGGCU AGCCCAUCCAUGAGGUCCUUU 2765
    R-008396394-000J 1573  481 GAUGAUGGUCUUCCAAGUG B GAUGAUGGUCUGCCAAGUGTT B 2766
    R-008396394-000J 1573  481 GAUGAUGGUCUGCCAAGUG CACUUGGCAGACCAUCAUCUU 2767
    R-008396397-000K 1446  482 CUAAACAGGAAGGGAUGGA B CUAAACAGGAAGGGAUGGATT B 2768
    R-008396397-000K 1446  482 CUAAACAGGAAGGGAUGGA UCCAUCCCUUCCUGUUUAGUU 2769
    R-008396400-000C 1868  483 CCACGACUAGUUCAGUUGC GCAACUGAACUAGUCGUGGUU 2771
    R-008396400-000C 1868  483 CCACGACUAGUUCAGUUGC B CCACGACUAGUUCAGUUGCTT B 2770
    R-008396403-000D 1873  484 ACUAGUUCAGUUGCUUGUU AACAAGCAACUGAACUAGUUU 2773
    R-008396403-000D 1873  484 ACUAGUUCAGUUGCUUGUU B ACUAGUUCAGUUGCUUGUUTT B 2772
    R-008396406-000E 1002  485 GUUCACCAGUGGAUUCUGU B GUUCACCAGUGGAUUCUGUTT B 2774
    R-008396406-000E 1002  485 GUUCACCAGUGGAUUCUGU ACAGAAUCCACUGGUGAACUU 2775
    R-008396409-000F  408  486 GUGGUAAAGGCAAUCCUGA B GUGGUAAAGGCAAUCCUGATT B 2776
    R-008396409-000F  408  486 GUGGUAAAGGCAAUCCUGA UCAGGAUUGCCUUUACCACUU 2777
    R-008396412-000M  287  487 UUGAUGGAGUUGGACAUGG CCAUGUCCAACUCCAUCAAUU 2779
    R-008396412-000M  287  487 UUGAUGGAGUUGGACAUGG B UUGAUGGAGUUGGACAUGGTT B 2778
    R-008396115-000N 1492  119 UCUGGGUUCAGAUGAUAUA UAUAUCAUCUGAACCCAGAUU 2781
    R-008396415-000N 1492  119 UCUGGGUUCAGAUGAUAUA B UCUGGGUUCAGAUGAUAUATT B 2780
    R-008396418-000P  517  187 UGGACAGUAUGCAAUGACU B UGGACAGUAUGCAAUGACUTT B 2782
    R-008396418-000P  517  187 UGGACAGUAUGCAAUGACU AGUCAUUGCAUACUGUCCAUU 2783
    R-008396421-000W  447  177 CCCAAGUCCUGUAUGAGUG B CCCAAGUCCUGUAUGAGUGTT B 2784
    R-008396421-000W  447  177 CCCAAGUCCUGUAUGAGUG CACUCAUACAGGACUUGGGUU 2785
    R-008396424-000X 2128  488 ACUUGCUCAGGACAAGGAA UUCCUUGUCCUGAGCAAGUUU 2787
    R-008396424-000X 2128  488 ACUUGCUCAGGACAAGGAA B ACUUGCUCAGGACAAGGAATT B 2786
    R-008396427-000Y 2513  489 CCAGUUGAUGGGCUGCCAG B CCAGUUGAUGGGCUGCCAGTT B 2788
    R-008396427-000Y 2513  489 CCAGUUGAUGGGCUGCCAG CUGGCAGCCCAUCAACUGGUU 2789
    R-008396430-000E 1196  490 GAAAGCAAGCUCAUCAUAC GUAUGAUGAGCUUGCUUUCUU 2791
    R-008396430-000E 1196  490 GAAAGCAAGCUCAUCAUAC B GAAAGCAAGCUCAUCAUACTT B 2790
    R-008396433-000F  572  491 ACAUUAGAUGAGGGCAUGC B ACAUUAGAUGAGGGCAUGCTT B 2792
    R-008396433-000F  572  491 ACAUUAGAUGAGGGCAUGC GCAUGCCCUCAUCUAAUGUUU 2793
    R-008396436-000G  622  492 UCCCACUAAUGUCCAGCGU B UCCCACUAAUGUCCAGCGUTT B 2794
    R-008396436-000G  622  492 UCCCACUAAUGUCCAGCGU ACGCUGGACAUUAGUGGGAUU 2795
    R-008396439-000H 1187  493 GGCAACCAAGAAAGCAAGC GCUUGCUUUCUUGGUUGCCUU 2797
    R-008396439-000H 1187  493 GGCAACCAAGAAAGCAAGC B GGCAACCAAGAAAGCAAGCTT B 2796
    R-008396442-000P 2098   49 CCAAAGAGUAGCUGCAGGG B CCAAAGAGUAGCUGCAGGGTT B 2798
    R-008396442-000P 2098   49 CCAAAGAGUAGCUGCAGGG CCCUGCAGCUACUCUUUGGUU 2799
    R-008396445-000R 1971  494 AAAUAGUUGAAGGUUGUAC B AAAUAGUUGAAGGUUGUACTT B 2800
    R-008396445-000R 1971  494 AAAUAGUUGAAGGUUGUAC GUACAACCUUCAACUAUUUUU 2801
    R-008396448-000S 3083  495 GGAUAUGUAUGGGUAGGGU ACCCUACCCAUACAUAUCCUU 2803
    R-008396448-000S 3083  495 GGAUAUGUAUGGGUAGGGU B GGAUAUGUAUGGGUAGGGUTT B 2802
    R-008396454-000Z 2944  496 UAAUCUGAAUAAAGUGUAA UUACACUUUAUUCAGAUUAUU 2805
    R-008396454-000Z 2944  496 UAAUCUGAAUAAAGUGUAA B UAAUCUGAAUAAAGUGUAATT B 2804
    R-008396457-000A 1894  497 UGCACAUCAGGAUACCCAG B UGCACAUCAGGAUACCCAGTT B 2806
    R-008396457-000A 1894  497 UGCACAUCAGGAUACCCAG CUGGGUAUCCUGAUGUGCAUU 2807
    R-008396460-000G 1323  498 GUAAUAAGCCGGCUAUUGU B GUAAUAAGCCGGCUAUUGUTT B 2808
    R-008396460-000G 1323  498 GUAAUAAGCCGGCUAUUGU ACAAUAGCCGGCUUAUUACUU 2809
    R-008396469-000K 1202  499 AAGCUCAUCAUACUGGCUA B AAGCUCAUCAUACUGGCUATT B 2810
    R-008396469-000K 1202  499 AAGCUCAUCAUACUGGCUA UAGCCAGUAUGAUGAGCUUUU 2811
    R-008396472-000S  718  500 ACGUGCAAUCCCUGAACUG CAGUUCAGGGAUUGCACGUUU 2813
    R-008396472-000S  718  500 ACGUGCAAUCCCUGAACUG B ACGUGCAAUCCCUGAACUGTT B 2812
    R-008396475-000T 2097   46 UCCAAAGAGUAGCUGGAGG CCUGCAGCUACUCUUUGGAUU 2815
    R-008396475-000T 2097   46 UCCAAAGAGUAGCUGCAGG B UCCAAAGAGUAGCUGCAGGTT B 2814
    R-008396478-000U 1744  501 AGUUGUGGUUAAGCUCUUA B AGUUGUGGUUAAGCUCUUATT B 2816
    R-008396478-000U 1714  501 AGUUGUGGUUAAGCUCUUA UAAGAGCUUAACCACAACUUU 2817
    R-008396481-000A  756  502 AGGACCAGGUGGUGGUUAA UUAACCACCACCUGGUCCUUU 2819
    R-008396481-000A  756  502 AGGACCAGGUGGUGGUUAA B AGGACCAGGUGGUGGUUAATT B 2818
    R-008396484-000B 1317  503 GCUCUAGUAAUAAGCCGGC GCCGGCUUAUUACUAGAGCUU 2821
    R-008396484-000B 1317  503 GCUCUAGUAAUAAGCCGGC B GCUCUAGUAAUAAGCCGGCTT B 2820
    R-008396487-000C  284  504 GAUUUGAUGGAGUUGGACA B GAUUUGAUGGAGUUGGACATT B 2822
    R-008396487-000C  284  504 GAUUUGAUGGAGUUGGACA UGUCCAACUCCAUCAAAUCUU 2823
    R-008396490-000J  886  505 UGAUGUAGAAACAGCUCGU B UGAUGUAGAAACAGCUCGUTT B 2824
    R-008396490-000J  886  505 UGAUGUAGAAACAGCUCGU ACGAGCUGUUUCUACAUCAUU 2825
    R-008396493-000K 2430  506 CUGGUGGAUAUGGCCAGGA B CUGGUGGAUAUGGCCAGGATT B 2826
    R-008396493-000K 2430  506 CUGGUGGAUAUGGCCAGGA UCCUGGCCAUAUCCACCAGUU 2827
    R-008396496-000L 1207  507 CAUCAUACUGGCUAGUGGU B CAUCAUACUGGCUAGUGGUTT B 2828
    R-008396496-000L 1207  507 CAUCAUACUGGCUAGUGGU ACCACUAGCCAGUAUGAUGUU 2829
    R-008396499-000M  592  508 GAUCCCAUCUACACAGUUU AAACUGUGUAGAUGGGAUCUU 2831
    R-008396499-000M  592  508 GAUCCCAUCUACACAGUUU B GAUCCCAUCUACACAGUUUTT B 2830
    R-008396502-000E  824  509 CACGCUAUCAUGCGUUCUC GAGAACGCAUGAUAGCGUGUU 2833
    R-008396502-000E  824  509 CACGCUAUCAUGCGUUCUC B CACGCUAUCAUGCGUUCUCTT B 2832
    R-008396505-000F  519  510 GACAGUAUGCAAUGACUCG B GACAGUAUGCAAUGACUCGTT B 2834
    R-008396505-000F  519  510 GACAGUAUGCAAUGACUCG CGAGUCAUUGCAUACUGUCUU 2835
    R-008396508-000G 3166  511 AAGUUGUUGUAACCUGCUG CAGCAGGUUACAACAACUUUU 2837
    R-008396508-000G 3166  511 AAGUUGUUGUAACCUGCUG B AAGUUGUUGUAACCUGCUGTT B 2836
    R-008396511-000N 1151  512 GCUAUUACGACAGACUGCC B GCUAUUACGACAGACUGCCTT B 2838
    R-008396511-000N 1151  512 GCUAUUACGACAGACUGCC GGCAGUCUGUCGUAAUAGCUU 2839
    R-008396514-000P 2566  513 GCCUCCAGGUGACAGCAAU B GCCUCCAGGUGACAGCAAUTT B 2840
    R-008396514-000P 2566  513 GCCUCCAGGUGACAGCAAU AUUGCUGUCACCUGGAGGCUU 2841
    R-008396517-000R  453  514 UCCUGUAUGAGUGGGAACA UGUUCCCACUCAUACAGGAUU 2843
    R-008396517-000R  453  514 UCCUGUAUGAGUGGGAACA B UCCUGUAUGAGUGGGAACATT B 2842
    R-008396520-000X  587  515 AUGCAGAUCCCAUCUACAC GUGUAGAUGGGAUCUGCAUUU 2845
    R-008396520-000X  587  515 AUGCAGAUCCCAUCUACAC B AUGCAGAUCCCAUCUACACTT B 2844
    R-008396523-000Y  930  516 UUUCCCAUCAUCGUGAGGG B UUUCCCAUCAUCGUGAGGGTT B 2846
    R-008396523-000Y  930  516 UUUCCCAUCAUCGUGAGGG CCCUCACGAUGAUGGGAAAUU 2847
    R-008396526-000Z 1585  517 CCAAGUGGGUGGUAUAGAG B CCAAGUGGCUGGUAUAGAGTT B 2848
    R-008396526-000Z 1585  517 CCAAGUGGGUGGUAUAGAG CUCUAUACCACCCACUUGGUU 2849
    R-008396529-000A  915  518 GGACCUUGCAUAACCUUUC B GGACCUUGCAUAACCUUUCTT B 2850
    R-008396529-000A  915  518 GGACCUUGCAUAACCUUUC GAAAGGUUAUGCAAGGUCCUU 2851
    R-008396532-000G  446  519 UCCCAAGUCCUGUAUGAGU ACUCAUACAGGACUUGGGAUU 2853
    R-008396532-000G  446  519 UCCCAAGUCCUGUAUGAGU B UCCCAAGUCCUGUAUGAGUTT B 2852
    R-008396535-000H 1869  520 CACGACUAGUUCAGUUGCU AGCAACUGAACUAGUCGUGUU 2855
    R-008396535-000H 1869  520 CACGACUAGUUCAGUUGCU B CACGACUAGUUCAGUUGCUTT B 2854
    R-008396538-000J 1960  521 CCGCAUGGAAGAAAUAGUU AACUAUUUCUUCCAUGCGGUU 2857
    R-008396538-000J 1960  521 CCGCAUGGAAGAAAUAGUU B CCGCAUGGAAGAAAUAGUUTT B 2856
    R-008396541-000R 1708  522 GGCCCAGAAUGCAGUUCGC B GGCCCAGAAUGCAGUUCGCTT B 2858
    R-008396541-000R 1708  522 GGCCCAGAAUGCAGUUCGC GCGAACUGCAUUCUGGGCCUU 2859
    R-008396544-000S  306  523 CCAUGGAACCAGACAGAAA UUUCUGUCUGGUUCCAUGGUU 2861
    R-008396544-000S  306  523 CCAUGGAACCAGACAGAAA B CCAUGGAACCAGACAGAAATT B 2860
    R-008396550-000Z 2281  524 GAAACGGCUUUCAGUUGAG B GAAACGGCUUUCAGUUGAGTT B 2862
    R-008396550-000Z 2281  524 GAAACGGCUUUCAGUUGAG CUCAACUGAAAGCCGUUUCUU 2863
    R-008396553-000A 3082  525 GGGAUAUGUAUGGGUAGGG B GGGAUAUGUAUGGGUAGGGTT B 2864
    R-008396553-000A 3082  525 GGGAUAUGUAUGGGUAGGG CCCUACCCAUACAUAUCCCUU 2865
    R-008396556-000B 1473  526 UUGGGACUCUUGUUCAGCU AGCUGAACAAGAGUCCCAAUU 2867
    R-008396556-000B 1473  526 UUGGGACUCUUGUUCAGCU B UUGGGACUCUUGUUCAGCUTT B 2866
    R-008396559-000C  559  527 UAUGUUCCCUGAGACAUUA UAAUGUCUCAGGGAACAUAUU 2869
    R-008396559-000C  559  527 UAUGUUCCCUGAGACAUUA B UAUGUUCCCUGAGACAUUATT B 2868
    R-008396562-000J 1416  528 GGACUCUCAGGAAUCUGUC B GGACUCUCAGGAAUCUUUCTT B 2870
    R-008396562-000J 1416  528 GGACUCUCAGGAAUCUGUC GAAAGAUUCCUGAGAGUCCUU 2871
    R-008396565-000K 2145  529 AAGCUGCAGAAGCUAUUGA B AAGCUGCAGAAGCUAUUGATT B 2872
    R-008396565-000K 2145  529 AAGCUGCAGAAGCUAUUGA UCAAUAGCUUCUGCAGCUUUU 2873
    R-008396568-000L 1994  530 GCCCUUCACAUCCUAGCUC B GCCCUUCACAUCCUAGCUCTT B 2874
    R-008396568-000L 1994  530 GCCCUUCACAUCCUAGCUC GAGCUAGGAUGUGAAGGGCUU 2875
    R-008396571-000T 1611   27 UGCGUACUGUCCUUCGGGC B UGCGUACUGUCCUUCGGGCTT B 2876
    R-008396571-000T 1611   27 UGCGUACUGUCCUUCGGGC GCCCGAAGGACAGUACGCAUU 2877
    R-008396574-000U 1702  531 AGAGAUGGCCCAGAAUGCA B AGAGAUGGCCCAGAAUGCATT B 2878
    R-008396574-000U 1702  531 AGAGAUGGCCCAGAAUGCA UGCAUUCUGGGCCAUCUCUUU 2879
    R-008396577-000V  417  532 GCAAUCCUGAGGAAGAGGA B GCAAUCCUGAGGAAGAGGATT B 2880
    R-008396577-000V  417  532 GCAAUCCUGAGGAAGAGGA UCCUCUUCCUCAGGAUUGCUU 2881
    R-008396580-000B 2444  533 CAGGAUGCCUUGGGUAUGG B CAGGAUGCCUUGGGUAUGGTT B 2882
    R-008396580-000B 2444  533 CAGGAUGCCUUGGGUAUGG CCAUACCCAAGGCAUCCUGUU 2883
    R-008396586-000D  555  534 CUGCUAUGUUCCCUGAGAC B CUGCUAUGUUCCCUGAGACTT B 2884
    R-008396586-000D  555  534 CUGCUAUGUUCCCUGAGAC GUCUCAGGGAACAUAGCAGUU 2885
    R-008396589-000E 2019  535 UUCACAACCGAAUUGUUAU B UUCAGAACCGAAUUGUUAUTT B 2886
    R-008396589-000E 2019  535 UUCACAACCGAAUUGUUAU AUAACAAUUCGGUUGUGAAUU 2887
    R-008396592-000L 1197  536 AAAGCAAGCUCAUCAUACU B AAAGCAAGCUCAUCAUACUTT B 2888
    R-008396592-000L 1197  536 AAAGCAAGCUCAUCAUACU AGUAUGAUGAGCUUGCUUUUU 2889
    R-008396595-000M  415  537 AGGCAAUCCUGAGGAAGAG CUCUUCCUCAGGAUUGCCUUU 2891
    R-008396595-000M  415  537 AGGCAAUCCUGAGGAAGAG B AGGCAAUCCUGAGGAAGAGTT B 2890
    R-008396598-000N 2061  538 UGUUUGUGCAGCUGCUUUA B UGUUUGUGCAGCUGCUUUATT B 2892
    R-008396598-000N 2061  538 UGUUUGUGCAGCUGCUUUA UAAAGCAGCUGCACAAACAUU 2893
    R-008396601-000F 1352  539 GGAAUGCAAGCUUUAGGAC B GGAAUGCAAGCUUUAGGACTT B 2894
    R-008396601-000F 1352  539 GGAAUGCAAGCUUUAGGAC GUCCUAAAGCUUGCAUUCCUU 2895
    R-008396604-000G 1502  135 GAUGAUAUAAAUGUGGUCA UGACCACAUUUAUAUCAUCUU 2897
    R-008396604-000G 1502  135 GAUGAUAUAAAUGUGGUCA B GAUGAUAUAAAUGUGGUCATT B 2896
    R-008396607-000H 1331  540 CCGGCUAUUGUAGAAGCUG B CCGGCUAUUGUAGAAGCUGTT B 2898
    R-008396607-000H 1331  540 CCGGCUAUUGUAGAAGCUG CAGCUUCUACAAUAGCCGGUU 2899
    R-008396610-000P 1325  541 AAUAAGCCGGCUAUUGUAG B AAUAAGCCGGCUAUUGUAGTT B 2900
    R-008396610-0001 1325  541 AAUAAGCCGGCUAUUGUAG CUACAAUAGCCGGCUUAUUUU 2901
    R-008396613-000R 1486  542 UCAGCUUCUGGGUUCAGAU B UCAGCUUCUGGGUUCAGAUTT B 2902
    R-008396613-000R 1486  542 UCAGCUUCUGGGUUCAGAU AUCUGAACCCAGAAGCUGAUU 2903
    R-008396616-000S  454  543 CCUGUAUGAGUGGGAACAG B CCUGUAUGAGUGGGAACAGTT B 2904
    R-008396616-000S  454  543 CCUGUAUGAGUGGGAACAG CUGUUCCCACUCAUACAGGUU 2905
    R-008396619-000T  490  544 CACUCAAGAACAAGUAGCU B CACUCAAGAACAAGUAGCUTT B 2906
    R-008396619-000T  490  544 CACUCAAGAACAAGUAGCU AGCUACUUGUUCUUGAGUGUU 2907
    R-008396622-000Z 1996  545 CCUUCACAUCCUAGCUCGG B CCUUCACAUCCUAGCUCGGTT B 2908
    R-008396622-000Z 1996  545 CCUUCACAUCCUAGCUCGG CCGAGCUAGGAUGUGAAGGUU 2909
    R-008396625-000A 1839  546 AUGCACCUUCGCGUGAGCA B AUGCACCUUUGCGUGAGCATT B 2910
    R-008396625-000A 1839  546 AUGCACCUUCGCGUGAGCA UGCUCACGCAAAGGUGCAUUU 2911
    R-008396628-000B 1888  547 UGUUCGUGCACAUCAGGAU AUCCUGAUGUGCACGAACAUU 2913
    R-008396628-000B 1888  547 UGUUCGUGCACAUCAGGAU B UGUUCGUGCACAUCAGGAUTT B 2912
    R-008396631-000H 1879  548 UCAGUUGCUUGUUCGUGCA B UCAGUUGCUUGUUCGUGCATT B 2914
    R-008396631-000H 1879  548 UCAGUUGCUUGUUCGUGCA UGGACGAACAAGCAACUGAUU 2915
    R-008396634-000J 2508  172 ACUAUCCAGUUGAUGGGCU B ACUAUCCAGUUGAUGGGCUTT B 2916
    R-008396634-000J 2508  172 ACUAUCCAGUUGAUGGGCU AGCCCAUCAACUGGAUAGUUU 2917
    R-008396637-000K 1829  549 CCCGCAAAUCAUGCACCUU AAGGUGCAUGAUUUGCGGGUU 2919
    R-008396637-000K 1829  549 CCCGCAAAUCAUGCACCUU B CCCGCAAAUCAUGCACCUUTT B 2918
    R-008396640-000S  281  550 GCUGAUUUGAUGGAGUUGG B GCUGAUUUGAUGGAGUUGGTT B 2920
    R-008396640-000S  281  550 GCUGAUUUGAUGGAGUUGG CCAACUCCAUCAAAUCAGCUU 2921
    R-008396643-000T 1598  551 AUAGAGGCUCUUGUGCGUA UACGCACAAGAGCCUCUAUUU 2923
    R-008396643-000T 1598  551 AUAGAGGCUCUUGUGCGUA B AUAGAGGCUCUUGUGCGUATT B 2922
    R-008396646-000U 2135  552 CAGGACAAGGAAGCUGCAG B CAGGACAAGGAAGCUGCAGTT B 2924
    R-008396646-000U 2135  552 CAGGACAAGGAAGCUGCAG CUGCAGCUUCCUUGUCCUGUU 2925
    R-008396649-000V  642   67 UGGCUGAACCAUCACAGAU AUCUGUGAUGGUUCAGCCAUU 2927
    R-008396649-000V  642   67 UGGCUGAACCAUCACAGAU B UGGCUGAACCAUCACAGAUTT B 2926
    R-008396652-000B 1755  553 AGCUCUUACACCCACCAUC B AGCUCUUACACCCACCAUCTT B 2928
    R-008396652-000B 1755  553 AGCUCUUACACCCACCAUC GAUGGUGGGUGUAAGAGCUUU 2929
    R-008396655-000C  651  554 CAUCACAGAUGCUGAAACA B CAUCACAGAUGCUGAAACATT B 2930
    R-008396655-000C  651  554 CAUCACAGAUGCUGAAACA UGUUUCAGCAUCUGUGAUGUU 2931
    R-008396658-000D 1335  555 CUAUUGUAGAAGCUGGUGG CCACCAGCUUCUACAAUAGUU 2933
    R-008396658-000D 1335  555 CUAUUGUAGAAGCUGGUGG B CUAUUGUAGAAGCUGGUGGTT B 2932
    R-008396661-000K 2541  556 AUGCCCAGGACCUCAUGGA UCCAUGAGGUCCUGGGCAUUU 2935
    R-008396661-000K 2541  556 AUGCCCAGGACCUCAUGGA B AUGCCCAGGACCUCAUGGATT B 2934
    R-008396664-000L  531  557 UGACUCGAGCUCAGAGGGU B UGACUCGAGCUCAGAGGGUTT B 2936
    R-008396664-000L  531  557 UGACUCGAGCUCAGAGGGU ACCCUCUGAGCUCGAGUCAUU 2937
    R-008396667-000M  606  558 AGUUUGAUGCUGCUCAUCC B AGUUUGAUGCUGCUCAUCCTT B 2938
    R-008396667-000M  606  558 AGUUUGAUGCUGCUCAUCC GGAUGAGCAGCAUCAAACUUU 2939
    R-008396670-000U 1620  559 UCCUUCGGGCUGGUGACAG B UCCUUCGGGCUGGUGACAGTT B 2940
    R-008396670-000U 1620  559 UCCUUCGGGCUGGUGACAG CUGUCACCAGCCCGAAGGAUU 2941
    R-008396673-000V 2211  560 AUGAAGGUGUGGCGACAUA B AUGAAGGUGUGGCGACAUATT B 2942
    R-008396673-000V 2211  560 AUGAAGGUGUGGCGACAUA UAUGUCGCCACACCUUCAUUU 2943
    R-008396676-000W 2293  561 AGUUGAGCUGACCAGCUCU B AGUUGAGCUGACCAGCUCUTT B 2944
    R-008396676-000W 2293  561 AGUUGAGCUGACCAGCUCU AGAGCUGGUCAGCUCAACUUU 2945
    R-008396679-000X 1511   65 AAUGUGGUCACCUGUGCAG B AAUGUGGUCACCUGUGCAGTT B 2946
    R-008396679-000X 1511   65 AAUGUGGUCACCUGUGCAG CUGCACAGGUGACCACAUUUU 2947
    R-008396682-000D  455  562 CUGUAUGAGUGGGAACAGG B CUGUAUGAGUGGGAACAGGTT B 2948
    R-008396682-000D  455  562 CUGUAUGAGUGGUAACAGG CCUGUUCCCACUCAUACAGUU 2949
    R-008396685-000E  540  563 CUCAGAGGGUACGAGCUGC B CUCAGAGGGUAGGAGCUGCTT B 2950
    R-008396685-000E  540  563 CUGAGAGGGUACGAGCUGC GCAGCUCGUACCCUCUGAGUU 2951
    R-008396688-000F  416  564 GGCAAUCCUGAGGAAGAGG CCUCUUCCUCAGGAUUGCCUU 2953
    R-008396688-000F  416  564 GGCAAUCCUGAGGAAGAGG B GGCAAUCCUGAGGAAGAGGTT B 2952
    R-008396691-000M 1669  130 UCUUCGUCAUCUGACCAGC GCUGGUCAGAUGACGAAGAUU 2955
    R-008396691-000M 1669  130 UCUUCGUCAUCUGACCAGC B UCUUCGUCAUCUGACCAGCTT B 2954
    R-008396694-000N 1210  565 CAUACUGGCUAGUGGUGGA B CAUACUGGCUAGUGGUGGATT B 2956
    R-008396694-000N 1210  565 CAUACUGGCUAGUGGUGGA UCCACCACUAGCCAGUAUGUU 2957
    R-008396697-000P 2262  566 ACAAGCCACAAGAUUACAA UUGUAAUCUUGUGGCUUGUUU 2959
    R-008396697-000P 2262  566 ACAAGCCACAAGAUUACAA B ACAAGCCACAAGAUUACAATT B 2958
    R-008396700-000G 1604  567 GCUCUUGUGCGUACUGUCC GGACAGUACGCACAAGAGCUU 2961
    R-008396700-000G 1604  567 GCUCUUGUGCGUACUGUCC B GCUCUUGUGCGUACUGUCCTT B 2960
    R-008396703-000H  435  568 AUGUGGAUACCUCCCAAGU B AUGUGGAUACCUCCCAAGUTT B 2962
    R-008396703-000H  435  568 AUGUGGAUACCUCCCAAGU ACUUGGGAGGUAUCCACAUUU 2963
    R-008396706-000J 2060  569 UUGUUUGUGCAGCUGCUUU B UUGUUUGUGCAGCUGCUUUTT B 2964
    R-008396706-000J 2060  569 UUGUUUGUGCAGCUGCUUU AAAGCAGCUGCACAAACAAUU 2965
    R-008396709-000K 2225  570 ACAUAUGCAGCUGCUGUUU B ACAUAUGGAGCUGCUGUUUTT B 2966
    R-008396709-000K 2225  570 ACAUAUGCAGCUGCUGUUU AAACAGCAGCUGCAUAUGUUU 2967
    R-008396712-000S 2510   47 UAUCCAGUUGAUGGGCUGC B UAUCCAGUUGAUGGGCUGCTT B 2968
    R-008396712-000S 2510   47 UAUCCAGUUGAUGGGCUGC GCAGCCCAUCAACUGGAUAUU 2969
    R-008396715-000T  481  571 UCAGUCCUUCACUCAAGAA UUCUUGAGUGAAGGACUGAUU 2971
    R-008396715-000T  481  571 UCAGUCCUUCACUCAAGAA B UCAGUCCUUCACUCAAGAATT B 2970
    R-008396718-000U  917  572 ACCUUGCAUAACCUUUCCC B ACCUUGCAUAACCUUUCCCTT B 2972
    R-008396718-000U  917  572 ACCUUGCAUAACCUUUCCC GGGAAAGGUUAUGCAAGGUUU 2973
    R-008396721-000A 2221  573 GGCGACAUAUGCAGCUGCU B GGCGACAUAUGCAGCUGCUTT B 2974
    R-008396721-000A 2221  573 GGCGACAUAUGCAGCUGCU AGCAGCUGCAUAUGUCGCCUU 2975
    R-008396724-000B  849  574 UGGUGUCUGCUAUUGUACG CGUACAAUAGCAGACACCAUU 2977
    R-008396724-000B  849  574 UGGUGUCUGCUAUUGUACG B UGGUGUCUGCUAUUGUACGTT B 2976
    R-008396727-000C  562  575 GUUCCCUGAGACAUUAGAU B GUUCCCUGAGACAUUAGAUTT B 2978
    R-008396727-000C  562  575 GUUCCCUGAGACAUUAGAU AUCUAAUGUCUCAGGGAACUU 2979
    R-008396730-000J  617  140 GCUCAUCCCACUAAUGUCC GGACAUUAGUGGGAUGAGCUU 2981
    R-008396730-000J  617  140 GCUCAUCCCACUAAUGUCC B GCUCAUCCCACUAAUGUCCTT B 2980
    R-008396733-000K 1787  576 AUAAAGGCUACUGUUGGAU B AUAAAGGCUACUGUUGGAUTT B 2982
    R-008396733-000K 1787  576 AUAAAGGCUACUGUUGGAU AUCCAACAGUAGCCUUUAUUU 2983
    R-008396736-000L 1860  577 GUGCCAUUCCACGACUAGU ACUAGUCGUGGAAUGGCACUU 2985
    R-008396736-000L 1860  577 GUGCCAUUCCACGACUAGU B GUGCCAUUCCACGACUAGUTT B 2984
    R-008396739-000M 1590  578 UGGGUGGUAUAGAGGCUCU B UGGGUGGUAUAGAGGCUCUTT B 2986
    R-008396739-000M 1590  578 UGGGUGGUAUAGAGGCUCU AGAGCCUCUAUACCACCCAUU 2987
    R-008396742-000U  955  579 GGCCAUCUUUAAGUCUGGA UCCAGACUUAAAGAUGGCCUU 2989
    R-008396742-000U  955  579 GGCCAUCUUUAAGUCUGGA B GGCCAUCUUUAAGUCUGGATT B 2988
    R-008396745-000V 2365  580 UAUUGGUGCCCAGGGAGAA B UAUUGGUGCCCAGGGAGAATT B 2990
    R-008396745-000V 2365  580 UAUUGGUGCCCAGGGAGAA UUCUCCCUGGGCACCAAUAUU 2991
    R-008396748-000W  534  581 CUCGAGCUCAGAGGGUACG B CUCGAGCUCAGAGGGUACGTT B 2992
    R-008396748-000W  534  581 CUCGAGCUCAGAGGGUACG CGUACCCUCUGAGCUCGAGUU 2993
    R-008396751-000C  706  582 AGAACUUGCCACACGUGCA UGCACGUGUGGCAAGUUCUUU 2995
    R-008396751-000C  706  582 AGAACUUGCCACACGUGCA B AGAACUUGCCACACGUGCATT B 2994
    R-008396754-000D 1740  583 UACCAGUUGUGGUUAAGCU B UACCAGUUGUGGUUAAGCUTT B 2996
    R-008396754-000D 1740  583 UACCAGUUGUGGUUAAGCU AGCUUAACCACAACUGGUAUU 2997
    R-008396757-000E  638  584 CGUUUGGCUGAACCAUCAC B CGUUUGGCUGAACCAUCACTT B 2998
    R-008396757-000E  638  584 CGUUUGGCUGAACCAUCAC GUGAUGGUUCAGCCAAACGUU 2999
    R-008396760-000L 1334  585 GCUAUUGUAGAAGCUGGUG CACCAGCUUCUACAAUAGCUU 3001
    R-008396760-000L 1334  585 GCUAUUGUAGAAGCUGGUG B GCUAUUGUAGAAGCUGGUGTT B 3000
    R-008396763-000M  971  586 GGAGGCAUUCCUGCCCUGG B GGAGGCAUUCCUGCCCUGGTT B 3002
    R-008396763-000M  971  586 GGAGGCAUUCCUGCCCUGG CCAGGGCAGGAAUGCCUCCUU 3003
    R-008396766-000N 2493  587 ACCACCCUGGUGCUGACUA UAGUCAGCACCAGGGUGGUUU 3005
    R-008396766-000N 2493  587 ACCACCCUGGUGCUGACUA B ACCACCCUGGUGCUGACUATT B 3004
    R-008396769-000P 1814  588 AAUCUUGCCGUUUGUCCCG B AAUCUUGCCCUUUGUCCCGTT B 3006
    R-008396769-000P 1814  588 AAUCUUGCCCUUUGUCCCG CGGGACAAAGGGCAAGAUUUU 3007
    R-008396772-000W 1088  589 CGUUUAGCUGGUGGGCUGC GCAGCCCACCAGCUAAACGUU 3009
    R-008396772-000W 1088  589 CGUUUAGCUGGUGGGCUGC B CGUUUAGCUGGUGGGCUGCTT B 3008
    R-008396775-000X 2292  590 CAGUUGAGCUGACCAGCUC GAGCUGGUCAGCUCAACUGUU 3011
    R-008396775-000X 2292  590 CAGUUGAGCUGACCAGCUC B CAGUUGAGCUGACCAGCUCTT B 3010
    R-008396778-000Y 1504  591 UGAUAUAAAUGUGGUCACC GGUGACCACAUUUAUAUCAUU 3013
    R-008396778-000Y 1504  591 UGAUAUAAAUGUGGUCACC B UGAUAUAAAUGUGGUCACCTT B 3012
    R-008396781-000E  404  592 CUGAGUGGUAAAGGCAAUC GAUUGCCUUUACCACUCAGUU 3015
    R-008396781-000E  404  592 CUGAGUGGUAAAGGCAAUC B CUGAGUGGUAAAGGCAAUCTT B 3014
    R-008396784-000F 1301  593 AAGGUGCUAUCUGUCUGCU AGCAGACAGAUAGCACCUUUU 3017
    R-008396784-000F 1301  593 AAGGUGCUAUCUGUCUGCU B AAGGUGCUAUCUGUCUGCUTT B 3016
    R-008396787-000G 2004  594 UCCUAGCUCGGGAUGUUCA UGAACAUCCCGAGCUAGGAUU 3019
    R-008396787-000G 2004  594 UCCUAGCUCGGGAUGUUCA B UCCUAGCUCGGGAUGUUCATT B 3018
    R-008396790-000N  853    6 GUCUGCUAUUGUACGUACC GGUACGUACAAUAGCAGACUU 3021
    R-008396790-000N  853     6 GUCUGCUAUUGUACGUACC B GUCUOCUAUUGUACGUACCTT B 3020
    R-008396793-000P  277  595 UCAAGCUGAUUUGAUGGAG B UCAAGCUGAUUUGAUGGAGTT B 3022
    R-008396793-000P  277  595 UCAAGCUGAUUUGAUGGAG CUCCAUCAAAUCAGCUUGAUU 3023
    R-008396796-000R 2304  596 CCAGCUCUCUCUUCAGAAC GUUCUGAAGAGAGAGCUGGUU 3025
    R-008396796-000R 2304  596 CCAGCUCUCUCUUCAGAAC B CCAGCUCUCUCUUCAGAACTT B 3024
    R-008396799-000S  300  597 ACAUGGCCAUGGAACCAGA B ACAUGGCCAUGGAACCAGATT B 3026
    R-008396799-000S  300  597 ACAUGGCCAUGGAACCAGA UCUGGUUCCAUGGCCAUGUUU 3027
    R-008396802-000J 1906  598 UACCCAGCGCCGUACGUCC B UACCCAGCGCCGUACGUCCTT B 3028
    R-008396802-000J 1906  598 UACCCAGCGCCGUACGUCC GGACGUACGGCGCUGGGUAUU 3029
    R-008396805-000K 1973  599 AUAGUUGAAGGUUGUACCG CGGUACAACCUUCAACUAUUU 3031
    R-008396805-000K 1973  599 AUAGUUGAAGGUUGUACCG B AUAGUUGAAGGUUGUACCGTT B 3030
    R-008396808-000L 1360  600 AGCUUUAGGACUUCACCUG B AGCUUUAGGACUUCACCUGTT B 3032
    R-008396808-000L 1360  600 AGCUUUAGGACUUCACCUG CAGGUGAAGUCCUAAAGCUUU 3033
    R-008396811-000T 2094  601 ACAUCCAAAGAGUAGCUGC GCAGCUACUCUUUGGAUGUUU 3035
    R-008396811-000T 2094  601 ACAUCCAAAGAGUAGCUGC B ACAUCCAAAGAGUAGCUGCTT B 3034
    R-008396814-000U  920  602 UUGGAUAACCUUUCCCAUC B UUGCAUAACCUUUCCCAUCTT B 3036
    R-008396814-000U  920  602 UUGCAUAACCUUUCCCAUC GAUGGGAAAGGUUAUGCAAUU 3037
    R-008396817-000V 1707  603 UGGCCCAGAAUGCAGUUCG CGAACUGCAUUCUGGGCCAUU 3039
    R-008396817-000V 1707  603 UGGCCCAGAAUGCAGUUCG B UGGCCCAGAAUGCAGUUCGTT B 3038
    R-008396820-000B 1808  604 AUUCGAAAUCUUGCCCUUU B AUUCGAAAUCUUGCCCUUUTT B 3040
    R-008396820-000B 1808  604 AUUCGAAAUCUUGCCCUUU AAAGGGCAAGAUUUCGAAUUU 3041
    R-008396823-000C 1326  605 AUAAGCCGGCUAUUGUAGA UGUACAAUAGCCGOCUUAUUU 3043
    R-008396823-000C 1326  605 AUAAGCCGGCUAUUGUAGA B AUAAGCCGGCUAUUGUAGATT B 3042
    R-008396826-000D 1158  606 CGACAGACUGCCUUCAAAU B CGACAGACUGCCUUCAAAUTT B 3044
    R-008396826-000D 1158  606 CGACAGACUGCCUUCAAAU AUUUGAAGGCAGUCUGUCGUU 3045
    R-008396829-000E  781  607 UGCAGUUAUGGUCCAUCAG B UGCAGUUAUGGUCCAUCAGTT B 3046
    R-008396829-000E  781  607 UGCAGUUAUGGUCCAUCAG CUGAUGGACCAUAACUGCAUU 3047
    R-008396832-000L  607  608 GUUUGAUGCUGGUCAUCCC B GUUUGAUGCUGCUCAUCCCTT B 3048
    R-008396832-000L  607  608 GUUUGAUGCUGCUCAUCCC GGGAUGAGCAGCAUCAAACUU 3049
    R-008396835-000M  627  609 CUAAUGUCCAGCGUUUGGC GCCAAACGCUGGACAUUAGUU 3051
    R-008396835-000M  627  609 CUAAUGUCCAGCGUUUGGC B CUAAUGUCCAGCGUUUGGCTT B 3050
    R-008396838-000N  500  610 CAAGUAGCUGAUAUUGAUG B CAAGUAGCUGAUAUUGAUGTT B 3052
    R-008396838-000N  500  610 CAAGUAGCUGAUAUUGAUG CAUCAAUAUCAGCUACUUGUU 3053
    R-008396841-000V 2185  611 UCUGACAGAGUUACUUCAC B UCUGACAGAGUUACUUCACTT B 3054
    R-008396841-000V 2185  611 UCUGACAGAGUUACUUCAC GUGAAGUAACUCUGUCAGAUU 3055
    R-008396844-000W 1592  612 GGUGGUAUAGAGGCUCUUG B GGUGGUAUAGAGGCUCUUGTT B 3056
    R-008396844-000W 1592  612 GGUGGUAUAGAGGCUCUUG CAAGAGCCUGUAUACCACCUU 3057
    R-008396847-000X  758  613 GACCAGGUGGUGGUUAAUA B GACCAGGUGGUGGUUAAUATT B 3058
    R-008396847-000X  758  613 GACCAGGUGGUGGUUAAUA UAUUAACCACCACCUGGUCUU 3059
    R-008396850-000D 2551  614 CCUCAUGGAUGGCCUGCCU B CCUCAUGGAUGGGCUGCCUTT B 3060
    R-008396850-000D 2551  614 CCUCAUGGAUGGCCUGCCU AGGCAGCCCAUCCAUGAGGUU 3061
    R-008396853-000E 1409  615 UGUCUUUGGACUCUCAGUA B UGUCUUUGGACUCUCAGGATT B 3062
    R-008396853-000E 1409  615 UGUCUUUGGACUCUCAGGA UCCUGAGAGUCCAAAGACAUU 3063
    R-008396856-000F  497  616 GAACAAGUAGCUGAUAUUG B GAACAAGUAGCUGAUAUUGTT B 3064
    R-008396856-000F  497  616 GAACAAGUAGCUGAUAUUG CAAUAUCAGCUACUUGUUCUU 3065
    R-008396859-000G  381  617 GUGCCACUACCACAGCUCC B GUGCCACUACCACAGCUCCTT B 3066
    R-008396859-000G  381  617 GUGCCACUACCACAGCUCC GGAGCUGUGGUAGUGGCACUU 3067
    R-008396862-000N 1841  618 GCACCUUUGCGUGAGCAGG CCUGCUCACGCAAAGGUGCUU 3069
    R-008396862-000N 1841  618 GCACCUUUGCGUGAGCAGG B GCACCUUUGCGUGAGCAGGTT B 3068
    R-008396865-000P 1368  619 GACUUCACCUGACAGAUCC B GACUUCACCUGACAGAUCCTT B 3070
    R-008396865-000P 1368  619 GACUUCACCUGACAGAUCC GGAUCUGUCAGGUGAAGUCUU 3071
    R-008396868-000R 2047  620 AAAUACCAUUCCAUUGUUU AAACAAUGGAAUGGUAUUUUU 3073
    R-008396868-000R 2047  620 AAAUACCAUUCCAUUGUUU B AAAUACCAUUCCAUUGUUUTT B 3072
    R-008396871-000X  492  621 CUCAAGAACAAGUAGCUGA B CUCAAGAACAAGUAGCUGATT B 3074
    R-008396871-000X  492  621 CUCAAGAACAAGUAGCUGA UCACCUACUUGUUCUUGAGUU 3075
    R-008396874-000Y  832  126 CAUGCGUUCUCCUCAGAUG B CAUGCGUUCUCCUCAGAUGTT B 3076
    R-008396874-000Y  832  126 CAUGCGUUCUCCUCAGAUG CAUCUGAGGAGAACGCAUGUU 3077
    R-008396877-000Z 2118  622 UCCUCUGUGAACUUGCUCA B UCCUCUGUGAACUUGCUCATT B 3078
    R-008396877-000Z 2118  622 UCCUCUGUGAACUUGCUCA UGAGCAAGUUCACAGAGGAUU 3079
    R-008396880-000F  968  623 UCUGGAGGCAUUCCUGCCC GGGCAGGAAUGCCUCCAGAUU 3081
    R-008396880-000F  968  623 UCUGGAGGCAUUCCUGCCC B UCUGGAGGCAUUCCUGCCCTT B 3080
    R-008396883-000G  965  624 AAGUCUGGAGGCAUUCCUG CAGGAAUGCCUCCAGACUUUU 3083
    R-008396883-000G  965  624 AAGUCUGGAGGCAUUCCUG B AAGUCUGGAGGCAUUCCUGTT B 3082
    R-008396886-000H 1977  625 UUGAAGGUUGUACCGGAGC GCUCCGGUACAACCUUCAAUU 3085
    R-008396886-000H 1977  625 UUGAAGGUUGUACCGGAGC B UUGAAGGUUGUACCGGAGCTT B 3084
    R-008396889-000J 2001  626 ACAUCCUAGCUCGGGAUGU B ACAUCCUAGCUCGGGAUGUTT B 3086
    R-008396889-000J 2001  626 ACAUCCUAGCUCGGGAUGU ACAUCCCGAGCUAGGAUGUUU 3087
    R-008396892-000R 1191  627 ACCAAGAAAGCAAGCUCAU B ACCAAGAAAGCAAGCUCAUTT B 3088
    R-008396892-000R 1191  627 ACCAAGAAAGCAAGCUCAU AUGAGCUUGCUUUCUUGGUUU 3089
    R-008396895-000S  640  628 UUUGGCUGAACCAUCACAG B UUUGGCUGAACCAUCACAGTT B 3090
    R-008396895-000S  640  628 UUUGGCUGAACCAUCACAG CUGUGAUGGUUCAGCCAAAUU 3091
    R-008396898-000T  715  629 CACACGUGCAAUCCCUGAA B CACACGUGCAAUCCCUGAATT B 3092
    R-008396898-000T  715  629 CACACGUGCAAUCCCUGAA UUCAGGGAUUGCACGUGUGUU 3093
    R-008396901-000K 1204  630 GCUCAUCAUACUGGCUAGU ACUAGCCAGUAUGAUGAGCUU 3095
    R-008396901-000K 1204  630 GCUCAUCAUACUGGCUAGU B GCUCAUCAUACUGGCUAGUTT B 3094
    R-008396904-000L 3093  631 GGGUAGGGUAAAUCAGUAA B GGGUAGGGUAAAUCAGUAATT B 3096
    R-008396904-000L 3093  631 GGGUAGGGUAAAUCAGUAA UUACUGAUUUACCCUACCCUU 3097
    R-008396907-000M 1371  632 UUCACCUGACAGAUCCAAG CUUGGAUCUGUCAGGUGAAUU 3099
    R-008396907-000M 1371  632 UUCACCUGACAGAUCCAAG B UUCACCUGACAGAUCCAAGTT B 3098
    R-008396910-000U 1424  121 AGGAAUCUUUCAGAUGCUG B AGGAAUCUUUCAGAUGCUGTT B 3100
    R-008396910-000U 1424  121 AGGAAUCUUUCAGAUGCUG CAGCAUCUGAAAGAUUCCUUU 3101
    R-008396913-000V  860  161 AUUGUACGUACCAUGCAGA B AUUGUACGUACCAUGCAGATT B 3102
    R-008396913-000V  860  161 AUUGUACGUACCAUGCAGA UCUGCAUGGUACGUACAAUUU 3103
    R-008396916-000W  409  633 UGGUAAAGGCAAUCCUGAG B UGGUAAAGGCAAUCCUGAGTT B 3104
    R-008396916-000W  409  633 UGGUAAAGGCAAUCCUGAG CUCAGGAUUGCCUUUACCAUU 3105
    R-008396919-000X 1143    7 AAUUCUUGGCUAUUACGAC GUCGUAAUAGCCAAGAAUUUU 3107
    R-008396919-000X 1143    7 AAUUCUUGGCUAUUACGAC B AAUUCUUGGCUAUUACGACTT B 3106
    R-008396922-000D 2405  634 GAUCCUAGCUAUCGUUCUU B GAUCCUAGCUAUCGUUCUUTT B 3108
    R-008396922-000D 2405  634 GAUCCUAGCUAUCGUUCUU AAGAACGAUAGCUAGGAUCUU 3109
    R-008396928-000F 1671  635 UUCGUCAUCUGACCAGCCG CGGCUGGUCAGAUGACGAAUU 3111
    R-008396928-000F 1671  635 UUCGUCAUCUGACCAGCCG B UUCGUCAUCUGACCAGCCGTT B 3110
    R-008396931-000M 1427  636 AAUCUUUCAGAUGCUGCAA B AAUCUUUCAGAUGCUGCAATT B 3112
    R-008396931-000M 1427  636 AAUCUUUCAGAUGCUGCAA UUGCAGCAUCUGAAAGAUUUU 3113
    R-008396934-000N 1717  637 UGCAGUUCGCCUUCACUAU AUAGUGAAGGCGAACUGCAUU 3115
    R-008396934-000N 1717  637 UGCAGUUCGCCUUCACUAU B UGCAGUUCGCCUUCACUAUTT B 3114
    R-008396937-000P 2400  638 AGGAUGAUCCUAGCUAUCG CGAUAGCUAGGAUCAUCCUUU 3117
    R-008396937-000P 2400  638 AGGAUGAUCCUAGCUAUCG B AGGAUGAUCCUAGCUAUCGTT B 3116
    R-008396940-000W 2305  639 CAGCUCUCUCUUCAGAACA B CAGCUCUCUCUUCAGAACATT B 3118
    R-008396940-000W 2305  639 CAGCUCUCUCUUCAGAACA UGUUCUGAAGAGAGAGCUGUU 3119
    R-008396943-000X 1928  640 GGUGGGACACAGCAGCAAU B GGUGGGACACAGCAGCAAUTT B 3120
    R-008396943-000X 1928  640 GGUGGGACACAGCAGCAAU AUUGCUGCUGUGUCCCACCUU 3121
    R-008396946-000Y 2399  641 CAGGAUGAUCCUAGCUAUC B CAGGAUGAUCCUAGCUAUCTT B 3122
    R-008396946-000Y 2399  641 CAGGAUGAUCCUAGCUAUC GAUAGCUAGGAUCAUCCUGUU 3123
    R-008396949-000Z  426  642 AGGAAGAGGAUGUGGAUAC B AGGAAGAGGAUGUGGAUACTT B 3124
    R-008396949-000Z  426  642 AGGAAGAGGAUGUGGAUAC GUAUCCACAUCCUCUUCCUUU 3125
    R-008396952-000F 1309  643 AUCUGUCUGCUCUAGUAAU AUUACUAGAGCAGACAGAUUU 3127
    R-008396952-000F 1309  643 AUGUGUCUGGUCUAGUAAU B AUCUGUCUGCUCUAGUAAUTT B 3126
    R-008396955-000G  925  644 UAACCUUUCCCAUCAUCGU B UAACCUUUCCCAUCAUCGUTT B 3128
    R-008396955-000G  925  644 UAACCUUUCCCAUCAUCGU ACGAUGAUGGGAAAGGUUAUU 3129
    R-008396958-000H 2072  645 CUGCUUUAUUCUCCCAUUG CAAUGGGAGAAUAAAGCAGUU 3131
    R-008396958-000H 2072  645 CUGCUUUAUUCUCCCAUUG B CUGCUUUAUUCUCCCAUUGTT B 3130
    R-008396964-000R 2939  646 AAUUGUAAUCUGAAUAAAG B AAUUGUAAUCUGAAUAAAGTT B 3132
    R-008396964-000R 2939  646 AAUUGUAAUCUGAAUAAAG CUUUAUUCAGAUUACAAUUUU 3133
    R-008396973-000Z 1480  647 UCUUGUUCAGCUUCUGGGU B UCUUGUUCAGCUUCUGGGUTT B 3134
    R-008396973-000Z 1480  647 UCUUGUUCAGCUUCUGGGU ACCCAGAAGCUGAACAAGAUU 3135
    R-008396976-000A 1889  648 GUUCGUGCACAUCAGGAUA B GUUCGUGCACAUCAGGAUATT B 3136
    R-008396976-000A 1889  648 GUUCGUGCACAUCAGGAUA UAUCCUGAUGUGCACGAACUU 3137
    R-008396979-000B  699  649 AUGAUGCAGAACUUGCCAC B AUGAUGCAGAACUUGCCACTT B 3138
    R-008396979-000B  699  649 AUGAUGCAGAACUUGCCAC GUGGCAAGUUCUGCAUCAUUU 3139
    R-008396982-000H  506  650 GCUGAUAUUGAUGGACAGU B GCUGAUAUUGAUGGACAGUTT B 3140
    R-008396982-000H  506  650 GCUGAUAUUGAUGGACAGU ACUGUCCAUCAAUAUCAGCUU 3141
    R-008396985-000J 1750  651 GGUUAAGCUCUUACACCCA UGGGUGUAAGAGCUUAACCUU 3143
    R-008396985-000J 1750  651 GGUUAAGCUCUUACACCCA B GGUUAAGCUCUUACACCCATT B 3142
    R-008396988-000K 1820  652 GCCCUUUGUCCCGCAAAUC B GCCCUUUGUCCCGCAAAUCTT B 3144
    R-008396988-000K 1820  652 GCCCUUUGUCCCGCAAAUC GAUUUGCGGGACAAAGGGCUU 3145
    R-008396991-000S  541  653 UCAGAGGGUACGAGCUGCU AGCAGCUCGUACCCUCUGAUU 3147
    R-008396991-000S  541  653 UCAGAGGGUACGAGCUGCU B UCAGAGGGUACGAGCUGCUTT B 3146
    R-008396994-000T  880  102 UACAAAUGAUGUAGAAACA B UACAAAUGAUGUAGAAACATT B 3148
    R-008396994-000T  880  102 UACAAAUGAUGUAGAAACA UGUUUCUACAUCAUUUGUAUU 3149
    R-008396997-000U  665  654 AAACAUGCAGUUGUAAACU B AAACAUGCAGUUGUAAACUTT B 3150
    R-008396997-000U  665  654 AAACAUGCAGUUGUAAACU AGUUUACAACUGCAUGUUUUU 3151
    R-008397000-000H 1817  655 CUUGCCCUUUGUCCCGCAA UUGCGGGACAAAGGGCAAGUU 3153
    R-008397000-000H 1817  655 CUUGCCCUUUGUCCCGCAA B CUUGCCCUUUGUCCCGCAATT B 3152
    R-008397003-000J 2275  656 UUACAAGAAACGGCUUUCA UGAAAGCCGUUUCUUGUAAUU 3155
    R-008397003-000J 2275  656 UUACAAGAAACGGCUUUCA B UUACAAGAAACGGCUUUCATT B 3154
    R-008397006-000K 2426  657 CACUCUGGUGGAUAUGGCC GGCCAUAUCCACCAGAGUGUU 3157
    R-008397006-000K 2426  657 CACUCUGGUGGAUAUGGCC B CACUCUGGUGGAUAUGGCCTT B 3156
    R-008397009-000L  958  658 CAUCUUUAAGUCUGGAGGC B CAUCUUUAAGUCUGGAGGCTT B 3158
    R-008397009-000L  958  658 CAUCUUUAAGUCUGGAGGC GCCUCCAGACUUAAAGAUGUU 3159
    R-008397012-000T 1657  659 UGCCAUCUGUGCUCUUCGU B UGCCAUCUGUGCUCUUCGUTT B 3160
    R-008397012-000T 1657  659 UGCCAUCUGUGCUCUUCGU ACGAAGAOCACAGAUGGCAUU 3161
    R-008397015-000U 1146  660 UCUUGGCUAUUACGACAGA UCUGUCGUAAUAGCCAAGAUU 3163
    R-008397015-000U 1146  660 UCUUGGCUAUUACGACAGA B UCUUGGCUAUUACGACAGATT B 3162
    R-008397018-000V 3078  661 AUUUGGGAUAUGUAUGGGU B AUUUGGGAUAUGUAUGGGUTT B 3164
    R-008397018-000V 3078  661 AUUUGGGAUAUGUAUGGGU ACCCAUACAUAUCCCAAAUUU 3165
    R-008397021-000B 1008  662 CAGUGGAUUCUGUGUUGUU AACAACACAGAAUCCACUGUU 3167
    R-008397021-000B 1008  662 CAGUGGAUUCUGUGUUGUU B CAGUGUAUUCUGUGUUGUUTT B 3166
    R-008397024-000C 1621  663 CCUUCGGGCUGGUGACAGG CCUGUCACCAGCCCGAAGGUU 3169
    R-008397024-000C 1611  663 CCUUCGGGCUGGUGACAGG B CCUUCGGGCUGGUGACAGGTT B 3168
    R-008397027-000D 1932  664 GGACACAGCAGCAAUUUGU B GGACACAGCAGCAAUUUGUTT B 3170
    R-008397027-000D 1932  664 GGACACAUCAGCAAUUUGU ACAAAUUGCUGCUGUGUCCUU 3171
    R-008397030-000K 1909  665 CCAGCGCCGUACGUCCAUG CAUGGACGUACGGCGCUGGUU 3173
    R-008397030-000K 1909  665 CCAGCGCCGUACGUCCAUG B CCAGCGCCGUACGUCCAUGTT B 3172
    R-008397033-000L 2279  666 AAGAAACGGCUUUCAGUUG CAACUGAAAGCCGUUUCUUUU 3175
    R-008397033-000L 2279  666 AAGAAACGGCUUUCAGUUG B AAGAAACGGCUUUCAGUUGTT B 3174
    R-008397036-000M  574  667 AUUAGAUGAGGGCAUGCAG B AUUAGAUGAGGGCAUGCAGTT B 3176
    R-008397036-000M  574  667 AUUAGAUGAGGGCAUGCAG CUGCAUGCCCUCAUCUAAUUU 3177
    R-008397039-000N 2303  668 ACCAGCUCUCUCUUCAGAA UUCUGAAGAGAGAGCUGGUUU 3179
    R-008397039-000N 2303  668 ACCAGCUCUCUCUUCAGAA B ACCAGCUCUCUCUUCAGAATT B 3178
    R-008397042-000V  784  669 AGUUAUGGUCCAUCAGCUU B AGUUAUGGUCCAUCAGCUUTT B 3180
    R-008397042-000V  784  669 AGUUAUGGUCCAUCAGCUU AAGCUGAUGGACCAUAACUUU 3181
    R-008397045-000W 2507  670 GACUAUCCAGUUGAUGGGC GCCCAUCAACUGGAUAGUCUU 3183
    R-008397045-000W 2507  670 GACUAUCCAGUUGAUGGGC B GACUAUCCAGUUGAUGGGCTT B 3182
    R-008397048-000X  995  671 AUGCUUGGUUCACCAGUGG B AUGCUUGGUUCACCAGUGGTT B 3184
    R-008397048-000X  995  671 AUGCUUGGUUCACCAGUGG CCACUGGUGAACCAAGCAUUU 3185
    R-008397051-000D 2006  672 CUAGCUCGGGAUGUUCACA UGUGAACAUCCCGAGCUAGUU 3187
    R-008397051-000D 2006  672 CUAGCUCGGGAUGUUCACA B CUAGCUCGGGAUGUUCACATT B 3186
    R-008397054-000E 1757  673 CUCUUACACCCACCAUCCC GGGAUGGUGGGUGUAAGAGUU 3189
    R-008397054-000E 1757  673 CUCUUACACCCACCAUCCC B CUCUUACACCCACCAUCCCTT B 3188
    R-008397057-000F 2129  674 CUUGCUCAGGACAAGGAAG B CUUGCUCAGGACAAGGAAGTT B 3190
    R-008397057-000F 2129  674 CUUGCUCAGGACAAGGAAG CUUCCUUGUCCUGAGCAAGUU 3191
    R-008397060-000M 2272  675 AGAUUACAAGAAACGGCUU B AGAUUACAAGAAACGGCUUTT B 3192
    R-008397060-000M 2272  675 AGAUUACAAGAAACGGCUU AAGCCGUUUCUUGUAAUCUUU 3193
    R-008397063-000N  389  676 ACCACAGCUCCUUCUCUGA B ACCACAGCUCCUUCUCUGATT B 3194
    R-008397063-000N  389  676 ACCACAGCUCCUUCUCUGA UCAGAGAAGGAGCUGUGGUUU 3195
    R-008397066-000P  708  176 AACUUGCCACACGUGCAAU B AACUUGCCACACGUGCAAUTT B 3196
    R-008397066-000P  708  176 AACUUGCCACACGUGCAAU AUUGCACGUGUGGCAAGUUUU 3197
    R-008397069-000R 1435  677 AGAUGCUGCAACUAAACAG CUGUUUAGUUGCAGCAUCUUU 3199
    R-008397069-000R 1435  677 AGAUGCUGCAACUAAACAG B AGAUGCUGCAACUAAACAGTT B 3198
    R-008397072-000X 1247   34 AUAAUGAGGACCUAUACUU B AUAAUGAGGACCUAUACUUTT B 3200
    R-008397072-000X 1247   34 AUAAUGAGGACCUAUACUU AAGUAUAGGUCCUCAUUAUUU 3201
    R-008397075-000Y 1752  678 UUAAGCUCUUACACCCACC GGUGGGUGUAAGAGCUUAAUU 3203
    R-008397075-000Y 1752  678 UUAAGCUCUUACACCCACC B UUAAGCUCUUACACCCACCTT B 3202
    R-008397078-000Z  773  679 AAUAAGGCUGCAGUUAUGG CCAUAACUGCAGCCUUAUUUU 3205
    R-008397078-000Z  773  679 AAUAAGGCUGCAGUUAUGG B AAUAAGGCUGCAGUUAUGGTT B 3204
    R-008397081-000F 3080  680 UUGGGAUAUGUAUGGGUAG CUACCCAUACAUAUCCCAAUU 3207
    R-008397081-000F 3080  680 UUGGGAUAUGUAUGGGUAG B UUGGGAUAUGUAUGGGUAGTT B 3206
    R-008397084-000G 3174  681 GUAACCUGCUGUGAUACGA B GUAACCUGCUGUGAUACGATT B 3208
    R-008397084-000G 3174  681 GUAACCUGCUGUGAUACGA UCGUAUCACAGCAGGUUACUU 3209
    R-008397087-000H 1578  682 UGGUCUGCCAAGUGGGUGG B UGGUCUGCCAAGUGGGUGGTT B 3210
    R-008397087-000H 1578  682 UGGUCUGCCAAGUGGGUGG CCACCCACUUGGCAGACCAUU 3211
    R-008397090-000P  398  683 CCUUCUCUGAGUGGUAAAG B CCUUCUCUGAGUGGUAAAGTT B 3212
    R-008397090-000P  398  683 CCUUCUCUGAGUGGUAAAG CUUUACCACUCAGAGAAGGUU 3213
    R-008397093-000R 2153  684 GAAGCUAUUGAAGCUGAGG CCUCAGCUUCAAVAGCUUCUU 3215
    R-008397093-000R 2153  684 GAAGCUAUUGAAGCUGAGG B GAAGCUAUUGAAGCUGAGGTT B 3214
    R-008397096-000S  702  685 AUGGAGAACUUGCCACACG CGUGUGGCAAGUUCUGCAUUU 3217
    R-008397096-000S  702  685 AUGCAGAACUUGCCACACG B AUGCAGAACUUGCCACACGTT B 3216
    R-008397099-000T  503  686 GUAGCUGAUAUUGAUGGAC B GUAGCUGAUAUUGAUGGACTT B 3218
    R-008397099-000T  503  686 GUAGCUGAUAUUGAUGGAC GUCCAUCAAUAUCAGCUACUU 3219
    R-008397102-000K  276  687 CUCAAGCUGAUUUGAUGGA B CUCAAGCUGAUUUGAUGGATT B 3220
    R-008397102-000K  276  687 CUCAAGCUGAUUUGAUGGA UCCAUCAAAUCAGCUUGAGUU 3221
    R-008397105-000L 1962  688 GCAUGGAAGAAAUAGUUGA B GCAUGGAAGAAAUAGUUGATT B 3222
    R-008397105-000L 1962  688 GCAUGGAAGAAAUAGUUGA UCAACUAUUUCUUCCAUGCUU 3223
    R-008397108-000M 1347  689 CUGGUGGAAUGCAAGCUUU B CUGGUGGAAUGCAAGCUUUTT B 3224
    R-008397108-000M 1347  689 CUGGUGGAAUGCAAGCUUU AAAGCUUGCAUUCCACCAGUU 3225
    R-008397111-000U 2544  690 CCCAGGACCUCAUGGAUGG CCAUCCAUGAGGUCCUGGGUU 3227
    R-008397111-000U 2544  690 CCCAGGACCUCAUGGAUGG B CCCAGGACCUCAUGGAUGGTT B 3226
    R-008397114-000V 3079  691 UUUGGGAUAUGUAUGGGUA B UUUGGGAUAUGUAUGGGUATT B 3728
    R-008397114-000V 3079  691 UUUGGGAUAUGUAUGGGUA UACCCAUACAUAUCCCAAAUU 3229
    R-008397117-000W 3164  692 CAAAGUUGUUGUAACCUGC GCAGGUUACAACAACUUUGUU 3231
    R-008397117-000W 3164  692 CAAAGUUGUUGUAACCUGC B CAAAGUUGUUGUAACCUGCTT B 3230
    R-008397120-000C 2026  693 CCGAAUUGUUAUCAGAGGA B CCGAAUUGUUAUCAGAGGATT B 3232
    R-008397120-000C 2026  693 CCGAAUUGUUAUCAGAGGA UCCUCUGAUAACAAUUCGGUU 3233
    R-008397123-000D 2938  694 UAAUUGUAAUCUGAAUAAA B UAAUUGUAAUCUGAAUAAATT B 3234
    R-008397123-000D 2938  694 UAAUUGUAAUCUGAAUAAA UUUAUUCAGAUUACAAUUAUU 3235
    R-008397126-000E 2940  695 AUUGUAAUCUGAAUAAAGU ACUUUAUUCAGAUUACAAUUU 3237
    R-008397126-000E 2940  695 AUUGUAAUCUGAAUAAAGU B AUUGUAAUCUGAAUAAAGUTT B 3236
    R-008397129-000F 2027  696 CGAAUUGUUAUCAGAGGAC B CGAAUUGUUAUCAGAGGACTT B 3238
    R-008397129-000F 2027  696 CGAAUUGUUAUCAGAGGAC GUCCUCUGAUAACAAUUCGUU 3239
    R-008397132-000M  448  697 CCAAGUCCUGUAUGAGUGG CCACUCAUACAGGACUUGGUU 3241
    R-008397132-000M  448  697 CCAAGUCCUGUAUGAGUUG B CCAAGUCCUGUAUGAGUGGTT B 3240
    R-008397135-000N 1328  698 AAGCCGGCUAUUGUAGAAG B AAGCCGGCUAUUGUAGAAGTT B 3242
    R-008397135-000N 1328  698 AAGCCGGCUAUUGUAGAAG CUUCUACAAUAGCCGGCUUUU 3243
    R-008397138-000P 1970   33 GAAAUAGUUGAAGGUUGUA UACAACCUUCAACUAUUUCUU 3245
    R-008397138-000P 1970   33 GAAAUAGUUGAAGGUUGUA B GAAAUAGUUGAAGGUUGUATT B 3244
    R-008397141-000W 2406  699 AUCCUAGCUAUCGUUCUUU AAAGAACGAUAGCUAGGAUUU 3247
    R-008397141-000W 2406  699 AUCCUAGCUAUCGUUCUUU B AUCCUAGCUAUCGUUCUUUTT B 3246
    R-008397144-000X  924  700 AUAACCUUUCCCAUCAUCG B AUAACCUUUCCCAUCAUCGTT B 3248
    R-008397144-000X  924  700 AUAACCUUUCCCAUCAUCG CGAUGAUGGGAAAGGUUAUUU 3249
    R-008397147-000Y 1584  701 GCCAAGUGGGUGGUAUAGA UCUAUACCACCCACUUGGCUU 3251
    R-008397147-000Y 1584  701 GCCAAGUGGGUGGUAUAGA B GCCAAGUGGGUGGUAUAGATT B 3250
    R-008397150-000E 1871  702 CGACUAGUUCAGUUGCUUG B CGACUAGUUCAGUUGCUUGTT B 3252
    R-008397150-000E 1871  702 CGACUAGUUCAGUUGCUUG CAAGCAACUGAACUAGUCGUU 3253
    R-008397153-000F  999  703 UUGGUUCACCAGUGGAUUC B UUGGUUCACCAGUGGAUUCTT B 3254
    R-008397153-000F  999  703 UUGGUUCACCAGUGGAUUC GAAUCCACUGGUGAACCAAUU 3255
    R-008397156-000G 1400  704 GUUCAGAACUGUCUUUGGA UCCAAAGACAGUUCUGAACUU 3257
    R-008397156-000G 1400  704 GUUCAGAACUGUCUUUGGA B GUUCAGAACUGUCUUUGGATT B 3256
    R-008397159-000H 3180  705 UGCUGUGAUACGAUGCUUC GAAGCAUCGUAUCACAGCAUU 3259
    R-008397159-000H 3180  705 UGCUGUGAUACGAUGCUUC B UGCUGUGAUACGAUGGUUCTT B 3258
    R-008397162-000P 2569  706 UCCAGGUGACAGCAAUCAG CUGAUUGCUGUCACCUGGAUU 3261
    R-008397162-000P 2569  706 UCCAGGUGACAGCAAUCAG B UCCAGGUGACAGCAAUCAGTT B 3260
    R-008397165-000R  787  707 UAUGGUCCAUCAGCUUUCU AGAAAGCUGAUGGACCAUAUU 3263
    R-008397165-000R  787  707 UAUGGUCCAUCAGCUUUCU B UAUGGUCCAUCAGCUUUCUTT B 3262
    R-008397168-000S 1861  708 UGCCAUUCCACGACUAGUU B UGCCAUUCCACGACUAGUUTT B 3264
    R-008397168-000S 1861  708 UGCCAUUCCACGACUAGUU AACUAGUCGUGGAAUGGCAUU 3265
    R-008397171-000Y 1190  709 AACCAAGAAAGCAAGCUCA UGAGCUUGCUUUCUUGGUUUU 3267
    R-008397171-000Y 1190  709 AACCAAGAAAGCAAGCUCA B AACCAAGAAAGCAAGCUCATT B 3266
    R-008397174-000Z 1557  710 AUAAUUAUAAGAACAAGAU AUCUUGUUCUUAUAAUUAUUU 3269
    R-008397174-000Z 1557  710 AUAAUUAUAAGAACAAGAU B AUAAUUAUAAGAACAAGAUTT B 3268
    R-008397177-000A 1751  711 GUUAAGCUCUUACACCCAC B GUUAAGCUCUUACACCCACTT B 3270
    R-008397177-000A 1751  711 GUUAAGCUCUUACACCCAC GUGGGUGUAAGAGCUUAACUU 3271
    R-008397180-000G 2897  712 UUGAGUAAUGGUGUAGAAC B UUGAGUAAUGGUGUAGAACTT B 3271
    R-008397180-000G 2897  712 UUGAGUAAUGGUGUAGAAC GUUCUACACCAUUACUCAAUU 3273
    R-008397183-000H 2217  713 GUGUGGCGACAUAUGCAGC GCUGCAUAUGUCGCCACACUU 3275
    R-008397183-000H 2217  713 GUGUGGCGACAUAUGCAGC B GUGUGGCGACAUAUGCAGCTT B 3274
    R-008397186-000J 2302  714 GACCAGCUCUCUCUUCAGA UCUGAAGAGAGAGCUGGUCUU 3277
    R-008397186-000J 2302  714 GACCAGCUCUCUCUUCAGA B GACCAGCUCUCUCUUCAGATT B 3276
    R-008397189-000K 1984  715 UUGUACCGGAGCCCUUCAC GUGAAGGGCUCCGGUACAAUU 3279
    R-008397189-000K 1984  715 UUGUACCGGAGCCCUUCAC B UUGUACCGGAGCCCUUCACTT B 3278
    R-008397192-000S  302  716 AUGGCCAUGGAACCAGACA B AUGGCCAUGGAACCAGACATT B 3280
    R-008397192-000S  302  716 AUGGCCAUGGAACCAGACA UGUCUGGUUCCAUGGCCAUUU 3281
    R-008397195-000T 2431  717 UGGUGGAUAUGGCCAGGAU B UGGUGGAUAUGGCCAGGAUTT B 3282
    R-008397195-000T 2431  717 UGGUGGAUAUGGCCAGGAU AUCCUGGCCAUAUCCACCAUU 3283
    R-008397198-000U 2183  718 CCUCUGACAGAGUUACUUC GAAGUAACUCUGUCAGAGGUU 3285
    R-008397198-000U 2183  718 CCUCUGACAGAGUUACUUC B CCUCUGACAGAGUUACUUCTT B 3284
    R-008397201-000L 2403  719 AUGAUCCUAGCUAUCGUUC GAACGAUAGCUAGGAUCAUUU 3287
    R-008397201-000L 2403  719 AUGAUCCUAGCUAUCGUUC B AUGAUCCUAGCUAUCGUUCTT B 3286
    R-008397204-000M  788  720 AUGGUCCAUCAGCUUUCUA B AUGGUCCAUCAGCUUUCUATT B 3288
    R-008397204-000M  788  720 AUGGUCCAUCAGCUUUCUA UAGAAAGCUGAUGGACCAUUU 3289
    R-008397207-000N 1476  721 GGACUCUUGUUCAGGUUCU B GGACUCUUGUUGAGCUUCUTT B 3290
    R-008397207-000N 1476  721 GGACUCUUGUUCAGGUUCU AGAAGCUGAACAAGAGUCCUU 3291
    R-008397210-000V  827  722 GCUAUCAUGCGUUCUCCUC B GCUAUCAUGCGUUCUCCUCTT B 3292
    R-008397210-000V  827  722 GGUAUCAUGCGUUCUCCUC GAGGAGAACGCAUGAUAGCUU 3293
    R-008397213-000W 2299  723 GCUGACCAGCUCUCUCUUC B GCUGACCAGCUCUCUCUUCTT B 3294
    R-008397213-000W 2299  723 GCUGACCAGCUCUCUCUUC GAAGAGAGAGCUGGUCAGCUU 3295
    R-008397216-000X 1891  724 UCGUGCACAUCAGGAUACC B UCGUGCACAUCAGGAUACCTT B 3296
    R-008397216-000X 1891  724 UCGUGCACAUCAGGAUACC GGUAUCCUGAUGUGCACGAUU 3297
    R-008397219-000Y 2196  725 UACUUCACUCUAGGAAUGA UCAUUCCUAGAGUGAAGUAUU 3299
    R-008397219-000Y 2196  725 UACUUCACUCUAGGAAUGA B UACUUCACUCUAGGAAUGATT B 3298
    R-008397222-000E  663  726 UGAAACAUGCAGUUGUAAA UUUACAACUGCAUGUUUCAUU 3301
    R-008397222-000E  663  726 UGAAACAUGCAGUUGUAAA B UGAAACAUGCAGUUGUAAATT B 3300
    R-008397225-000F 1028  727 UAUGCCAUUACAACUCUCC GGAGAGUUGUAAUGGCAUAUU 3303
    R-008397225-000F 1028  727 UAUGCCAUUACAACUCUCC B UAUGCCAUUACAACUCUCCTT B 3302
    R-008397228-000G 2032  728 UGUUAUCAGAGGACUAAAU AUUUAGUCCUCUGAUAACAUU 3305
    R-008397228-000G 2032  728 UGUUAUCAGAGGACUAAAU B UGUUAUCAGAGGACUAAAUTT B 3304
    R-008397231-000N 1459  729 GAUGGAAGGUCUCCUUGGG B GAUGGAAGGUCUCCUUGGGTT B 3306
    R-008397231-000N 1459  729 GAUGGAAGGUCUCCUUGGG CCCAAGGAGACCUUCCAUCUU 3307
    R-008397234-000P 2095  730 CAUCCAAAGAGUAGCUGCA UGCAGCUACUCUUUGGAUGUU 3309
    R-008397234-000P 2095  730 CAUCCAAAGAGUAGCUGCA B CAUCCAAAGAGUAGCUGCATT B 3308
    R-008397237-000R 1686  731 GCCGACACCAAGAAGCAGA B GCCGACACCAAGAAGCAGATT B 3310
    R-008397237-000R 1686  731 GCCGACACCAAGAAGCAGA UCUGCUUCUUGGUGUCGGCUU 3311
    R-008397240-000X 1412  732 CUUUGGACUCUCAGGAAUC B CUUUGGACUCUCAGGAAUCTT B 3312
    R-008397240-000X 1412  732 CUUUGGACUCUCAGGAAUC GAUUCCUGAGAGUCCAAAGUU 3313
    R-008397243-000Y 2473  733 GGAACAUGAGAUGGGUGGC GCCACCCAUCUCAUGUUCCUU 3315
    R-008397243-000Y 2473  733 GGAACAUGAGAUGGGUGGC B GGAACAUGAGAUGGGUGGCTT B 3314
    R-008397246-000Z 1080  734 UGGCAGUGCGUUUAGCUGG CCAGCUAAACGCACUGCCAUU 3317
    R-008397246-000Z 1080  734 UGGCAGUGCGUUUAGCUGG B UGGCAGUGCGUUUAGCUGGTT B 3316
    R-008397249-000A 2143  735 GGAAGGUGCAGAAGCUAUU AAUAGCUUCUGCAGCUUCCUU 3319
    R-008397249-000A 2143  735 GGAAGGUGCAGAAGCUAUU B GGAAGCUGCAGAAGCUAUUTT B 3318
    R-008397252-000G 2203  736 CUCUAGGAAUGAAGGUGUG B CUCUAGGAAUGAAGGUGUGTT B 3320
    R-008397252-000G 2203  736 CUCUAGGAAUGAAGGUGUG CACACCUUCAUUCCUAGAGUU 3321
    R-008397255-000H  548  737 GUACGAGCUGCUAUGUUCC B GUACGAGCUGCUAUGUUCCTT B 3322
    R-008397255-000H  548  737 GUACGAGCUGCUAUGUUCC GGAACAUAGCAGCUCGUACUU 3323
    R-008397258-000J 2050   45 UACCAUUCCAUUGUUUGUG CACAAACAAUGGAAUGGUAUU 3325
    R-008397258-000J 2050   45 UACCAUUCCAUUGUUUGUG B UACCAUUCCAUUGUUUGUGTT B 3324
    R-008397261-000R 1867  738 UCCACGACUAGUUCAGUUG B UCCACGACUAGUUCAGUUGTT B 3326
    R-008397261-000R 1867  738 UCCACGACUAGUUCAGUUG CAACUGAACUAGUCGUGGAUU 3327
    R-008397264-000S  842  739 CCUCAGAUGGUGUCUGCUA B CCUCAGAUGGUGUCUGCUATT B 3328
    R-008397264-000S  842  739 CCUCAGAUGGUGUCUGCUA UAGCAGACACCAUCUGAGGUU 3329
    R-008397267-000T 2120  740 CUCUGUGAACUGGCUCAGG CCUGAGCAAGUUCACAGAGUU 3331
    R-008397267-000T 2120  740 CUCUGUGAACUUGCUCAGG B CUCUGUGAACUUGCUCAGGTT B 3330
    R-008397270-000Z  782  741 GCAGUUAUGGUCCAUCAGC B GCAGUUAUGGUCCAUCAGCTT B 3332
    R-008397270-000Z  782  741 GCAGUUAUGGUCCAUCAGC GCUGAUGGACCAUAACUGCUU 3333
    R-008397273-000A 1758  742 UCUUACACCCACCAUCCCA UGGGAUGGUGGGUGUAAGAUU 3335
    R-008397273-000A 1758  742 UCUUACACCCACCAUCCCA B UCUUACACCCACCAUCCCATT B 3334
    R-008397276-000B 2396  743 CGCCAGGAUGAUCCUAGCU B CGCCAGGAUGAUCCUAGCUTT B 3336
    R-008397276-000B 2396  743 CGCCAGGAUGAUCCUAGCU AGCUAGGAUCAUCCUGGCGUU 3337
    R-008397279-000C 1373  744 CACCUGACAGAUCCAAGUC GACUUGGAUCUGUCAGGUGUU 3339
    R-008397279-000C 1373  744 CACCUGACAGAUCCAAGUC B CACCUGACAGAUCCAAGUCTT B 3338
    R-008397282-000J 1518  745 UCACCUGUGCAGCUGGAAU B UCACCUGUGCAGCUGGAAUTT B 3340
    R-008397282-000J 1518  745 UCACCUGUGCAGCUGGAAU AUUCCAGCUGCACAGGUGAUU 3341
    R-008397285-000K 2557  746 GGAUGGGCUGCCUCCAGGU ACCUGGAGGCAGCCCAUCCUU 3343
    R-008397285-000K 2557  746 GGAUGGGCUGCCUCCAGGU B GGAUGGGCUGCCUCCAGGUTT B 3342
    R-008397288-000L 1987  747 UACCGGAGCCCUUCACAUC B UACCGGAGCCCUUCACAUCTT B 3344
    R-008397288-000L 1987  747 UACCGGAGCCCUUCACAUC GAUGUGAAGGGCUCCGGUAUU 3345
    R-008397291-000T  568  748 UGAGACAUUAGAUGAGGGC GCCCUCAUCUAAGGUCUCAUU 3347
    R-008397291-000T  568  748 UGAGACAUUAGAUGAGGGC B UGAGACAUUAGAUGAGGGCTT B 3346
    R-008397294-000U 2201  749 CACUCUAGGAAUGAAGGUG B CACUCUAGGAAUGAAGGUGTT B 3348
    R-008397294-000U 2201  749 CACUCUAGGAAUGAAGGUG CACCUUCAUUCCUAGAGUGUU 3349
    R-008397297-000V  609  750 UUGAUGCUGCUCAUCCCAC GUGGGAUGAGCAGCAUCAAUU 3351
    R-008397297-000V  609  750 UUGAUGCUGCUCAUCCCAC B UUGAUGCUGCUCAUCCCACTT B 3350
    R-008397300-000M  400  751 UUCUCUGAGUGGUAAAGGC GCCUUUACCACUCAGAGAAUU 3353
    R-008397300-000M  400  751 UUCUCUGAGUGGUAAAGGC B UUCUCUGAGUGGUAAAGGCTT B 3352
    R-008397303-000N  331  752 UGUUAGUCACUGGCAGCAA UUGCUGCCAGUGACUAACAUU 3355
    R-008397303-000N  331  752 UGUUAGUCACUGGCAGCAA B UGUUAGUCACUGGCAGCAATT B 3354
    R-008397306-000P 1967  753 GAAGAAAUAGUUGAAGGUU AACCUUCAACUAUUUCUUCUU 3357
    R-008397306-000P 1967  753 GAAGAAAUAGUUGAAGGUU B GAAGAAAUAGUUGAAGGUUTT B 3356
    R-008397309-000R 2198  754 CUUCACUCUAGGAAUGAAG CUUCAUUCCUAGAGUGAAGUU 3359
    R-008397309-000R 2198  754 CUUCACUCUAGGAAUGAAG B CUUCACUCUAGGAAUGAAGTT B 3358
    R-008397312-000X 1493  755 CUGGGUUCAGAUGAUAUAA UUAUAUCAUCUGAACCCAGUU 3361
    R-008397312-000X 1493  755 CUGGGUUCAGAUGAUAUAA B CUGGGUUCAGAUGAUAUAATT B 3360
    R-008397315-000Y 2260  756 GGACAAGCCACAAGAUUAC GUAAUCUUGUGGCUUGUCCUU 3363
    R-008397315-000Y 2260  756 GGACAAGCCACAAGAUUAC B GGACAAGCCACAAGAUUACTT B 3362
    R-008397318-000Z 2496  757 ACCCUGGUGCUGACUAUCC B ACCCUGGUGCUGACUAUCCTT B 3364
    R-008397318-000Z 2496  757 ACCCUGGUGCUGACUAUCC GGAUAGUCAGCACCAGGGUUU 3365
    R-008397321-000F 2361  758 UUGAUAUUGGUGCCCAGGG B UUGAUAUUGGUGCCCAGGGTT B 3366
    R-008397321-000F 2361  758 UUGAUAUUGGUGCCCAGGG CCCUGGGCACCAAUAUCAAUU 3367
    R-008397324-000G  443  759 ACCUCCCAAGUCCUGUAUG CAUACAGGACUUGGGAGGUUU 3369
    R-008397324-000G  443  759 ACCUCCCAAGUCCUGUAUG B ACCUCCCAAGUCCUGUAUGTT B 3368
    R-008397327-000H  523  760 GUAUGCAAUGACUCGAGCU B GUAUGCAAUGACUCGAGCUTT B 3370
    R-008397327-000H  523  760 GUAUGGAAUGACUCGAGCU AGCUCGAGUCAUUGCAUACUU 3371
    R-008397330-000P 1742  761 CCAGUUGUGGLUAAGCUCU B CCAGUUGUGGUUAAGCUCUTT B 3372
    R-008397330-000P 1742  761 CCAGUUGUGGLUAAGCUCU AGAGCUUAACCACAACUGGUU 3373
    R-008397333-000R  530  762 AUGACUCGAGCUCAGAGGG B AUGACUCGAGCUCAGAGGGTT B 3374
    R-008397333-000R  530  762 AUGACUCGAGCUCAGAGGG CCCUCUGAGCUCGAGUCAUUU 3375
    R-008397336-000S 3169  763 UUGUUGUAACCUGCUGUGA B UUGUUGUAACCUGGUGUGATT B 3376
    R-008397336-000S 3169  763 UUGUUGUAACCUGCUGUGA UCACAGCAGGUUACAACAAUU 3377
    R-008397339-000T 1385  764 CCAAGUCAACGUCUUGUUC B CCAAGUCAACGUCUUGUUCTT B 3378
    R-008397339-000T 1385  764 CCAAGUCAACGUCUUGUUC GAACAAGACGUUGACUUGGUU 3379
    R-008397342-000Z 2123  131 UGUGAACUUGCUCAGGACA B UGUGAACUUGCUCAGGACATT B 3380
    R-008397342-000Z 2123  131 UGUGAACUUGCUCAGGACA UGUCCUGAGCAAGUUCACAUU 3381
    R-008397345-000A 2036  765 AUCAGAGGACCAAAUACCA B AUCAGAGGACUAAAUACCATT B 3382
    R-008397345-000A 2036  765 AUCAGAGGACUAAAUACCA UGGUAUUUAGUCCUCUGAUUU 3383
    R-008397348-000B 3088  766 UGUAUGGGUAGGGUAAAUC GAUUUACCCUACCCAUACAUU 3385
    R-008397348-000B 3088  766 UGUAUGGGUAGGGUAAAUC B UGUAUGGGUAGGGUAAAUCTT B 3384
    R-008397351-000H 2051   56 ACCAUUCCAUUGUUUGUGC GCACAAACAAUGGAAUGGUUU 3387
    R-008397351-000H 2051   56 ACCAUUCCAUUGUUUGUGC B ACCAUUCCAUUGUUUGUGCTT B 3386
    R-008397354-000J  288  170 UGAUGGAGUUGGACAUGGC GCCAUGUCCAACUCCAUCAUU 3389
    R-008397354-000J  288  170 UGAUGGAGUUGGACAUGGC B UGAUGGAGUUGGACAUGGCTT B 3388
    R-008397357-000K 1850  767 CGUGAGCAGGGUGCCAUUC B CGUGAGCAGGGUGCCAUUCTT B 3390
    R-008397357-000K 1850  767 CGUGAGCAGGGUGCCAUUC GAAUUGCACCCUGCUCACGUU 3391
    R-008397360-000S 2548   82 GGACCUCAUGGAUGGGCUG B GGACCUCAUGGAUGGGCUGTT B 3392
    R-008397360-000S 2548   82 GGACCUCAUGGAUGGGCUG CAGCCCAUCCAUGAGGUCCUU 3393
    R-008397363-000T 2518  768 UGAUGCGCUGCCAGAUCUG B UGAUGGGCUGCCAGAUCUGTT B 3394
    R-008397363-000T 2518  768 UGAUGCGCUGCCAGAUCUG CAGAUCUGGCAGCCCAUCAUU 3395
    R-008397366-000U 1886  769 CUUGUUCGUGCACAUCAGG B CUUGUUCGUGCACAUCAGGTT B 3396
    R-008397366-000U 1886  769 CUUGUUCGUGCACAUCAGG CCUGAUGUGCACGAACAAGUU 3397
    R-008397369-000V  650  770 CCAUCACAGAUGCUGAAAC GUUUCAGCAUCUGUGAUGGUU 3399
    R-008397369-000V  650  770 CCAUCACAGAUGCUGAAAC B CCAUCACAGAUGCUGAAACTT B 3398
    R-008397372-000B 3139  771 ACAGUUUACCAGUUGCCUU AAGGCAACUGGUAAACUGUUU 3401
    R-008397372-000B 3139  771 ACAGUUUACCAGUUGCCUU B ACAGUUUACCAGUUGCCUUTT B 3400
    R-008397375-000C 2025  772 ACCGAAUUGUUAUCAGAGG CCUCUGAUAACAAUUCGGUUU 3403
    R-008397375-000C 2025  772 ACCGAAUUGUUAUCAGAGG B ACCGAAUUGUUAUCAGAGGTT B 3402
    R-008397378-000D 1082  773 GCAGUGCGUDUAGCUGGUG CACCAGCUAAACGCACUGCUU 3405
    R-008397378-000D 1082  773 GCAGUGCGUUUAGCUGGUG B GCAGUGCGUUUAGCUGGUGTT B 3404
    R-008397381-000K 2475  774 AACAUGAGAUGGGUGGCCA UGGCCACCCAUCUCAUGUUUU 3407
    R-008397381-000K 2475  774 AACAUGAGAUGGGUGGCCA B AACAUGAGAUGGGUGGCCATT B 3406
    R-008397384-000L 1375  775 CCUGACAGAUCCAAGUCAA UUGACUUGGAUCUGUCAGGUU 3409
    R-008397384-000L 1375  775 CCUGACAGAUCCAAGUCAA B CCUGACAGAUCCAAGUCAATT B 3408
    R-008397387-000M 2013  776 GGGAUGUUCACAACCGAAU B GGGAUGUUCACAACCGAAUTT B 3410
    R-008397387-000M 2013  776 GGGAUGUUCACAACCGAAU AUUCGCUUGUGAACAUCCCUU 3411
    R-008397390-000U 1236   41 CUDUAGUAAAUAUAAUGAG CUCAUUAUAUUUACUAAAGUU 3413
    R-008397390-000U 1236   41 CUDUAGUAAAUAUAAUGAG B CUUUAGUAAAUAUAAUGAGTT B 3412
    R-008397393-000V 1653  128 AGCCUGCCAUCUGUGCUCU B AGCCUGCCAUCUGUGCUCUTT B 3414
    R-008397393-000V 1653  128 AGCCUGCCAUCUGUGCUCU AGAGCACAGAUGGCAGGCUUU 3415
    R-008397396-000W 1802  777 GGAUUGAUUCGAAAUCUUG B GGAUUGAUUCGAAAUCUUGTT B 3416
    R-008397396-000W 1802  777 GGAUUGAUUCGAAAUCUUG CAAGAUUUCGAAUCAAUCCUU 3417
    R-008397399-000X 2144  778 GAAGCUGCAGAAGCUAUUG CAAUAGCUUCUGCAGCUUCUU 3419
    R-008397399-000X 2144  778 GAAGCUGCAGAAGCUAUUG B GAAGCUGCAGAAGCUAUUGTT B 3418
    R-008397402-000P  529  779 AAUGACUCGAGCUCAGAGG B AAUGACUCGAGCUCAGAGGTT B 3420
    R-008397402-000P  529  779 AAUGACUCGAGCUCAGAGG CCUCUGAGCUCGAGUCAUUUU 3421
    R-008397405-000R 1482  780 UUGUUCAGCUUCUGGGUUC GAACCCAGAAGCUGAACAAUU 3423
    R-008397405-000R 1482  780 UUGUUCAGCUUCUGGGUUC B UUGUUCAGCUUCUGGGUUCTT B 3422
    R-008397408-000S 1546  781 CCUCACUUGCAAUAAUUAU B CCUCACUUGCAAUAAUUAUTT B 3424
    R-008397408-000S 1546  781 CCUCACUUGCAAUAAUUAU AUAAUUAUUGCAAGUGAGGUU 3425
    R-008397411-000Y  845  782 CAGAUGGUGUGUGCUAUUG CAAUAGCAGACACCAUCUGUU 3427
    R-008397411-000Y  845  782 CAGAUGGUGUGUGCUAUUG B CAGAUGGUGUCUGCUAUUGTT B 3426
    R-008397414-000Z  487  783 CUUCACUCAAGAACAAGUA B CUUCACUCAAGAACAAGUATT B 3428
    R-008397414-000Z  487  783 CUUCACUCAAGAACAAGUA UACUUGUUCUUGAGUGAAGUU 3429
    R-008397417-000A  652  784 AUCACAGAUGCUGAAACAU AUGUUUCAGCAUCUGUGAUUU 3431
    R-008397417-000A  652  784 AUCACAGAUGCUGAAACAU B AUCACAGAUGCUGAAACAUTT B 3430
    R-008397420-000G 1720  785 AGUUCGCCUUCACUAUGGA UCCAUAGUGAAGGCGAACUUU 3433
    R-008397420-000G 1720  785 AGUUCGCCUUCACUAUGGA B AGUUCGCCUUCACUAUGGATT B 3432
    R-008397423-000H  951  786 UACUGGCCAUCUUUAAGUC GACUUAAAGAUGGCCAGUAUU 3435
    R-008397423-000H  951  786 UACUGGCCAUCUUUAAGUC B UACUGGCCAUCUUUAAGUCTT B 3434
    R-008397426-000J 1232  787 CAAGCUUUAGUAAAUAUAA UUAUAUUUACUAAAGCUUGUU 3437
    R-008397426-000J 1232  787 CAAGCUUUAGUAAAUAUAA B CAAGCUUUAGUAAAUAUAATT B 3436
    R-008397429-000K 2269   28 ACAAGAUUACAAGAAACGG B ACAAGAUUACAAGAAACGGTT B 3438
    R-008397429-000K 2269   28 ACAAGAUUACAAGAAACGG CCGUUUCUUGUAAUCUUGUUU 3439
    R-008397432-000S 2265  788 AGCCACAAGAUUACAAGAA B AGCCACAAGAUUACAAGAATT B 3440
    R-008397432-000S 2265  788 AGCCACAAGAUUACAAGAA UUCUUGUAAUCUUGUGGCUUU 3441
    R-008397435-000T 1698  789 AAGCAGAGAUGGCCCAGAA B AAGCAGAGAUGGCCCAGAATT B 3442
    R-008397435-000T 1698  789 AAGCAGAGAUGGCCCAGAA UUCUGGGCCAUCUCUGCUUUU 3443
    R-008397438-000U  701  790 GAUGCAGAACUUGCCACAC GUGUGGCAAGUUCUGCAUCUU 3445
    R-008397438-000U  701  790 GAUGCAGAACUUGCCACAC B GAUGCAGAACUUGCCACACTT B 3444
    R-008397441-000A 1428  791 AUCUUUCAGAUGCUGCAAC GUUGCAGCAUCUGAAAGAUUU 3447
    R-008397441-000A 1428  791 AUCUUUCAGAUGCUGCAAC B AUCUUUCAGAUGCUGCAACTT B 3446
    R-008397444-000B 1930  792 UGGGACACAGCAGCAAUUU B UGGGACACAGCAGCAAUUUTT B 3448
    R-008397444-000B 1930  792 UGGGACACAGCAGCAAUUU AAAUUGCUGCUGUGUCCCAUU 3449
    R-008397447-000C 1379  793 ACAGAUCCAAGUCAACGUC GACGUUGACUUGGAUCUGUUU 3451
    R-008397447-000C 1379  793 ACAGAUCCAAGUCAACGUC B ACAGAUCCAAGUCAACGUCTT B 3450
    R-008397450-000J 1936  794 ACAGCAGCAAUUUGUGGAG B ACAGCAGCAAUUUGUGGAGTT B 3452
    R-008397450-000J 1936  794 ACAGCAGCAAUUUGUGGAG CUCCACAAAUUGCUGCUGUUU 3453
    R-008397453-000K 1441  795 UGCAACUAAACAGGAAGGG CCCUUCCUGUUUAGUUGCAUU 3455
    R-008397453-000K 1491  795 UGCAACUAAACAGGAAGGG B UGCAACUAAACAGGAAGGGTT B 3454
    R-008397456-000L 2132  796 GCUCAGGACAAGGAAGCUG CAGCUUCCUUGUCCUGAGCUU 3457
    R-008397456-000L 2132  796 GCUCAGGACAAGGAAGCUG B GCUCAGGACAAGGAAGCUGTT B 3456
    R-008397459-000M 2443  165 CCAGGAUGCCUUGGGUAUG B CCAGGAUGCCUUGGGUAUGTT B 3458
    R-008397459-000M 2443  165 CCAGGAUGCCUUGGGUAUG CAUACCCAAGGCAUCCUGGUU 3459
    R-008397462-000U 1800  163 UUGGAUUGAUUCGAAAUCU AGAUUUCGAAUCAAUCCAAUU 3461
    R-008397462-000U 1800  163 UUGGAUUGAUUCGAAAUCU B UUGGAUUGAUUCGAAAUCUTT B 3460
    R-008397465-000V  403  185 UCUGAGUGGUAAAGGCAAU AUGGCCUUUACCACUCAGAUU 3463
    R-008397465-000V  403  185 UCUGAGUGGUAAAGGCAAU B UCUGAGUGGUAAAGGCAAUTT B 3462
    R-008397468-000W 1007  105 CCAGUGGAUUCUGUGUUGU ACAACACAGAAUCCACUGGUU 3465
    R-008397468-000W 1007  105 CCAGUGGAUUCUGUGUUGU B CCAGUGGAUUCUGUGUUGUTT B 3464
    R-008397471-000C 1057  113 AUUACAUCAAGAAGGAGCU AGCUCCUUCUUGAUGUAAUUU 3467
    R-008397471-000C 1057  113 AUUACAUCAAGAAGGAGCU B AUUACAUCAAGAAGGAGCUTT B 3466
    R-008397474-000D 2267   87 CCACAAGAUUACAAGAAAC B CCACAAGAUUACAAGAAACTT B 3468
    R-008397474-000D 2267   87 CCACAAGAUUACAAGAAAC GUUUCUUGUAAUCUUGUGGUU 3469
    R-008397477-000E 1240  158 AGUAAAUAUAAuGAGGACC B AGUAAAUAUAAUGAGGACCTT B 3470
    R-008397477-000E 1240  158 AGUAAAUAUAAuGAGGACC GGUCCUCAUUAUAUUUACUUU 3471
    R-008397480-000L 2043  797 GACUAAAUACCAUUCCAUU AAUGGAAUGGUAUUUAGUCUU 3473
    R-008397480-000L 2043  797 GACUAAAUACCAUUCCAUU B GACUAAAUACCAUUCCAUUTT B 3472
    R-008397483-000M  608  798 UUUGAUGCUGCUCAUCCCA UGGGAUGAGCAGCAUCAAAUU 3475
    R-008397483-000M  608  798 UUUGAUGCUGCUCAUCCCA B UUUGAUGCUGCUCAUCCCATT B 3474
    R-008397486-000N  341  799 UGGCAGCAACAGUCUUACC B UGGCAGCAACAGUCUUACCTT B 3476
    R-008397486-000N  341  799 UGGCAGCAACAGUCUUACC GGUAAGACUGUUGCUGCCAUU 3477
    R-008397489-000P 1194  800 AAGAAAGCAAGCUCAUCAU B AAGAAAGCAAGCUCAUCAUTT B 3478
    R-008397489-000P 1194  800 AAGAAAGCAAGCUCAUCAU AUGAUGAGCUUGCUUUCUUUU 3479
    R-008397492-000W 2350  801 UGAUCUUGGACUUGAUAUU B UGAUCUUGGACUUGAUAUUTT B 3480
    R-008397492-000W 2350  801 UGAUCUUGGACUUGAUAUU AAUAUCAAGUCCAAGAUCAUU 3481
    R-008397495-000X 2948  802 CUGAAUAAAGUGUAACAAU B CUGAAUAAAGUGUAACAAUTT B 3482
    R-008397495-000X 2948  802 CUGAAUAAAGUGUAACAAU AUUGUUACACUUUAUUCAGUU 3483
    R-008397507-000T 2044  803 ACUAAAUACCAUUCCAUUG B ACUAAAUACCAUUCCAUUGTT B 3484
    R-008397507-000T 2044  803 ACUAAAUACCAUUCCAUUG CAAUGGAAUGGUAUUUAGUUU 3485
    R-008397510-000Z  621  804 AUCCCACUAAUGUCCAGCG CGCUGGACAUUAGUGGGAUUU 3487
    R-008397510-000Z  621  804 AUCCCACUAAUGUCCAGCG B AUCCCACUAAUGUCCAGCGTT B 3486
    R-008397513-000A  384  805 CCACUACCACAGCUCCUUC B CCACUACCACAGCUCCUUCTT B 3488
    R-008397513-000A  384  805 CCACUACCACAGCUCCUUC GAAGGAGCUGUGGUAGUGGUU 3489
    R-008397516-000B 1898  806 CAUCAGGAUACCCAGCGCC B CAUCAGGAUACCCAGCGCCTT B 3490
    R-008397516-000B 1898  806 CAUCAGGAUACCCAGCGCC GGCGCUGGGUAUCCUGAUGUU 3491
    R-008397519-000C 1795   15 UACUGUUGGAUUGAUUCGA UCGAAUCAAUCCAACAGUAUU 3493
    R-008397519-000C 1795   15 UACUGUUGGAUUGAUUCGA B UACUGUUGGAUUGAUUCGATT B 3492
    R-008397522-000J  653  807 UCACAGAUGCUGAAACAUG CAUGUUUCAGCAUCUGUGAUU 3495
    R-008397522-000J  653  807 UCACAGAUGCUGAAACAUG B UCACAGAUGCUGAAACAUGTT B 3494
    R-008397525-000K 1846  808 UUUGCGUGAGCAGGGUGCC GGCACCCUGCUCACGCAAAUU 3497
    R-008397525-000K 1846  808 UUUGCGUGAGCAGGGUGCC B UUUGCGUGAGCAGGGUGCCTT B 3496
    R-008397528-000L 2348  809 GCUGAUCUUGGACUUGAUA UAUCAAGUCCAAGAUCAGCUU 3499
    R-008397528-000L 2348  809 GCUGAUCUUGGACUUGAUA B GCUGAUCUUGGACUUGAUATT B 3498
    R-008397531-000T 1798   19 UGUUGGAUUGAUUCGAAAU AUUUCGAAUCAAUCCAACAUU 3501
    R-008397531-000T 1798   19 UGUUGGAUUGAUUCGAAAU B UGUUGGAUUGAUUCGAAAUTT B 3500
    R-008397534-000U 1150  810 GGCUAUUACGACAGACUGC B GGCUAUUACGACAGACUGCTT B 3502
    R-008397534-000U 1150  810 GGCUAUUACGACAGACUGC GCAGUCUGUCGUAAUAGCCUU 3503
    R-008397537-000V 1009  180 AGUGGAUUCUGUGUUGUUU AAACAACACAGAAUCCACUUU 3505
    R-008397537-000V 1009  180 AGUGGAUUCUGUGUUGUUU B AGUGGAUUCUGUGUUGUUUTT B 3504
    R-008397540-000B  654  178 CACAGAUGCUGAAACAUGC B CACAGAUGCUGAAACAUGCTT B 3506
    R-008397540-000B  654  178 CACAGAUGCUGAAACAUGC GCAUGUUUCAGCAUCUGUGUU 3507
    R-008397543-000C  298  811 GGACAUGGCCAUGGAACCA B GGACAUGGCCAUGGAACCATT B 3508
    R-008397543-000C  298  811 GGACAUGGCCAUGGAACCA UGGUUCCAUGGCCAUGUCCUU 3509
    R-008397546-000D 1568  812 AACAAGAUGAUGGUCUGCC B AACAAGAUGAUGGUCUGCCTT B 3510
    R-008397546-000D 1568  812 AACAAGAUGAUGGUCUGCC GGCAGACCAUCAUCUUGUUUU 3511
    R-008397549-000E 1058  813 UUACAUCAAGAAGGAGCUA B UUACAUCAAGAAGGAGCUATT B 3512
    R-008397549-000E 1058  813 UUACAUCAAGAAGGAGCUA UAGCUCCUUCUUGAUGUAAUU 3513
    R-008397552-000L 1835  814 AAUCAUGCACCUUUGCGUG B AAUCAUGCACCUUUGCGUGTT B 3514
    R-008397552-000L 1835  814 AAUCAUGCACCUUUGCGUG CACGCAAAGGUGCAUGAUUUU 3515
    R-008397555-000M 1832  815 GCAAAUCAUGCACCUUUGC B GCAAAUCAUGCACCUUUGCTT B 3516
    R-008397555-000M 1832  815 GCAAAUCAUGCACCUUUGC GCAAAGGUGCAUGAUUUGCUU 3517
    R-008397558-000N 2550   55 ACCUCAUGGAUGGGCUGCC GGCAGCCCAUCCAUGAGGUUU 3519
    R-008397558-000N 2550   55 ACCUCAUGGAUGGGCUGCC B ACCUCAUGGAUGGGCUGCCTT B 3518
    R-008397561-000V  406  816 GAGUGGUAAAGGCAAUCCU AGGAUUGCCUUUACCACUCUU 3521
    R-008397561-000V  406  816 GAGUGGUAAAGGCAAUCCU B GAGUGGUAAAGGCAAUCCUTT B 3520
    R-008397564-000W 1723  817 UCGCCUUCACUAUGGACUA B UCGCCUUCACUAUGGACUATT B 3522
    R-008397564-000W 1723  817 UCGCCUUCACUAUGGACUA UAGUCCAUAGUGAAGGCGAUU 3523
    R-008397567-000X  371  818 AUCCAUUCUGGUGCCACUA UAGUGGCACCAGAAUGGAUUU 3525
    R-008397567-000X  371  818 AUCCAUUCUGUUGCCACUA B AUCCAUUCUGGUGCCACUATT B 3524
    R-008397570-000D 1899  519 AUCAGGAUACCCAGCGCCG CGGCGCUGGGUAUCCUGAUUU 3527
    R-008397570-000D 1899  819 AUCAGGAUACCCAGCGCCG B AUCAGGAUACCCAGCGCCGTT B 3526
    R-008397573-000E  522  820 AGUAUGCAAUGACUCGAGC B AGUAUGCAAUGACUCGAGCTT B 3528
    R-008397573-000E  522  820 AGUAUGCAAUGACUCGAGC GCUCGAGUCAUUGCAUACUUU 3529
    R-008397576-000F 2285  821 CGGCUUUCAGUUGAGCUGA B CGGCUUUCAGUUGAGCUGATT B 3530
    R-008397576-000F 2285  821 CGGCUUUCAGUUGAGCUGA UCAGCUCAACUGAAAGCCGUU 3531
    R-008397579-000G  779  822 GCUGCAGUUAUGGUCCAUC GAUGGACCAUAACUGCAGCUU 3533
    R-008397579-000G  779  822 GCUGCAGUUAUGGUCCAUC B GCUGCAGUUAUGGUCCAUCTT B 3532
    R-008397582-000N 2896  823 AUUGAGUAAUGGUGUAGAA B AUUGAGUAAUGGUGUAGAATT B 3534
    R-008397582-000N 2896  823 AUUGAGUAAUGGUGUAGAA UUCUACACCAUUAGUCAAUUU 3535
    R-008397588-000R 2943  824 GUAAUCUGAAUAAAGUGUA UACACUUUAUUCAGAUUACUU 3537
    R-008397588-000R 2943  824 GUAAUCUGAAUAAAGUGUA B GUAAUCUGAAUAAAGUGUATT B 3536
    R-008397591-000X  513  825 UUGAUGGACAGUAUGCAAU B UUGAUGGACAGUAUGCAAUTT B 3538
    R-008397591-000X  513  825 UUGAUGGACAGUAUGCAAU AUUGCAUACUGUCCAUCAAUU 3539
    R-008397594-000Y 3084  826 GAUAUGUAUGGGUAGGGUA B GAUAUGUAUGGGUAGGGUATT B 3540
    R-008397594-000Y 3084  826 GAUAUGUAUGGGUAGGGUA UACCCUACCCAUACAUAUCUU 3541
    R-008397597-000Z 1567  827 GAACAAGAUGAUGGUCUGC B GAACAAGAUGAUGGUCUGCTT B 3542
    R-008397597-000Z 1567  827 GAACAAGAUGAUGGUCUGC GCAGACCAUCAUCUUGUUCUU 3543
    R-008397600-000S 2034  828 UUAUCAGAGGACUAAAUAC B UUAUCAGAGGACUAAAUACTT B 3544
    R-008397600-000S 2034  828 UUAUCAGAGGACUAAAUAC GUAUUUAGUCCUCUGAUAAUU 3545
    R-008397603-000T 1003  829 UUCACCAGUGGAUUCUGUG B UUCACCAGUGGAUUCUGUGTT B 3546
    R-008397603-000T 1003  829 UUCACCAGUGGAUUCUGUG CACAGAAUCCACUGGUGAAUU 3547
    R-008397606-000U 1980  830 AAGGUUGUACCGGAGCCCU AGGGCUCCGGUACAACCUUUU 3549
    R-008397606-000U 1980  830 AAGGUUGUACCGGAGCCCU B AAGGUUGUACCGGAGCCCUTT B 3548
    R-008397609-000V 1340  831 GUAGAAGCUGGUGGAAUGC GCAUUCCACCAGCUUCUACUU 3551
    R-008397609-000V 1340  831 GUAGAAGCUGGUGGAAUGC B GUAGAAGCUGGUGGAAUGCTT B 3550
    R-008397612-000B 1437  832 AUGCUGCAACUAAACAGGA B AUGCUGCAAGUAAACAGGATT B 3552
    R-008397612-000B 1437  832 AUGCUGCAACUAAACAGGA UCCUGUUUAGUUGCAGCAUUU 3553
    R-008397615-000C 2499  145 CUGGUGCUGACUAUCCAGU B CUGGUGCUGACUAUCCAGUTT B 3554
    R-008397615-000C 2499  145 CUGGUGCUGACUAUCCAGU ACUGGAUAGUCAGCACCAGUU 3555
    R-008397618-000D  785   64 GUUAUGGUCCAUCAGCUUU AAAGCUGAUGGACCAUAACUU 3557
    R-008397618-000D  785     64 GUUAUGGUCCAUCAGCUUU B GUUAUGGUCCAUCAGCUUUTT B 3556
    R-008397621-000K 2425  833 UCACUCUGGUGGAUAUGGC B UCACUCUGGUGGAUAUGGCTT B 3558
    R-008397621-000K 2425  833 UCACUCUGGUGGAUAUGGC GCCAUAUCCACCAGAGUGAUU 3559
    R-008397624-000L  282  834 CUGAUUUGAUGGAGUUGGA UCCAACUCCAUCAAAUCAGUU 3561
    R-008397624-000L  282  834 CUGAUUUGAUGGAGUUGGA B CUGAUUUGAUGGAGUUGGATT B 3560
    R-008397627-000M 1206  835 UCAUCAUACUGGCUAGUGG B UCAUCAUACUGGCUAGUGGTT B 3562
    R-008397627-000M 1206  835 UCAUCAUACUGGCUAGUGG CCACUAGCCAGUAUGAUGAUU 3563
    R-008397630-000U 1885  836 GCUUGUUCGUGCACAUCAG CUGAUGUGCACGAACAAGCUU 3565
    R-008397630-000U 1885  836 GCUUGUUCGUGCACAUCAG B GCUUGUUCGUGCACAUCAGTT B 3564
    R-008397633-000V 1314  837 UCUGCUCUAGUAAAUAGCC B UCUGCUCUAGUAAUAAGCCTT B 3566
    R-008397633-000V 1314  837 UCUGCUCUAGUAAAUAGCC GGCUUAUUACUAGAGCAGAUU 3567
    R-008397636-000W 2388  174 UUGGAUAUCGCCAGGAUGA B UUGGAUAUCGCCAGGAUGATT B 3568
    R-008397636-000W 2388  174 UUGGAUAUCGCCAGGAUGA UCAUCCUGGCGAUAUCCAAUU 3569
    R-008397639-000X 1308  838 UAUCUGUCUGCUCUAGUAA B UAUCUGUCUGCUCUAGUAUTT B 3570
    R-008397639-000X 1308  838 UAUCUGUCUGCUGUAGUAA UUACUAGAGCAGACAGAUAUU 3571
    R-008397642-000D 1200  839 GCAAGCUCAUCAUACUGGC GCCAGUAUGAUGAGCUUGCUU 3573
    R-008397642-000D 1200  839 GCAAGCUCAUCAUACUGGC B GCAAGCUCAUCAUACUGGCTT B 3572
    R-008397645-000E  543  840 AGAGGGUACGAGCUGCUAU B AGAGGGUACGAGCUGCUAUTT B 3574
    R-008397645-000E  543  840 AGAGGGUACGAGCUGCUAU AUAGCAGCUCGUACCCUCUUU 3575
    R-008397648-000F 1609  841 UGUGCGUACUGUCCUUCGG B UGUGCGUACUGUCCUUCGGTT B 3576
    R-008397648-000F 1609  841 UGUGCGUACUGUCCUUCGG CCGAAGGACAGUACGCACAUU 3577
    R-008397651-000M 1453  842 GGAAGGGAUGGAAGGUCUC B GGAAGGGAUGGAAGGUCUCTT B 3578
    R-008397651-000M 1453  842 GGAAGGGAUGGAAGGUCUC GAGACCUUCCAUCCCUUCCUU 3579
    R-008397654-000N 2127  138 AACUUGCUCAGGAGAAGGA B AACUUGCUCAGGACAAGGATT B 3580
    R-008397654-000N 2127  138 AACUUGCUCAGGACAAGGA UCCUUGUCCUGAGCAAGUUUU 3581
    R-008397657-000P  833  843 AUGCGUUCUCCUCAGAUGG B AUGCGUUCUCCUCAGAUGGTT B 3582
    R-008397657-000P  833  843 AUGCGUUCUCCUCAGAUGG CCAUCUGAGGAGAACGCAUUU 3583
    R-008397660-000W 2188  844 GACAGAGUUACUUCACUCU B GACAGAGUUACUUCACUCUTT B 3584
    R-008397660-000W 2188  844 GACAGAGUUACUUCACUCU AGAGUGAAGUAACUCUGUCUU 3585
    R-008397663-000X 1148  845 UUGGCUAUUACGACAGACU B UUGGCUAUUACGACAGACUTT B 3586
    R-008397663-000x 1148  845 UUGGCUAUUACGACAGACU AGUCUGUCGUAAUAGCCAAUU 3587
    R-008397666-000Y 1736  846 GGACUACCAGUUGUGGUUA B GGACUACCAGUUGUGGUUATT B 3588
    R-008397666-000Y 1736  846 GGACUACCAGUUGUGGUUA UAACCACAACUGGUAGUCCUU 3589
    R-008397669-000Z 1401  847 UUCAGAACUGUCUUUGGAC GUCCAAAGACAGUUCUGAAUU 3591
    R-008397669-000Z 1401  847 UUCAGAACUGUCUUUGGAC B UUCAGAACUGUCUUUGGACTT B 3590
    R-008397672-000F 1677  848 AUCUGACCAGCCGACACCA UGGUGUCGGCUGGUCAGAUUU 3593
    R-008397672-000F 1677  848 AUCUGACCAGCCGACACCA B AUCUGACCAGCCGACACCATT B 3592
    R-008397675-000G 1934  849 ACACAGCAGCAAUUUGUGG B ACACAGCAGCAAUUUGUGGTT B 3594
    R-008397675-000G 1934  849 ACACAGCAGCAAUUUGUGG CCACAAAUUGCUGCUGUGUUU 3595
    R-008397678-000H  388  850 UACCACAGCUCCUUCUCUG CAGAGAAGGAGCUGUGGUAUU 3597
    R-108397678-000H  388  850 UACCACAGCUCCUUCUCUG B UACCACACCUCCUUCUCUGTT B 3596
    R-008397681-000P 1920  851 CGUCCAUGGGUGGUACACA B CGUCCAUGGGUGGGACACATT B 3598
    R-008397681-000P 1920  851 CGUCCAUGGGUGGUACACA UGUGUCCCACCCAUGGACGUU 3599
    R-008397684-000R 1747  852 UGUGGUUAAGCUCUUACAC GUGUAAGAGCUUAACCACAUU 3601
    R-008397684-000R 1747  852 UGUGGUUAAGCUCUUACAC B UGUGGUUAAGCUCUUACACTT B 3600
    R-008397687-000S  861  853 UUGUACGUACCAUGCAGAA B UUGUACGUACCAUGCAGAATT B 3602
    R-008397687-000S  861  853 UUGUACGUACCAUGCAGAA UUCUGCNUGGUACGUACAAUU 3603
    R-008397690-000Y 1904  854 GAUACCCAGCGCCGUACGU B GAUACCCAGCGCCGUAUGUTT B 3604
    R-008397690-000Y 1904  854 GAUACCCAGCGCCGUACGU ACGUACGGCGCUGGGUAUCUU 3605
    R-008397693-000Z  831  855 UCAUGCGUUCUCCUCAGAU B UCAUGCGUUCUCCUCAGAUTT B 3606
    R-008397693-000Z  831  855 UCAUGCGUUCUCCUCAGAU AUCUGAGGAGAACGCAUGAUU 3607
    R-008397696-000A 1895  856 GCACAUCAGGAUACCCAGC GCUGGGUAUCCUGAUGUGCUU 3609
    R-008397696-000A 1895  856 GCACAUCAGGAUACCCAGC B GCACAUCAGGAUACCCAGCTT B 3608
    R-008397699-000B 2273  857 GAUUACAAGAAACGGCUUU AAAGCCGUUUCUUGUAAUCUU 3611
    R-008397699-000B 2273  857 GAUUACAAGAAACGGCUUU B GAUUACAAGAAACGGCUUUTT B 3610
    R-008397702-000U 1738  858 ACUACCAGUUGUGGUUAAG B ACUACCAGUUGUGGUUAAGTT B 3612
    R-008397702-000U 1738  858 ACUACCAGUUGUGGUUAAG CUUAACCACAACUGGUAGUUU 3613
    R-008397705-000V 1395  859 GUCUUGUUCAGAACUGUCU B GUCUUGUUCAGAACUGUCUTT B 3614
    R-008397705-000V 1395  859 GUCUUGUUCAGAACUGUCU AGACAGUUCUGAACAAGACUU 3615
    R-008397708-000W 1675  860 UCAUCUGACCAGCCGACAC B UCAUCUGACCAGCCGACACTT B 3616
    R-008397708-000W 1675  860 UCAUCUGACCAGCCGACAC GUGUCGGCUGGUCAGAUGAUU 3617
    R-008397711-000C 1895  861 CUCUCCGUGAGCAGGGUGC B CUUUGCGUGAGCAGGGUGCTT B 3618
    R-008397711-000C 1845  861 CUUUGCGUGAGCAGGGUGC GCACCCUGCUCACGCAAAGUU 3619
    R-008397714-000D 1408  862 CUGUCUUUGGACUCUCAGG CCUGAGAGUCCAAAGACAGUU 3621
    R-008397714-000D 1408  862 CUGUCUUUGGACUCUCAGG B CUGUCUUUGGACUCUCAGGTT B 3620
    R-008397717-000E 1059  863 UACAUCAAGAAGGAGCUAA B UACAUCAAGAAGGAGCUAATT B 3622
    R-008397717-000E 1059  863 UACAUCAAGAAGGAGCUAA UUAGCUCCUDCUUGAUGUAUU 3623
    R-008397720-000L 1381  864 AGAUCCAAGUCAACGUCUU AAGACGUUGACUUGGAUCUUU 3625
    R-008397720-000L 1381  864 AGAUCCAAGUCAACGUCUU B AGAUCCAAGUCAACGUCUUTT B 3624
    R-008397723-000M 1386  865 CAAGUCAACGUCUUGUUCA B CAAGUCAACGUCUUGUUCATT B 3626
    R-008397723-000M 1386  865 CAAGUCAACGUCUUGUUCA UGAACAAGACGUUGACUUGUU 3627
    R-008397726-000N 1470  866 UCCUUGGGACUCUUGUUCA UGAACAAGAGUCCCAAGGAUU 3629
    R-008397726-000N 1470  866 UCCUUGGGACUCUUGUUCA B UCCUUGGGACUCUUGUUCATT B 3628
    R-008397729-000P 1349  867 GGUGGAAUGCAAGCUUUAG CUAAAGCUUGCAUUCCACCUU 3631
    R-008397729-000P 1349  867 GGUGGAAUGCAAGCUUUAG B GGUGGAAUGCAAGCUUUAGTT B 3630
    R-008397732-000W 1440  868 CUGCAACUAAACAGGAAGG CCUUCCUGUUUAGUUGCAGUU 3633
    R-008397732-000W 1490  868 CUGCAACUAAACAGGAAGG B CUGCAACUAAACAGGAAGGTT B 3632
    R-008397735-000X 1364  869 UUAGGACUUCACCUGACAG CUGUCAGGUGNAGUCCUAAUU 3635
    R-008397735-000X 1364  869 UUAGGACUUCACCUGACAG B UUAGGACUUCACCUGACAGTT B 3634
    R-008397738-000Y  502  870 AGUAGCUGAUAUUGAUGGA B AGUAGCUGAUAUUGAUGGATT B 3636
    R-008397738-000Y  502  870 AGUAGCUGAUAUUGAUGGA UCCAUCAAUAUCAGCUACUUU 3637
    R-008397791-000E 1246  871 UAUAAUGAGGACCUAUACU AGUAUAGGUCCUCAUUAUAUU 3639
    R-008397741-000E 1246  871 UAUAAUGAGGACCUAUACU B UAUAAUGAGGACCUAUACUTT B 3638
    R-008397794-000F 3178  872 CCUGCUGUGAUACGAUGCU AGCAUCGUAUCACAGCAGGUU 3641
    R-008397744-000F 3178  872 CCUGCUGUGAUACGAUGCU B CCUGCUGUGAUACGAUGCUTT B 3640
    R-008397797-000G 2483  873 AUGGGUGGCCACCACCCUG B AUGGGUGGCCACCACCCUGTT B 3642
    R-008397747-000G 2483  873 AUGGGUGGCCACCACCCUG CAGGGUGGUGGCCACCCAUUU 3643
    R-008397750-000N 1417  874 GACUCUCAGGAAUCUUUCA B GACUCUCAGGAAUCUUUCATT B 3644
    R-008397750-000N 1417  874 GACUCUCAGGAAUCUUUCA UGAAAGAUUCCUGAGAGUCUU 3645
    R-008397753-000P 1893  875 GUGCACAUCAGGAUACCCA B GUGCACAUCAGGAUACCCATT B 3646
    R-008397753-000P 1893  875 GUGCACAUCAGGAUACCCA UGGGUAUCCUGAUGUGCACUU 3647
    R-008397756-000R  817  876 UUCCAGACACGCUAUCAUG CAUGAUAGCGUGUCUGGAAUU 3649
    R-008397756-000R  817  876 UUCCAGACACGCUAUCAUG B UUCCAGACACGCUAUCAUGTT B 3648
    R-008397759-000S  711  877 UUGCCACACGUGCAAUCCC GGGAUUGCACGUGUGGCAAUU 3651
    R-008397759-000S  711  877 UUGCCACACGUGCAAUCCC B UUGCCACACGUGCAAUCCCTT B 3650
    R-008397762-000Y 1433  878 UCAGAUGCUGCAACUAAAC GUUUAGUUGCAGCAUCUGAUU 3653
    R-008397762-000Y 1433  878 UCAGAUGCUGCAACUAAAC B UCAGAUGCUGCAACUAAACTT B 3652
    R-008397765-000Z 1362  879 CUUUAGGACUUCACCUGAC GUCAGGUGAAGUCCUAAAGUU 3655
    R-008397765-000Z 1362  879 CUUUAGGACUUCACCUGAC B CUUUAGGACUUCACCUGACTT B 3654
    R-008397768-000A 1838  880 CAUGCACCUUUGCGUGAGC B CAUGCACCUUUGCGUGAGCTT B 3656
    R-008397768-000A 1838  880 CAUGCACCUUUGCGUGAGC GCUCACGCAAAGGUGCAUGUU 3657
    R-008397771-000G 1037  881 ACAACUCUCCACAACCUUU AAAGGUUGUGGAGAGUUGUUU 3659
    R-008397771-000G 1037  881 ACAACUCUCCACAACCUUU B ACAACUCUCCACAACCUUUTT B 3658
    R-008397774-000H 1474  882 UGGGACUCUUGUUCAGCUU B UGGGACUCUUGUUCAGCUUTT B 3660
    R-008397774-000H 1474  882 UGGGACUCUUGUUCAGCUU AAGCUGAACAAGAGUCCCAUU 3661
    R-008397777-000J  997  883 GCUUGGUUCACCAGUGGAU B GCUUGGUUCACCAGUGGAUTT B 3662
    R-008397777-000J  997  883 GCUUGGUUCACCAGUGGAU AUCCACUGGUGAACCAAGCUU 3663
    R-008397780-000R  931  884 UUCCCAUCAUCGUGAGGGC B UUCCCAUCAUCGUGAGGGCTT B 3664
    R-008397780-000R  931  884 UUCCCAUCAUCGUGAGGGC GCCCUCACGAUGAUGGGAAUU 3665
    R-008397783-000S 1313  885 GUCUGCUCUAGUAAUAAGC GCUUAUUACUAGAGCAGACUU 3667
    R-008397783-000S 1313  885 GUCUGCUCUAGUAAUAAGC B GUCUGCUCUAGUAAUAAGCTT B 3666
    R-008397786-000T 1487  886 CAGCUUCUGGGUUCAGAUG B CAGCUCCUGGGUUCAGAUGTT B 3668
    R-008397786-000T 1487  886 CAGCUUCUGGGUUCAGAUG CAUCUGAACCCAGAAGCUGUU 3669
    R-008397789-000U 1673  887 CGUCAUCUGACCAGCCGAC B CGUCAUCUGACCAGCCGACTT B 3670
    R-008397789-000U 1673  887 CGUCAUCUGACCAGCCGAC GUCGGCUGGUCAGAUGACGUU 3671
    R-008397792-000A  561  888 UGUUCCCUGAGACAUUAGA UCUAAUGUCUCAGGGAACAUU 3673
    R-008397792-000A  561  888 UGUUCCCUGAGACAUUAGA B UGUUCCCUGAGACAUUAGATT B 3672
    R-008397795-000B 1188  889 GCAACCAAGAAAGCAAGCU B GCAACCAAGAAAGCAAGCUTT B 3674
    R-008397795-000B 1188  889 GCAACCAAGAAAGCAAGGU AGCUUGCUUUCUUGGUUGCUU 3675
    R-008397798-000C  292  890 GGAGUUGGACAUGGCCAUG B GGAGUUGGACAUGGCCAUGTT B 3676
    R-008397798-000C  292  890 GGAGUUGGACAUGGCCAUG CAUGGCCAUGUCCAACUCCUU 3677
    R-008397801-000V 1958  891 GUCCGCAUGGAAGAAAUAG B GUCCGCAUGGAAGAAAUAGTT B 3678
    R-008397801-000V 1958  891 GUCCGCAUGGAAGAAAUAG CUAUUUCUUCCAUGCGGACUU 3679
    R-008397804-000W 2349  892 CUGAUCUUGGACUUGAUAU B CUGAUCUUGGACUUGAUAUTT B 3680
    R-008397804-000W 2349  892 CUGAUCUUGGACUUGAUAU AUAUCAAGUCCAAGAUCAGUU 3681
    R-008397807-000X 1460  893 AUGGAAGGUCUCCUUGGGA UCCCAAGGAGACCUUCCAUUU 3683
    R-008397807-000X 1460  893 AUGGAAGGUCUCCUUGGGA B AUGGAAGGUCUCCUUGGGATT B 3682
    R-008397810-000D 1576  894 GAUGGUCUGCCAAGUGGGU B GAUGGUCUGCCAAGUGGGUTT B 3684
    R-008397810-000D 1576  894 GAUGGUCUGCCAAGUGGGU ACCCACUUGGCAGACCAUCUU 3685
    R-008397813-000E  536    4 CGAGCUCAGAGGGUACGAG B CGAGCUCAGAGGGUACGAGTT B 3686
    R-008397813-000E  536    4 CGAGCUCAGAGGGCACGAG CUCGUACCCUCUGAGCUCGUU 3687
    R-008397816-000F  690  895 ACUAUCAAGAUGAUGCAGA UCUGCAUCAUCUUGAUAGUUU 3689
    R-008397816-000F  690  895 ACUAUCAAGAUGAUGCAGA B ACUAUCAAGAUGAUGGAGATT B 3688
    R-008397819-000G  655  896 ACAGAUGCUGAAACAUGCA B ACAGAUGCUGAAACAUGCATT B 3690
    R-008397819-000G  655  896 ACAGAUGCUGAAACAUGCA UGCAUGUUUCAGCAUCUGUUU 3691
    R-008397822-000N 2290  897 UUCAGUUGAGCUGACCACC GCUGGUCAGCUCAACUGAAUU 3693
    R-008397822-000N 2290  897 UUCAGUUGAGCUGACCACC B UUCAGUUGAGCUGACCAGCTT B 3692
    R-008397825-000P 1600  898 AGAGGCUCUUGUGCGUACU B AGAGGCUCUUGUGCGUACUTT B 3694
    R-008397825-000P 1600  898 AGAGGCUCUUGUGCGUACU AGUACGCACAAGAGCCUCUUU 3695
    R-008397828-000R 2432  899 GGUGGADAUGGCCAGGAUG CAUCCUGGCCAUAUCCACCUU 3697
    R-008397828-000R 2432  899 GGUGGAUAUGGCCAGGAUG B GGUGGAUAUGGCCAGGAUGTT B 3696
    R-008397831-000X  710  900 CUUGCCACACGUGCAAUCC B CUUGCCACACGUGCAAUCCTT B 3698
    R-008397831-000X  710  900 CUUGCCACACGUGCAAUCC GGAUUGCACGUGUGGCAAGUU 3699
    R-008397834-000Y 1714  901 GAAUGCAGUUCGCCUUCAC B GAAUGCAGUUCGCCUUCACTT B 3700
    R-008397834-000Y 1714  901 GAAUGCAGUUCGCCUUCAC GUGAAGGCGAACUGCAUUCUU 3701
    R-008397837-000Z 2005  902 CCUAGCUCGGGAUGUUCAC B CCUAGCUCGGGAUGUUCACTT B 3702
    R-008397837-000Z 2005  902 CCUAGCUCGGGAUGUUCAC GUGAACAUCCCGAGCUAGGUU 3703
    R-008397840-000F 1728  903 UUCACUAUGGAGUACCAGU B UUCACUAUGGACUACCAGUTT B 3704
    R-008397840-000F 1728  903 UUCACUAUGGACUACCAGU ACUGGUAGUCCAUAGUGAAUU 3705
    R-008397843-000G 2482  904 GAUGGGUGGCCACCACCCU AGGGUGGUGGCCACCCAUCUU 3707
    R-008397843-000G 2482  904 GAUGGGUGGCCACCACCCU B GAUGGGUGGCCACCACCCUTT B 3706
    R-008397846-000H  768  905 UGGUUAAUAAGGCUGCAGU B UGGUUAAUAAGGCUGCAGUTT B 3708
    R-008397846-000H  768  905 UGGUUAAUAAGGCUGCAGU ACUGCAGCCUUAUUAACCAUU 3709
    R-008397849-000J  693  906 AUCAAGAUGAUGCAGAACU B AUCAAGAUGAUGCAGAACUTT B 3710
    R-008397849-000J  693  906 AUCAAGAUGAUGCAGAACU AGUUCUGCAUCAUCUUGAUUU 3711
    R-008397852-000R 3179  907 CUGCUGUGAUACGAUGCUU B CUGCUGUGAUACGAUGCUUTT B 3712
    R-008397852-000R 3179  907 CUGCUGUGAUACGAUGCUU AAGCAUCGUAUCACAGCAGUU 3713
    R-008397855-000S 1549   89 CACUUGCAAUAAUUAUAAG CUUAUAAUUAUUGCAAGUGUU 3715
    R-008397855-000S 1549   89 CACUUGCAAUAAUUAUAAG B CACUUGCAAUAAUUAUAAGTT B 3714
    R-008397858-000T 1792  167 GGCUACUGUUGGAUUGAUU AAUCAAUCCAACAGUAGCCUU 3717
    R-008397858-000T 1792  167 GGCUACUGUUGGAUUGAUU B GGCUACUGUUGGAUUGAUUTT B 3716
    R-008397861-000Z 2448  908 AUGCCUUGGGUAUGGACCC GGGUCCAUACCCAAGGCAUUU 3719
    R-008397861-000Z 2448  908 AUGCUUUGGGUAUGGACCC B AUGCCUUGGGUAUGGACCCTT B 3718
    R-008397864-000A 3183  909 UGUGAUACGAUGCUUCAAG B UGUGAUACGAUGCUUCAAGTT B 3720
    R-008397864-000A 3183  909 UGUGAUACGAUGCUUCAAG CUUCAAGCAUCGUAUCACAUU 3721
    R-008397867-000B 1293  910 GAGUGCUGAAGGUGCUAUC GAUAGCACCUUCAGCACUCUU 3723
    R-008397867-000B 1293  910 GAGUGCUGAAGGUGCUAUC B GAGUGCUGAAGGUGCUAUCTT B 3722
    R-008397870-000H  544  911 GAGGGUACGAGCUGCUAUG CAUAGCAGCUCGUACCCUCUU 3725
    R-008397870-000H  544  911 GAGGGUACGAGCUGCUAUG B GAGGGUACGAGCUGCUAUGTT B 3724
    R-008397873-000J 1676   26 CAUCUGACCAGCCGACACC GGUGUCGGCUGGUCAGAUGUU 3727
    R-008397873-000J 1676   26 CAUCUGACCAGCCGACACC B CAUCUGACCAGCCGACACCTT B 3726
    R-008397876-000K 2937  912 UUAAUUGUAAUCUGAAUAA B UUAAUUGUAAUCUGAAUAATT B 3728
    R-008397876-000K 2937  912 UUAAUUGUAAUCUGAAUAA UUAUUCAGAUUACAAUUAAUU 3729
    R-008397879-000L 1691  913 CACCAAGAAGCAGAGAUGG CCAUCUCUGCUUCUUGGUGUU 3731
    R-008397879-000L 1691  913 CACCAAGAAGCAGAGAUGG B CACCAAGAAGCAGAGAUGGTT B 3730
    R-008397882-000T 2195  120 UUACUUCACUCUAGGAAUG B UUACUUCACUCUAGGAAUGTT B 3732
    R-008397882-000T 2195  120 UUACUUCACUCUAGGAAUG CAUUCCUAGAGUGAAGUAAUU 3733
    R-008397885-000U 1356  186 UGCAAGCUUUAGGACUUCA B UGCAAGCUUUAGGACUUCATT B 3734
    R-008397885-000U 1356  186 UGCAAGCUUUAGGACUUCA UGAAGUCCUAAAGCUUGCAUU 3735
    R-008397888-000V  557  184 GCUAUGUUCCCUGAGACAU AUGUCUCAGGGAACAUAGCUU 3737
    R-008397888-000V  557  184 GCUAUGUUCCCUGAGACAU B GCUAUGUUCCCUGAGACAUTT B 3736
    R-008397897-000D 1353  914 GAAUGCAAGCUUUAGGACU AGUCCUAAAGCUUGCAUUCUU 3739
    R-008397897-000D 1353  914 GAAUGCAAGCUUUAGGACU B GAAUGCAAGCUUUAGGACUTT B 3738
    R-008397900-000W 1843  915 ACCUUUGCGUGAGCAGGGU B ACCUUUGCGUGAGCAGGGUTT B 3740
    R-008397900-000W 1843  915 ACCUUUGCGUGAGCAGGGU ACCCUGCUCACGCAAAGGUUU 3741
    R-008397903-000X 1302  916 AGGUGGUAUCUGUCUGCUC B AGGUGCUAUCUGUCUGCUCTT B 3742
    R-008397903-000X 1302  916 AGGUGGUAUCUGUCUGCUC GAGCAGACAGAUAGCACCUUU 3743
    R-008397906-000Y 2130  917 UUGCUCAGGACAAGGAAGC B UUGCUCAGGACAAGGAAGCTT B 3744
    R-008397906-000Y 2130  917 UUGCUCAGGACAAGGAAGC GCUUCCUUGUCCUGAGCAAUU 3745
    R-008397909-000Z 2165  918 GCUGAGUGAGCCACAGCUC B GCUGAGGGAGCCACAGCUCTT B 3746
    R-008397909-000Z 2165  918 GCUGAGGGAGCCACAGCUC GAGCUGUGGCUCCCUCAGCUU 3747
    R-008397912-000F  387  919 CUACCACAGCUCCUUCUCU B CUACCACAGCUCCUUCUCUTT B 3748
    R-008397912-000F  387  919 CUACCACAGCUCCUUCUCU AGAGAAGGAGCUGUGGUAGUU 3749
    R-008397915-000G 2472  920 UGGAACAUGAGAUGGGUGG CCACCCAUCUCAUGUUCCAUU 3751
    R-008397915-000G 2472  920 UGGAACAUGAGAUGGGUGG B UGGAACAUGAGAUGGGUGGTT B 3750
    R-008397918-000H  857  921 GCUAUUGUACGUACCAUGC B GCUAUUGUACGUACCAUGCTT B 3752
    R-008397918-000H  857  921 GCUAUUGUACGUACCAUGC GCAUGGUACGUACAAUAGCUU 3753
    R-008397921-000P 1816  922 UCUUGCCCUUUGUCCCGCA UGCGGGACAAAGGGCAAGAUU 3755
    R-008397921-000P 1816  922 UCUUGCCCUUUGUCCCGCA B UCUUGCCCUUUGUCCCGCATT B 3754
    R-008397924-000R 1561  923 UUAUAAGAACAAGAUGAUG CAUCAUCUUGUUCUUAUAAUU 3757
    R-008397924-000R 1561  923 UUAUAAGAACAAGAUGAUG B UUAUAAGAACAAGAUGAUGTT B 3756
    R-008397927-000S  811  924 GGAAGCUUCCAGAGACGCU B GGAAGCUUCCAGACACGCUTT B 3758
    R-008397927-000S  811  924 GGAAGCUUCCAGAGACGCU AGCGUGUCUGGAAGCUUCCUU 3759
    R-008397930-000Y 1327  925 UAAGCCGGCUAUUGUAGAA B UAAGCCGGCUAUUGUAGAATT B 3760
    R-008397930-000Y 1327  925 UAAGCCGGCUAUUGUAGAA UUCUACAAUAGCCGGCUUAUU 3761
    R-008397933-000Z  757  926 GGACCAGGUGGUGGUUAAU B GGACCAGGUGGUGGUUAAUTT B 3762
    R-008397933-000Z  757  926 GGACCAGGUGGUGGUUAAU AUUAACCACCACCUGGUCCUU 3763
    R-008397936-000A  507  927 CUGAUAUUGAUGGACAGUA B CUGAUAUUGAUGGACAGUATT B 3764
    R-008397936-000A  507  927 CUGAUAUUGAUGGACAGUA UACUGUCCAUCAAUAUCAGUU 3765
    R-008397939-000B 3092  928 UGGGUAGGGUAAAUCAGUA B UGGGUAGGGUAAAUCAGUATT B 3766
    R-008397939-000B 3092  928 UGGGUAGGGUAAAUCAGUA UACUGAUUUACCCUACCCAUU 3767
    R-008397942-000H 2359  929 ACUUGAUAUUGGUGCCCAG B ACUUGAUAUUGGUGCCCAGTT B 3768
    R-008397942-000H 2359  929 ACUUGAUAUUGGUGCCCAG CUGGGCACCAAUAUCAAGUUU 3769
    R-008397945-000J 1753  930 UAAGCUCUUACACCCACCA B UAAGCUCUUACACCCACCATT B 3770
    R-008397945-000J 1753  930 UAAGCUCUUACACCCACCA UGGUGGGUGUAAGAGCUUAUU 3771
    R-008397948-000K  273  931 CUACUCAAGCUGAUUUGAU AUCAAAUCAGCUUGAGUAGUU 3773
    R-008397948-000K  273  931 CUACUCAAGCUGAUUUGAU B CUACUCAAGCUGAUUUGAUTT B 3772
    R-008397951-000S 1859  932 GGUGCCAUUCCACGACUAG CUAGUCGUGGAAUGGCACCUU 3775
    R-008397951-000S 1859  932 GGUGCCAUUCCACGACUAG B GGUGCCAUUCCACGACUAGTT B 3774
    R-008397954-000T  296  933 UUGGACAUGGCCAUGGAAC B UUGGACAUGGCCAUGGAACTT B 3776
    R-008397954-000T  296  933 UUGGACAUGGCCAUGGAAC GUUCCAUGGCCAUGUCCAAUU 3777
    R-008397957-000U  615  934 CUGCUCAUCCCACUAAUGU ACAUUAGUGGGAUGAGCAGUU 3779
    R-008397957-000U  615  934 CUGCUCAUCCCACUAAUGU B CUGCUCAUCCCACUAAUGUTT B 3778
    R-008397960-000A  301  935 CAUGGCCAUGGAACCAGAC GUCUGGUUCCAUGGCCAUGUU 3781
    R-008397960-000A  301  935 CAUGGCCAUGGAACCAGAC B CAUGGCCAUGGAACCAGACTT B 3780
    R-008397963-000B 1184  936 UAUGGCAACCAAGAAAGCA B UAUGGCAACCAAGAAAGCATT B 3782
    R-008397963-000B 1184  936 UAUGGCAACCAAGAAAGCA UGCUUUCUUGGUUGCCAUAUU 3783
    R-008397966-000C 1006  937 ACCAGUGGAUUCUGUGUUG B ACCAGUGGAUUCUGUGUUGTT B 3784
    R-008397966-000C 1006  937 ACCAGUGGAUUCUGUGUUG CAACACAGAAUCCACUGGUUU 3785
    R-008397969-000D 2189  938 ACAGAGUUACUUCACUCUA B ACAGAGUUACUUCACUCUATT B 3786
    R-008397969-000D 2189  938 ACAGAGUUACUUCACUCUA UAGAGUGAAGUAACUCUGUUU 3787
    R-008397972-000K 1365  939 UAGGACUUCACCUGACAGA UCUGUCAGGUGAAGUCCUAUU 3789
    R-008397972-000K 1365  939 UAGGACUUCACCUGACAGA B UAGGACUUCACCUGACAGATT B 3788
    R-008397975-000L 2442  940 GCCAGGAUGCCUUGGGUAU B GCCAGGAUGCCUUGGGUAUTT B 3790
    R-008397975-000L 2442  940 GCCAGGAUGCCUUGGGUAU AUACCCAAGGCAUCCUGGCUU 3791
    R-008397978-000M 1249  941 AAUGAGGACCUAUACUUAC B AAUGAGGACCUAUACUUACTT B 3792
    R-008397978-000M 1249  941 AAUGAGGACCUAUACUUAC GUAAGUAUAGGUCCUCAUUUU 3793
    R-008397981-000U 1144  942 AUUCUUGGCUAUUACGACA B AUUCUUGGCUAUUACGACATT B 3794
    R-008397981-000U 1144  942 AUUCUUGGCUAUUACGACA UGUCGUAAUAGCCAAGAAUUU 3795
    R-008397984-000V 2075  943 CUUUAUUCUCCCAUUGAAA B CUUUAUUCUCCCAUUGAAATT B 3796
    R-008397984-000V 2075  943 CUUUAUUCUCCCAUUGAAA UUUCAAUGGGAGAAUAAAGUU 3797
    R-008397987-000W  759   94 ACCAGGUGGUGGUUAAUAA B ACCAGGUGGUGGUUAAUAATT B 3798
    R-008397987-000W  759   94 ACCAGGUGGUGGUUAAUAA UUAUUAACCACCACCUGGUUU 3799
    R-008397990-000C 1545   44 ACCUCACUUGCAAUAAUUA B ACCUCACUUGCAAUAAUUATT B 3800
    R-008397990-000C 1545   44 ACCUCACUUGCAAUAAUUA UAAUUAUUGCAAGUGAGGUUU 3801
    R-008397993-000D  504  944 UAGCUGAUAUUGAUGGACA UGUCCAUCAAUAUCAGCUAUU 3803
    R-008397993-000D  504  944 UAGCUGAUAUUGAUGGACA B UAGCUGAUAUUGAUGGACATT B 3802
    R-008397996-000E 1405  945 GAACUGUCULUGGACUCUC B GAACUGUCUUUGGACUCUCTT B 3804
    R-008397996-000E 1405  945 GAACUGUCUUUGGACUCUC GAGAGUCCAAAGACAGUUCUU 3805
    R-008397999-000F  333  946 UUAGUCACUGGCAGCAAGA UGUUGCUGCCAGUGACUAAUU 3807
    R-008397999-000F  333  946 UUAGUCACUGGCAGCAAGA B UUAGUCACUGGCAGCAACATT B 3806
    R-008398002-000V 1032  947 CCAUUACAACUCUCCACAA B CCAUUACAACUCUCCACAATT B 3808
    R-008398002-000V 1032  947 CCAUUACAACUCUCCACAA UUGUGGAGAGUUGUAAUGGUU 3809
    R-008398005-000W 1748  948 GUGGUUAAGCUCUUACACC B GUGGUUAAGCUCUUACACCTT B 3810
    R-008398005-000W 1748  948 GUGGUUAAGCUCUUACACC GGUGUAAGAGCUUAACCACUU 3811
    R-008398008-000X  283  949 UGAUUUGAUGGAGUUGGAC GUCCAACUCCAUCAAAUCAUU 3813
    R-008398008-000X  283  949 UGAUUUGAUGGAGUUGGAC B UGAUUGAUUGGAGUUGGACTT B 3812
    R-008398011-000D 1700  950 GCAGAGAUGGCCCAGAAUG B GCAGAGAUGGCCCAGAAUGTT B 3814
    R-008398011-000D 1700  950 GCAGAGAUGGCCCAGAAUG CAUUCUGGGCCAUGUCUGCUU 3815
    R-008398014-000E 1445  951 ACUAAACAGGAAGGGAUGG B ACUAAACAGGAAGGGAUGGTT B 3816
    R-008398014-000E 1445  951 ACUAAACAGGAAGGGAUGG CCAUCCCUUCCUGUUUAGUUU 3817
    R-008398017-000F 1133  952 ACAAAUGUUAAAUUCUUGG CCAAGAAUUUAACAUUUGUUU 3819
    R-008398017-000F 1133  952 ACAAAUGUUAAAUUCUUGG B ACAAAUGUUAAAUUCUUGGTT B 3818
    R-008398020-000M  527  953 GCAAUGACUCGAGCUCAGA UCUGAGCUCGAGUCAUUGCUU 3821
    R-008398020-000M  527  953 GCAAUGACUCGAGCUCAGA B GCAAUGACUCGAGCUCAGATT B 3820
    R-008398023-000N 2010  954 CUCGGGAUGUUCACAACCG CGGUUGUGAACAUCCCGAGUU 3823
    R-008398023-000N 2010  954 CUCGGGAUGUUCACAACCG B CUCGGGAUGUUCACAACCGTT B 3822
    R-008398026-000P  851  955 GUGUCUGCUAUUGUACGUA UACGUACAAUAGCAGACACUU 3825
    R-008398026-000P  851  955 GUGUCUGCUAUUGUACGUA B GUGUCUGCUAUUGUACGUATT B 3824
    R-008398029-000R  436  956 UGUGGAUACCUCCCAAGUC B UGUGGAUACCUCCCAAGUCTT B 3826
    R-008398029-000R  436  956 UGUGGAUACCUCCCAAGUC GACUUGGGAGGUAUCCACAUU 3827
    R-008398032-000X 1601    2 GAGGCUCUUGUGCGUACUG B GAGGCUCUUGUGCGUACUGTT B 3828
    R-008398032-000X 1601    2 GAGGCUCUUGUGCGUACUG CAGUACGCACAAGAGCCUCUU 3829
    R-008398035-000Y 2446  957 GGAUGCCUUGGGUAUGGAC B GGAUGCCUUGGGUAUGGACTT B 3830
    R-008398035-000Y 2446  957 GGAUGCCUUGGGUAUGGAC GUCCAUACCCAAGGCAUCCUU 3831
    R-008398038-000Z 1142  958 AAAUUCUUGGCUAUUACGA B AAAUUCUUGGCUAUUACGATT B 3832
    R-008398038-000Z 1142  958 AAAUUCUUGGCUAUUACGA UCGUAAUAGCCAAGAAUUUUU 3833
    R-008398041-000F  599  959 UACGAGCUGCUAUGUUCCC B UACGAGCUGCUAUGUUCCCTT B 3834
    R-008398091-000F  549  959 UACGAGCUGCUAUGUUCCC GGGAACAUAGCAGCUCGUAUU 3835
    R-008398044-000G 1083  960 CAGUGCGUUUAGCUGGUGG CCACCAGCUAAACGGACUGUU 3837
    R-008398044-000G 1083  960 CAGUGCGUUUAGCUGGUGG B CAGUGCGUUUAGCUGGUGGTT B 3836
    R-008398047-000H  695  961 CAAGAUGAUGCAGAACUUG CAAGUUCUGCAUCAUCUUGUU 3839
    R-008398047-000H  695  961 CAAGAUGAUGCAGAACUUG B CAAGAUGAUGCAGAACUUGTT B 3838
    R-008398050-000P  885  962 AUGAUGUAGAAACAGCUCG B AUGAUGUAGAAACAGCUCGTT B 3840
    R-008398050-000P  885  962 AUGAUGUAGAAACAGCUCG CGAGCUGUUUCUACAUCAUUU 3841
    R-008398056-000S 2067  963 UGCAGCUGCUUUAUUCUCC B UUCAGCUGCUUUAUUCUCCTT B 3842
    R-008398056-000S 2067  963 UGCAGCUGCUUUAUUCUCC GGAGAAUAAAGCAGCUGCAUU 3843
    R-008398059-000T  390  964 CCACAGCUCCUUCUCUGAG CUCAGAGAAGGAGCUGUGGUU 3845
    R-008398059-000T  390  964 CCACAGCUCCUUCUCUGAG B CCACAGCUCCUUCUCUGAGTT B 3844
    R-008398062-000Z 1719  965 CAGUUCGCCUUCACUAUGG B CAGUUCGCCUUCACUAUGGTT B 3846
    R-008398062-000Z 1719  965 CAUUUCGCCUUCACUAUGG CCAUAGUGAAGGCGAACUGUU 3847
    R-008398065-000A  813  966 AAGCUUCCAGACACGCUAU AUAGCGUGUCUGGAAGCUUUU 3849
    R-008398065-000A  813  966 AAGCUUCCAGACACGCUAU B AAGCUUCCAGACACGCUAUTT B 3848
    R-008398068-000B 2289  967 UUUCAGUUGAGCUGACCAG B UUUCAGUUGAGCUGACCAGTT B 3850
    R-008398068-000B 2289  967 UUUCAGUUGAGCUGACCAG CUGGUCAGCUCAACUGAAAUU 3851
    R-008398071-000H  377  968 UCUGGUGCCACUACCACAG B UCUGGUGCCACUACCACAGTT B 3852
    R-008398071-000H  377  968 UCUGGUGCCACUACCACAG CUGUGGUAGUGGCACCAGAUU 3853
    R-008398074-000J  826  969 CGCUAUCAUGCGUUCUCCU AGGAGAACGCAUGAUAGCGUU 3855
    R-008398074-000J  826  969 CGCUAUCAUGCGUUCUCCU B CGCUAUCAUGCUTUCUCCUTT B 3854
    R-008398077-000K 1634  970 GACAGGGAAGACAUCACUG CAGUGAUGUCUUCCCUGUCUU 3857
    R-008398077-000K 1634  970 GACAGGGAAGACAUCACUG B GACAGGGAAGACAUCACUGTT B 3856
    R-008398080-000S 1208  971 AUCAUACUGGCUAGUGGUG B AUCAUACUGGCUAGUGGUGTT B 3858
    R-008398080-000S 1208  971 AUCAUACUGGCUAGUGGUG CACCACUAGCCAGUAUGAUUU 3859
    R-008398083-000T 1628  972 GCUGGUGACAGGGAAGACA UGUCUUCCCUGUCACCAGCUU 3861
    R-008398083-000U 1628  972 GCUGGUGACAGGGAAGACA B GCUGGUGACAGGGAAGACATT B 3860
    R-008398086-000U 2003  973 AUCCUAGCUCGGGAUGUUC GAACAUCCCGAGCUAGGAUUU 3863
    R-008398086-000U 2003  973 AUCCUAGCUCGGGAUGUUC B AUCCUAGCUCUGGAUGUUCTT B 3862
    R-008398089-000V  452  974 GUCCUGUAUGAGUGGGAAC B GUCCUGUAUGAGUGGGAACTT B 3864
    R-008398089-000V  452  974 GUCCUGUAUGAGUGGGAAC GUUCCCACUCAUACAGGACUU 3865
    R-008398092-000B 2543  175 GCCCAGGACCUCAUGGAUG CAUCCAUGAGGUCCUGGGCUU 3867
    R-008398092-000B 2543  175 GCCCAGGACCUCAUGGAUG B GCCCAGGACCUCAUGGAUGTT B 3866
    R-008398095-000C 3081  975 UGGGAUAUGUAUGGGUAGG CCUACCCAUACAUAUCCCAUU 3869
    R-008398095-000C 3081  975 UGGGAUAUGUAUGGGUAGG B UGGGAUAUGUAUGGGUAGGTT B 3868
    R-008398098-000D 2354  976 CUUGGACUUGAUAUUGGUG B CUUGGACUUGAUAUUGGUGTT B 3870
    R-008398098-000D 2354  976 CUUGGACUUGAUAUUGGUG CACCAAUAUCAAGUCCAAGUU 3871
    R-008398101-000W 1822  977 CCUUUGUCCCGCAAAUCAU B CCUUUGUCCCGCAAAUCAUTT B 3872
    R-008398101-000W 1822  977 CCUUUGUCCCGCAAAUCAU AUGAUUUGCGGGACAAAGGUU 3873
    R-008398107-000Y 1299  978 UGAAGGUGCUAUCUGUCUG CAGACAGAUAGCACCUUCAUU 3875
    R-008398107-000Y 1299  978 UGAAGGUGCUAUCUGUCUG B UGAAGGUGCUAUCUGUCUGTT B 3874
    R-008398110-000E  486  979 CCUUCACUCAAGAACAAGU B CCUUCACUCAAGAACAAGUTT B 3876
    R-008398110-000E  486  979 CCUUCACUCAAGAACAAGU ACUUGUUCUUGAGUGAAGGUU 3877
    R-008398116-000G 1463  980 GAAGGUCUCCUUGGGACUC B GAAGGLCUCCUUGGGACUCTT B 3878
    R-008398116-000G 1463  980 GAAGGUCUCCUUGGGACUC GAGUCCCAAGGAGACCUUCUU 3879
    R-008398119-000H 2280  981 AGAAACGGCUUUCAGUUGA B AGAAACGGCUUUCAGUUGATT B 3880
    R-008398119-000H 2280  981 AGAAACGGCUUUCAGUUGA UCAACUGAAAGCCGUUUCUUU 3881
    R-008398122-000P 1907  982 ACCCAGCGCCGUACGUCCA B ACCCAGCGCCGUACGUCCATT B 3882
    R-008398122-000P 1907  982 ACCCAGCGCCGUACGUCCA UGGACGUACGGCGCUGGGUUU 3883
    R-008398125-000R  923  983 CAUAACCUUUCCCAUCAUC B CAUAACCUUUCCCAUCAUCTT B 3884
    R-008398125-000R  923  983 CAUAACCUUUCCCAUCAUC GAUGAUGGGAAAGGUUAUGUU 3885
    R-008398128-000S 1979  984 GAAGGUUGUACCGGAGCCC B GAAGGUUGUACCGGAGCCCTT B 3886
    R-008398128-000S 1979  984 GAAGGUUGUACCGGAGCCC GGGCUCCGGUACAACCUUCUU 3887
    R-008398131-000Y 1827  985 GUCCCGCAAAUCAUGCACC B GUCCCGCAAAUCAUGCACCTT B 3888
    R-008398131-000Y 1827  985 GUCCCGCAAAUCAUGCACC GGUGCAUGAUUUGCGGGACUU 3889
    R-008398134-000Z 1201  986 CAAGCUCAUCAUACUGGCU AGCCAGUAUGAUGAGCUUGUU 3891
    R-008398134-000Z 1201  986 CAAGCUCAUCAUACUGGCU B CAAGCUCAUCAUACUGGCUTT B 3890
    R-008398137-000A 1913  987 CGCCGUACGUCCAUGGGUG B CGCCGUACGUCCAUGGGUGTT B 3892
    R-008398137-000A 1913  987 CGCCGUACGUCCAUGGGUG CACCCAUGGACGUACGGCGUU 3893
    R-008398140-000G 2191  988 AGAGUUACUUCACUCUAGG CCUAGAGUGAAGUAACUCUUU 3895
    R-008398140-000G 2191  988 AGAGUUACUUCACUCUAGG B AGAGUUACUUCACUCUAGGTT B 3894
    R-008398143-000H  295  989 GUUGGACAUGGCCAUGGAA UUCCAUGGCCAUGUCCAACUU 3897
    R-008398143-000H  295  989 GUUGGACAUGGCCAUGGAA B GUUGGACAUGGCCAUGGAATT B 3896
    R-008398146-000J 1149  990 UGGCUAUUACGACAGACUG B UGGCUAUUACGACAGACUGTT B 3898
    R-008398146-000J 1149  990 UGGCUAUUACGACAGACUG CAGUCUGUCGUAAUAGCCAUU 3899
    R-008398149-000K  533  991 ACUCGAGCUCAGAGGGUAC B ACUCGAGCUCAGAGGGUACTT B 3900
    R-008398149-000K  533  991 ACUCGAGCUCAGAGGGUAC GUACCCUCUGAGCUCGAGUUU 3901
    R-008398152-000S  604  992 ACAGUUUGAUGCUGCUCAU B ACAGUUUGAUGCUGCUCAUTT B 3902
    R-008398152-000S  604  992 ACAGUUUGAUGCUGCUCAU AUGAGCAGCAUCAAACUGUUU 3903
    R-008398155-000T  766  993 GGUGGUUAAUAAGGCUGCA B GGUGGUUAAUAAGGCUGCATT B 3904
    R-008398155-000T  766  993 GGUGGUUAAUAAGGCUGCA UGCAGCCUUAUUAACCACCUU 3905
    R-008398158-000U 1823  994 CUUUGUCCCGCAAAUCAUG B CUUUGUCCCGCAAAUCAUGTT B 3906
    R-008398158-000U 1823  994 CUUUGUCCCGCAAAUCAUG CAUGAUUUGCGGGACAAAGUU 3907
    R-008398161-000A 2048  995 AAUACCAUUCCAUUGUUUG CAAACAAUGGAAUGGUAUUUU 3909
    R-008398161-000A 2048  995 AAUACCAUUCCAUUGUUUG B AAUACCAUUCCAUUGUUUGTT B 3908
    R-008398164-000B  714  996 CCACACGUGCAAUCCCUGA B CCACACGUGCAAUCCCUGATT B 3910
    R-008398164-000B  714  996 CCACACGUGCAAUCCCUGA UCAGGGAUUGCACGUGUGGUU 3911
    R-008398167-000C 2439  997 AUGGCCAGGAUGCCUUGGG CCCAAGGCAUCCUGGCCAUUU 3913
    R-008398167-000C 2439  997 AUGGCCAGGAUGCCUUGGG B AUGGCCAGGAUGCCUUGGGTT B 3912
    R-008398170-000J 1903  998 GGAUACCCAGCGCCGUACG B GGAUACCCAGCGCCGUACGTT B 3914
    R-008398170-000J 1903  998 GGAUACCCAGCGCCGUACG CGUACGGCGCUGGGUAUCCUU 3915
    R-008398173-000K 2395  999 UCGCCAGGAUGAUCCUAGC GCUAGGAUCAUCCUGGCGAUU 3917
    R-008398173-000K 2395  999 UCGCCAGGAUGAUCCUAGC B UCGCCAGGAUGAUCCUAGCTT B 3916
    R-008398176-000L  789 1000 UGGUCCAUCAGCUUUCUAA UUAGAAAGCUGAUGGACCAUU 3919
    R-008398176-000L  789 1000 UGGUCCAUCAGCUUUCUAA B UGGUCCAUCAGUTUUCUAATT B 3918
    R-008398179-000M 3085 1001 AUAUGUAUGGGUAGGGUAA UUACCCUACCCAUACAUAUUU 3921
    R-008398179-000M 3085 1001 AUAUGUAUGGGUAGGGUAA B AUAUGUAUGGGUAGGGUAATT B 3920
    R-008398182-000U 1710 1002 CCCAGAAUGCAGUUCGCCU B CCCAGAAUGCAGUUCGCCUTT B 3922
    R-008398182-000U 1710 1002 CCCAGAAUGCAGUUCGCCU AGGCGAACUGCAUUCUGGGUU 3923
    R-008398185-000V 1336 1003 UAUUGUAGAAGCUGGUGGA B UAUUGUAGAAGCUGGUGGATT B 3924
    R-008398185-000V 1336 1003 UAUUGUAGAAGCUGGUGGA UCCACCAGCUUCUACAAUAUU 3925
    R-008398188-000W 3089 1004 GUAUGGGUAGGGUAAAUCA UGAUUUACCCUACCCAUACUU 3927
    R-008398188-000W 3089 1004 GUAUGGGUAGGGUAAAUCA B GUAUGGGUAGGGUAAAUCATT B 3926
    R-008398191-000C 2351 1005 GAUCUUGGACUUGAUAUUG B GAUCUUGGACUUGAUAUUGTT B 3928
    R-008398191-000C 2351 1005 GAUCUUGGACUUGAUAUUG CAAUAUCAAGUCCAAGAUCUU 3929
    R-008398194-000D  716 1006 ACACGUGCAAUCCCUGAAC B ACACGUGCAAUCCCUGAACTT B 3930
    R-008398194-000D  716 1006 ACACGUGCAAUCCCUGAAC GUUCAGGGAUUGCACGUGUUU 3931
    R-008398197-000E 1911 1007 AGCGCCGUACGUCCAUGGG B AGCGCCGUACGUCCAUGGGTT B 3932
    R-008398197-000E 1911 1007 AGCGCCGUACGUCCAUGGG CCCAUGGACGUACGGCGCUUU 3933
    R-008398200-000X 1985 1008 UGUACCGGAGCCCUUCACA UGUGAAGGGCUCCGGUACAUU 3935
    R-008398200-000X 1985 1008 UGUACCGGAGCCCUUCACA B UGUACCGGAGCCCUUCACATT B 3934
    R-008398203-000Y 2516 1009 GUUGAUGGGCUGCCAGAUC B GUUGAUGGGCUGCCAGAUCTT B 3936
    R-008398203-000Y 2516 1009 GUUGAUGGGCUGCCAGAUC GAUCUGGCAGCCCAUCAACUU 3937
    R-008398206-000Z 1762 1010 ACACCCACCAUCCCACUGG CCAGUGGGAUGGUGGGUGUUU 3939
    R-008398206-000A 1762 1010 ACACCCACCAUCCCACUGG B ACACCCACCAUCCCACUGGTT B 3938
    R-008398209-000A 1156 1011 UACGACAGACUGCCUUCAA B UACGACAGACUGCCUUCAATT B 3940
    R-008398209-000A 1156 1011 UACGACAGACUGCCUUCAA UUGAAGGCAGUCUGUCGUAUU 3941
    R-008398212-000G 1887 1012 UUGUUCGUGCACAUCAGGA B UUGUUCGUGCACAUCAGGATT B 3942
    R-008398212-000G 1887 1012 UUGUUCGUGCACAUCAGGA UCCUGAUGUGCACGAACAAUU 3943
    R-008398215-000H 1833 1013 CAAAUCAUGCACCUUUGCG CGCAAAGGUGCAUGAUUUGUU 3945
    R-008398215-000H 1833 1013 CAAAUCAUGCACCUUUGCG B CAAAUCAUGCACCUUUGCGTT B 3944
    R-008398218-000J  967 1014 GUCUGGAGGCAUUCCUGCC GGCAGGAAUGCCUCCAGACUU 3947
    R-008398218-000J  967 1014 GUCUGGAGGCAUUCCUGCC B GUCUGGAGGCAUUCCUGCCTT B 3946
    R-008398221-000R 1730 1015 CACUAUGGACUACCAGUUG CAACUGGUAGUCCAUAGUGUU 3949
    R-008398221-000R 1730 1015 CACUAUGGACUACCAGUUG B CACUAUGGACUACCAGUUGTT B 3948
    R-008398224-000S  829 1016 UAUCAUGCGUUCUCCUCAG CUGAGGAGAACGCAUGAUAUU 3951
    R-008398224-000S  829 1016 UAUCAUGCGUUCUCCUCAG B UAUCAUGCGUUGUCCUCAGTT B 3950
    R-008398227-000T  890 1017 GUAGAAACAGCUCGUUGUA B GUAGAAACAGCUCGUUGUATT B 3952
    R-008398227-000T  890 1017 GUAGAAACAGCUCGUUGUA UACAACGAGCUGUUUCUACUU 3953
    R-008398230-000Z 2181 1018 CUCCUCUGACAGAGUUACU AGUAACUCUGUCAGAGGAGUU 3955
    R-008398230-000Z 2181 1018 CUCCUCUGACAGAGUUACU B CUCCUCUGACAGAGUUACUTT B 3954
    R-008398233-000A 2131 1019 UGCUCAGGACAAGGAAGCU B UGCUCAGGACAAGGAAGCUTT B 3956
    R-008398233 000A 2131 1019 UGCUCAGGACAAGGAAGCU AGCUUCCUUGUCCUGAGCAUU 3957
    R-008398236-000B 1586 1020 CAAGUGGGUGGUAUAGAGG B CAAGUGGGUGGUAUAGAGGTT B 3958
    R-008398236-000B 1586 1020 CAAGUGGGUGGUAUAGAGG CCUCUAUACCACCCACUUGUU 3959
    R-008398239-000C  765 1021 UGGUGGUUAAUAAGGCUGC B UGGUGGUUAAUAAGGCUGCTT B 3960
    R-008398239-000C  765 1021 UGGUGGUUAAUAAGGCUGC GCAGCCUUAUUAACCACCAUU 3961
    R-008398242-000J 1369 1022 ACUUCACCUGACAGAUCCA B ACUUCACCUGACAGAUCCATT B 3962
    R-008398242-000J 1369 1022 ACUUCACCUGACAGAUCCA UGGAUCUGUCAGGUGAAGUUU 3963
    R-008398245-000K 1724 1023 CGCCUUCACUAUGGACUAC GUAGUCCAUAGUGAAGGCGUU 3965
    R-008398245-000K 1724 1023 CGCCUUCACUAUGGACUAC B CGCCUUCACUAUGGACUACTT B 3964
    R-008398248-000L  834 1024 UGCGUUCUCCUCAGAUGGU ACCAUCUGAGGAGAACGCAUU 3967
    R-008398248-000L  834 1024 UGCGUUCUCCUCAGAUGGU B UGCGUUCUCCUCAGAUGGUTT B 3966
    R-008398251-000T 1983 1025 GUUGUACCGGAGCCCUUCA B GUUGUACCGGAGCCCUUCATT B 3968
    R-008398251-000T 1983 1025 GUUGUACCGGAGCCCUUCA UGAAGGGCUCCGGUACAACUU 3969
    R-008398254-000U 1688 1026 CGACACCAAGAAGCAGAGA B CGACACCAAGAAGCAGAGATT B 3970
    R-008398254-000U 1688 1026 CGACACCAAGAAGCAGAGA UCUCUGCUUCUUGGUGUCGUU 3971
    R-008398257-000V 1004 1027 UCACCAGUGGAUUCUGUGU B UCACCAGUGGAUUCUGUGUTT B 3972
    R-008398257-000V 1004 1027 UCACCAGUGGAUUCUGUGU ACACAGAAUCCACUGGUGAUU 3973
    R-008398260-000B 1631 1028 GGUGACAGGGAAGACAUCA UGAUGUCUUCCCUGUCACCUU 3975
    R-008398260-000B 1631 1028 GGUGACAGGGAAGACAUCA B GGUGACAGGGAAGACAUCATT B 3974
    R-008398263-000C 1319 1029 UCUAGUAAUAAGCCGGCUA UAGCCGGCUUAUUACUAGAUU 3977
    R-008398263-000C 1319 1029 UCUAGUAAUAAGCCGGCUA B UCUAGUAAUAAGCCGGCUATT B 3976
    R-008398266-000D  767 1030 GUGGUUAAUAAGGCUGCAG B GUGGUUAAUAAGGCUGCAGTT B 3978
    R-008398266-000D  767 1030 GUGGUUAAUAAGGCUGCAG CUGCAGCCUUAUUAACCACUU 3979
    R-008398269-000E  841 1031 UCCUCAGAUGGUGUCUGCU AGCAGACACCAUCUGAGGAUU 3981
    R-008398269-000E  841 1031 UCCUCAGAUGGUGUCUGCU B UCCUCAGAUGGUGUCUGCUTT B 3980
    R-008398272-000L  516 1032 AUGGACAGUAUGCAAUGAC B AUGGACAGUAUGCAAUGACTT B 3982
    R-008398272-000L  516 1032 AUGGACAGUAUGCAAUGAC GUCAUUGCAUACUGUCCAUUU 3983
    R-008398275-000M 1848 1033 UGCGUGAGCAGGGUGCCAU AUGGCACCCUGCUCACGCAUU 3985
    R-008398275-000M 1848 1033 UGCGUGAGCAGGGUGCCAU B UGCGUGAGCAGGGUGCCAUTT B 3984
    R-008398278-000N 2202 1034 ACUCUAGGAAUGAAGGUGU B ACUCUAGGAAUGAAGGUGUTT B 3986
    R-008398278-000N 2202 1034 ACUCUAGGAAUGAAGGUGU ACACCUUCAUUCCUAGAGUUU 3987
    R-008398281-000V  571 1035 GACAUUAGAUGAGGGCAUG B GACAUUAGAUGAGGGCAUGTT B 3988
    R-008398281-000V  571 1035 GACAUUAGAUGAGGGCAUG CAUGCCCUCAUCUAAUGUCUU 3989
    R-008394284-000W 1629 1036 CUGGUGACAGGGAAGACAU B CUGGUGACAGGGAAGACAUTT B 3990
    R-008398284-000W 1629 1036 CUGGUGACAGGGAAGACAU AUGUCUUCCCUGUCACCAGUU 3991
    R-008398287-000x 1806 1037 UGAUUCGAAAUCUUGCCCU B UGAUUCGAAAUCUUGCCCUTT B 3992
    R-008398287-000X 1806 1037 UGAUUCGAAAUCUUGCCCU AGGGCAAGAUUUCGAAUCAUU 3993
    R-008398290-000D 1756 1038 GCUCUUACACCCACCAUCC B GCUCUUACACCCACCAUCCTT B 3994
    R-008398290-000D 1756 1038 GCUCUUACACCCACCAUCC GGAUGGUGGGUGUAAGAGCUU 3995
    R-008398293-000E 1619 1039 GUCCUUCGGGCUGGUGACA UGUCACCAGCCCGAAGGACUU 3997
    R-008398293-000E 1619 1039 GUCCUUCGGGCUGGUGACA B GUCCUUCGGGCUGGUGACATT B 3996
    R-008398296-000F 1610 1040 GUGCGUACUGUCCUUCGGG B GUGCGUACUGUCCUUCGGGTT B 3998
    R-008398296-000F 1610 1040 GUGCGUACUGUCCUUCGGG CCCGAAGGACAGUACGCACUU 3999
    R-008398299-000G 2500 1041 UGGUGCUGACUAUCCAGUU B UGGUGCUGACUAUCCAGUUTT B 4000
    R-008398299-000G 2500 1041 UGGUGCUGACUAUCCAGUU AACUGGAUAGUCAGCACCAUU 4001
    R-008398302-000Z 2156 1042 GCUAUUGAAGGUGAGGGAG B GCUAUUGAAGCUGAGGGAGTT B 4002
    R-008398302-000Z 2156 1042 GCUAUUGAAGCUGAGGGAG CUUCCUCAGCUUCAAUAGCUU 4003
    R-008398305-000A 1189 1043 CAACCAAGAAAGCAAGCUC GAGCUUGCUUUCUUGGUUGUU 4005
    R-008398305-000A 1189 1043 CAACCAAGAAAGCAAGCUC B CAACCAAGAAAGCAAGCUCTT B 4004
    R-008398308-000B 2066 1044 GUGCAGCUGCUUUAUUCUC GAGAAUAAAGCAGCUGCACUU 4007
    R-008398308-000B 2066 1044 GUGCAGCUGCUUUAUUCUC B GUGCAGCUGCUUUAUUCUCTT B 4006
    R-008398311-000H 1307 1045 CUAUCUGUCUGCUCUAGUA UACUAGAGGAGACAGAUAGUU 4009
    R-008398311-000H 1307 1045 CUAUCUGUCUGCUCUAGUA B CUAUCUGUCUGCUCUAGUATT B 4008
    R-008398314-000J 1448 1046 AAACAGGAAGGGAUGGAAG CUUCCAUCCCUUCCUGUUUUU 4011
    R-008398314-000J 1448 1046 AAACAGGAAGGGAUGGAAG B AAACAUGAAGGGAUGGAAGTT B 4010
    R-008398317-000K 1213 1047 ACUGGCUAGUGGUGGACCC B ACUGGCUAGUGGUGGACCCTT B 4012
    R-008398317-000K 1213 1047 ACUGGCUAGUGGUGGACCC GGGUCCACCACUAGCCAGUUU 4013
    R-008398320-000S 2119 1048 CCUCUGUGAACUUGCUCAG B CCUCUGUGAACUUGCUCAGTT B 4014
    R-008398320-000S 2119 1048 CCUCUGUGAACUUGCUCAG CUGAGCAAGUUCACAGAGGUU 4015
    R-008398323-000T 2546   72 CAGGACCUCAUGGAUGGGC B CAGGACCUCAUGGAUGGGCTT B 1016
    R-008398323-000T 2546   72 CAGGACCUCAUGGAUGGGC GCCCAUCCAUGAGGUCCUGUU 4017
    R-008398326-000U  889 1049 UGUAGAAACAGCUCGUUGU B UGUAGAAACAGCUCGUUGUTT B 4018
    R-008398326-000U  889 1049 UGUAGAAACAGCUCGUUGU ACAACGAGCUGUUUCUACAUU 4019
    R-008398329-000V 1376 1050 CUGACAGAUCCAAGUCAAC B CUGACAGAUCCAAGUCAACTT B 4020
    R-008398329-000V 1376 1050 CUGACAGAUCCAAGUCAAC GUUGACUUGGAUCUGUCAGUU 4021
    R-008398332-000B  427 1051 GGAAGAGGAUGUGGAUACC GGUAUCCACAUCCUCUUCCUU 4023
    R-008398332-000B  427 1051 GGAAGAGGAUGUGGAUACC B GGAAGAGGAUGUGGAUACCTT B 4022
    R-008398335-000C  649 1052 ACCAUCACAGAUGCUGAAA B ACCAUCACAGAUGCUGAAATT B 4024
    R-008398335-000C  649 1052 ACCAUCACAGAUGCUGAAA UUUCAGCAUCUGUGAUGGUUU 4025
    R-008398338-000D 1915 1053 CCGUACGUCCAUGGGUGGG B CCGUACGUCCAUGGGUGGGTT B 4026
    R-008398338-000D 1915 1053 CCGUACGUCCAUGGGUGGG CCCACCCAUGGACGUACGGUU 4027
    R-008398341-000K 2053 1054 CAUUCCAUUGUUUGUGCAG B CAUUCCAUUGUUUGUGCAGTT B 4028
    R-008398341-000K 2053 1054 CAUUCCAUUGUUUGUGCAG CUGCACAAACAAUGGAAUGUU 4029
    R-008398344-000L 2000   24 CACAUCCUAGCUCGGGAUG CAUCCCGAGCUAGGAUGUGUU 4031
    R-008398344-000L 2000   24 CACAUCCUAGCUCGGGAUG B CACAUCCUAGCUCGGGAUGTT B 4030
    R-008398347-000M 2568 1055 CUCCAGGUGACAGCAAUCA B CUCCAGGUGACAGCAAUCATT B 4032
    R-008398397-000M 2568 1055 CUCCAGGUGACAGCAAUCA UGAUUGCUGUCACCUGGAGUU 4033
    R-008398350-000U 1739 1056 CUACCAGUUGUGGUUAAGC GCUUAACCACAACUGGUAGUU 4035
    R-008398350-000U 1739 1056 CUACCAGUUGUGGUUAAGC B CUACCAGUUGUGGUUAAGCTT B 4034
    R-008398353-000V 1746 1057 UUGUGGUUAAGCUCUUACA B UUGUGGUUAAGCUCUUACATT B 4036
    R-008398353-000V 1746 1057 UUGUGGUUAAGCUCUUACA UGUAAGAGCUUAACCACAAUU 4037
    R-008398356-000W 1321 1058 UAGUAAUAAGCCGGCUAUU AAUAGCCGGCUUAUUACUAUU 4039
    R-008398356-000W 1321 1058 UAGUAAUAAGCCGGCUAUU B UAGUAAUAAGCCGGCUAUUTT B 4038
    R-008398359-000X  482 1059 CAGUCCUUCACUCAAGAAC GUUCUUGAGUGAAGGACUGUU 4041
    R-008398359-000X  482 1059 CAGUCCUUCACUCAAGAAC B CAGUCCUUCACUCAAGAACTT B 4040
    R-008398362-000D  280 1060 AGCUGAUUUGAUGGAGUUG CAACUCCAUCAAAUCAGGUUU 4043
    R-008398362-000D  280 1060 AGCUGAUUUGAUGGAGUUG B AGCUGAUUUGAUGGAGUUGTT B 4042
    R-008398365-000E 1465 1061 AGGUCUCCUUGGGACUCUU B AGGUCUCCUUGGGACUCUUTT B 4044
    R-008398365-000E 1465 1061 AGGUCUCCUUGGGACUCUU AAGAGUCCCAAGGAGACCUUU 4045
    R-008398368-000F 1731 1062 ACUAUGGACUACCAGUUGU ACAACUGGUAGUCCAUAGUUU 4047
    R-008398368-000F 1731 1062 ACUAUGGACUACCAGUUGU B ACUAUGGACUACCAGUUGUTT B 4046
    R-008398371-000M 1937 1063 CAGCAGCAAUUUGUGGAGG B CAGCAGCAAUUUGUGGAGGTT B 4048
    R-008398371-000M 1937 1063 CAGCAGCAAUUUGUGGAGG CCUCCACAAMAJGCUGCUGUU 4049
    R-008398374-000N 1892 1064 CGUGCACAUCAGGAUACCC B CGUGCACAUGAGGAUACCCTT B 4050
    R-008398374-000N 1892 1064 CGUGCACAUCAGGAUACCC GGGUAUCCUGAUGUGCACGUU 4051
    R-008398377-000P  836 1065 CGUUCUCCUCAGAUGGUGU B CGUUCUCCUCAGAUGGUGUTT B 4052
    R-008398377-000P  836 1065 CGUUCUCCUCAGAUGGUGU ACACCAUCUGAGGAGAACGUU 4053
    R-008398380-000W  521 1066 CAGUAUGCAAUGACUCGAG CUCGAGUCAUUGCAUACUGUU 4055
    R-008398380-000W  521 1066 CAGUAUGCAAUGACUCGAG B CAGUAUGCAAUGACUCGAGTT B 4054
    R-008398383-000X 1595 1067 GGUAUAGAGGCUCUUGUGC GCACAAGAGCCUCUAUACCUU 4057
    R-008398383-000X 1595 1067 GGUAUAGAGGCUCUUGUGC B GGUAUAGAGGCUCUUGUGCTT B 4056
    R-008398386-000Y 2511 1068 AUCCAGUUGAUGGGCUGCC GGCAGCCCAUCAACUGGAUUU 4059
    R-008398386-000Y 2511 1068 AUCCAGUUGAUGGGCUGCC B AUCCAGUUGAUGGGCUGCCTT B 4058
    R-008398389-000Z 1583 1069 UGCCAAGUGGGUGGUAUAG B UGCCAAGUGGGUGGUAUAGTT B 4060
    R-008398389-000Z 1583 1069 UGCCAAGUGGGUGGUAUAG CUAUACCACCCACUUGGCAUU 4061
    R-008398392-000F 1897 1070 ACAUCAGGAUACCCAGCGC GCGCUGGGUAUCCUGAUGUUU 4063
    R-008398392-000F 1897 1070 ACAUCAGGAUACCCAGCGC B ACAUCAGGAUACCCAGCGCTT B 4062
    R-008398395-000G  956 1071 GCCAUCUUUAAGUCUGGAG CUCCAGACUUAAAGAUGGCUU 4065
    R-008398395-000G  956 1071 GCCAUCUUUAAGUCUGGAG B GCCAUCUUUAAGUCUGGAGTT B 4064
    R-008398398-000H  926 1072 AACCUUUCCCAUCAUCGUG B AACCUUUCCCAUCAUCGUGTT B 4066
    R-008398398-000H  926 1072 AACCUUUCCCAUCAUCGUG CACGAUGAUGGGAAAGGUUUU 4067
    R-008398401-000A 1874 1073 CUAGUUCAGUUGCUUGUUC GAACAAGCAACUGAACUAGUU 4069
    R-008398101-000A 1874 1073 CUAGUUCAGUUGCUUGUUC B CUAGUUCAGUUGCUUGUUCTT B 4068
    R-008398404-000B  488 1074 UUCACUCAAGAACAAGUAG B UUCACUCAAGAACAAGUAGTT B 4070
    R-008398404-000B  488 1074 UUCACUCAAGAACAAGUAG CUACUUGUUCUUGAGUGAAUU 4071
    R-008398407-000C 1602   21 AGGCUCUUGUGCGUACUGU B AGGCUCUUGUGCGUACUGUTT B 4072
    R-008398407-000C 1602   21 AGGCUCUUGUGCGUACUGU ACAGUACGCACAAGAGCCUUU 4073
    R-008398410-000J 1695 1075 AAGAAGCAGAGAUGGCCCA UGGGCCAUCUCUGGUUCUUUU 4075
    R-008398410-000J 1695 1075 AAGAAGCAGAGAUGGCCCA B AAGAAGCAGAGAUGGCCCATT B 4074
    R-008398413-000K 2182 1076 UCCUCUGACAGAGUUACUU B UCCUCUGACAGAGUUACUUTT B 4076
    R-008398413-000K 2182 1076 UCCUCUGACAGAGUUACUU AAGUAACUCUGUCAGAGGAUU 4077
    R-008398416-000L 2029 1077 AAUUGUUAUCAGAGGACUA UAGUCCUCUGAUAACAAUUUU 4079
    R-008398416-000L 2029 1077 AAUUGUUAUCAGAGGACUA B AAUUGUUAUCAGAGGACUATT B 4078
    R-008398419-000M  479 1078 UCUCAGUCCUUCACUCAAG B UCUCAGUCCUUCACUCAAGTT B 4080
    R-008398419-000M  479 1078 UCUCAGUCCUUCACUCAAG CUUGAGUGAAGGACUGAGAUU 4081
    R-008398422-000U  818 1079 UCCAGACACGCUAUCAUGC GCAUGAUAGCGUGUCUGGAUU 4083
    R-008398422-000U  818 1079 UCCAGACACGCUAUCAUGC B UCCAGACACGCUAUCAUGCTT B 4082
    R-008398425-000V  625 1080 CACUAAUGUCCAGCGUUUG B CACUAAUGUCCAGCGUUUGTT B 4084
    R-008398425-000V  625 1080 CACUAAUGUCCAGCGUUUG CAAACGCUGGACAUUAGUGUU 4085
    R-008398428-000W 3172 1181 UUGUAACCUGCUGUGAUAC B UUGUAACCUGCUGUGAUACTT B 4086
    R-008398428-000W 3172 1081 UUGUAACCUGCUGUGAUAC GUAUCACAGCAGGUUACAAUU 4087
    R-008398431-000C 1490 1082 CUUCUGGGUUCAGAUGAUA B CUUCUGGGUUCAGAUGAUATT B 4088
    R-008398431-000C 1490 1082 CUUCUGGGUUCAGAUGAUA UAUCAUCUGAACCCAGAAGUU 4089
    R-008398434-000D 1914 1083 GCCGUACGUCCAUGGGUGG B GCCGUACGUCCAUGGGUGGTT B 4090
    R-008398434-000D 1914 1083 GCCGUACGUCCAUGGGUGG CCACCCAUGGACGUACGGCUU 4091
    R-008398437-000E  882  100 CAAAUGAUGUAGAAACAGC GCUGUUUCUACAUCAUUUGUU 4093
    R-008398437-000E  882  100 CAAAUGAUGUAGAAACAGC B CAAAUGAUGUAGAAACAGCTT B 4092
    R-008398440-000L 1974 1084 UAGUUGAAGGUUGUACCGG CCGGUACAACCUUCAACUAUU 4095
    R-008398440-000L 1974 1084 UAGUUGAAGGUUGUACCGG B UAGUUGAAGGUUGUACCGGTT B 4094
    R-008398443-000M 2258 1085 GAGGACAAGCCACAAGAUU B GAGGACAAGCCACAAGAUUTT B 4096
    R-008398443-000M 2258 1085 GAGGACAAGCCACAAGAUU AAUCUUGUGGCUUGUCCUCUU 4097
    R-008398446-000N 2170 1086 GGGAGCCACAGCUCCUCUG CAGAGGAGCUGUGGCUCCCUU 4099
    R-008398446-000N 2170 1086 GGGAGCCACAGCUCCUCUG B GGGAGCCACAGCUCCUCUGTT B 4098
    R-008398449-000P 1370 1087 CUUCACCUGACAGAUCCAA B CUUCACCUGACAGAUCCAATT B 4100
    R-008398449-000P 1370 1087 CUUCACCUGACAGAUCCAA UUGGAUCUGUCAGGUGAAGUU 4101
    R-008398452-000W 1429 1088 UCUUUCAGAUGCUGCAACU B UCUUUCAGAUGCUGCAACUTT B 4102
    R-008398452-000W 1429 1088 UCUUUCAGAUGCUGCAACU AGUUGCAGCAUCUGAAAGAUU 4103
    R-008398455-000X 3173 1089 UGUAACCUGCUGUGAUACG B UGUAACCUGCUGUGAUACGTT B 4104
    R-008398455-000X 3173 1089 UGUAACCUGCUGUGAUACG CGUAUCACAGCAGGUUACAUU 4105
    R-008398458-000Y  444 1090 CCUCCCAAGUCCUGUAUGA B CCUCCCAAGUCCUGUAUGATT B 4106
    R-008398458-000Y  444 1090 CCUCCCAAGUCCUGUAUGA UCAUACAGGACUUGGGAGGUU 4107
    R-008398461-000E 1081 1091 GGCAGUGCGUUUAGCUGGU B GGCAGUGCGUUUAGCUGGUTT B 4108
    R-008398461-000E 1081 1091 GGCAGUGCGUUUAGCUGGU ACCAGCUAAACGCACUGCCUU 4109
    R-098398464-000F 1318 1092 CUCUAGUAAUAAGCCGGCU AGCCGGCUUAUUACUAGAGUU 4111
    R-008398464-000F 1318 1092 CUCUAGUAAUAAGCCGGCU B CUCUAGUAAUAAGCCGGCUTT B 4110
    R-008398467-000G  329 1093 GCUGUUAGUCACUGGCAGC B GCUGUUAGUCACUGGCAGCTT B 4112
    R-008398467-000G  329 1093 GCUGUUAGUCACUGGCAGC GCUGCCAGUGACUAACAGCUU 4113
    R-098398470-000N 1389 1094 GUCAACGUCUUGUUCAGAA UUCUGAACAAGACGUUGACUU 4115
    R-008398470-000N 1389 1094 GUCAACGUCUUGUUCAGAA B GUCAACGUCUUGUUCAGAATT B 4114
    R-008398473-000P  428 1095 GAAGAGGAUGUGGAUACCU AGGUAUCCACAUCCUCUUCUU 4117
    R-008398473-000P  428 1095 GAAGAGGAUGUGGAUACCU B GAAGAGGAUGUGGAUACCUTT B 4116
    R-098398476-000R 3175 1096 UAACCUGCUGUGAUACGAU AUCGUAUCACAGCAGGUUAUU 4119
    R-008398476-000R 3175 1096 UAACCUGCUGUGAUACGAU B UAACCUGCUGUGAUACGAUTT B 4118
    R-008398479-000S 1422  114 UCAGGAAUCUUUCAGAUGC B UCAGGAAUCUUUCAGAUGCTT B 4120
    R-008398479-000S 1422  114 UCAGGAAUCUUUCAGAUGC GCAUCUGAAAGAUUCCUGAUU 4121
    R-008398482-000Y 1500   97 CAGAUGAUAUAAAUGUGGU ACCACAUUUAUAUCAUCUGUU 4123
    R-008398482-000Y 1500   97 CAGAUGAUAUAAAUGUGGU B CAGAUGAUAUAAAUGUGGUTT B 4122
    R-008398485-000Z 3117 1097 GUUAUUUGGAACCUUGUUU B GUUAUUUGGAACCUUGUUUTT B 4124
    R-008398485-000Z 3117 1097 GUUAUUUGGAACCUUGUUU AAACAAGGUUGCAAAUAACUU 4125
    R-008398488-000A 2020 1098 UCACAACCGAAUUGUUAUC B UCACAACCGAAUUGUUAUCTT B 4126
    R-008398488-000A 2020 1098 UCACAACCGAAUUGUUAUC GAUAACAAUUCGGUUGUGAUU 4127
    R-008398491-000G 1625 1099 CGGGCUGGUGACAGGGAAG B CGGGCUGGUGACAGGGAAGTT B 4128
    R-008398491-000G 1625 1099 CUGGCUGGUGACAGGGAAG CUUCCCUGUCACCAGCCCGUU 4129
    R-008398494-000H 2022 1100 ACAACCGAAUUGUUAUCAG B ACAACCGAAUUGUUAUCAGTT B 4130
    R-008398494-000H 2022 1100 ACAACCGAAUUGUUAUCAG CUGAUAACAAUUCGGUUGUUU 4131
    R-008398497-000J  624 1101 CCACUAAUGUCCAGCGUUU B CCACUAAUGUCCAGCGUUUTT B 4132
    R-008398497-000J  624 1101 CCACUAAUGUCCAGCGUUU AAACGCUGGACAUUAGUGGUU 4133
    R-008398500-000B 1648 1102 CACUGAGCCUGCCAUCUGU ACAGAUGGCAGGCUCAGUGUU 4135
    R-008398500-000B 1648 1102 CACUGAGCCUGCCAUCUGU B CACUGAGCCUGCCAUCUGUTT B 4134
    R-008398503-000C  790 1103 GGUCCAUCAGCUUUCUAAA B GGUCCAUCAGUUUUCUAAATT B 4136
    R-008398503-000C  790 1103 GGUCCAUCAGCUUUCUAAA UUUAGAAAGCUGAUGGACCUU 4137
    R-008398506-000D 2122   59 CUGUGAACUUGCUCAGGAC B CUGUGAACUUGCUCAGGACTT B 4138
    R-008398506-000D 2122   59 CUGUGAACUUGCUCAGGAC GUCCUGAGCAAGUUCACAGUU 4139
    R-008398509-000E 3160 1104 AUCCCAAAGUUGUUGUAAC B AUCCCAAAGUUGUUGUAACTT B 4140
    R-008398509-000E 3160 1104 AUCCCAAAGUUGUUGUAAC GUUACAACAACUUUGGGAUUU 4141
    R-008398512-000L 1251 1105 UGAGGACCUAUACUUACGA B UGAGGACCUAUACUUACGATT B 4142
    R-008398512-000L 1251 1105 UGAGGACCUAUACUUACGA UCGUAAGUAUAUGUCCUCAUU 4143
    R-008398518-000N 2253 1106 UGUCUGAGGACAAGCCACA UGUGGCUUGUCCUCAGACAUU 4145
    R-008398518-000N 2253 1106 UGUCUGAGGACAAGCCACA B UGUCUGAGGACAAGCCACATT B 4144
    R-008398521-000V 2515 1107 AGUUGAUGGGCUGCCAGAU B AGUUGAUGGGCUGCCAGAUTT B 4146
    R-008398521-000V 2515 1107 AGUUGAUGGGCUGCCAGAU AUCUGGCAGCCCAUCAACUUU 4147
    R-008398524-000W 1680 1108 UGACCAGCCGACACCAAGA B UGACCAGCCGACACCAAGATT B 4148
    R-008398524-000W 1680 1108 UGACCAGCCGACACCAAGA UCUUGGUGUCGGCUGGUCAUU 4149
    R-008398527-000X 2169 1109 AGGGAGCCACAGCUCCUCU B AGGGAGCCACAGCUCCUCUTT B 4150
    R-008398527-000X 2169 1109 AGGGAGCCACAGCUCCUCU AGAUGAGCLGUGGCUCCCUUU 4151
    R-008398530-000D 3165 1110 AAAGUUGUUGUAACCUGCU AGCAGGUUACAACAACUUUUU 4153
    R-008398530-000D 3165 1110 AAAGUUGUUGUAACCUGCU B AAAGUUGUUGUAACCUGCUTT B 4152
    R-008398533-000E  780 1111 CUGGAGUUAUGGUCCAUCA UGAUGGACCAUAACUGCAGUU 4155
    R-008398533-000E  780 1111 CUGCAGUUAUGGUCCAUCA B CUGCAGUUAUGGUCCAUCATT B 4154
    R-008398536-000F 1978 1112 UGAAGGUUGUACCGGAGCC B UGAAGGUUGUACCGGAGCCTT B 4156
    R-008398536-000F 1978 1112 UGAAGGUUGUACCGGAGCC GGCUCCGGUACAACCUUCAUU 4157
    R-008398539-000G  661  122 GCUGAAACAUGCAGUUGUA B GCUGAAACAUGCAGUUGUATT B 4158
    R-008398539-000G  661  122 GCUGAAACAUGCAGUUGUA UACAACUGCAUGUUUCAGCUU 4159
    R-008398542-000N 1354  181 AAUGCAAGCUUUAGGACUU B AAUGCAAGCUUUAGGACUUTT B 4160
    R-008398542-000N 1354  181 AAUGCAAGCUUUAGGACUU AAGUCCUAAAGCUUGCAUUUU 4161
    R-008398545-000P  563 1113 UUCCCUGAGACAUUAGAUG B UUCCCUGAGACAUUAGAUGTT B 4162
    R-008398545-000P  563 1113 UUCCCUGAGACAUUAGAUG CAUCUAAUGUCUCAGGGAAUU 4163
    R-008398548-000R 1622 1114 CUUCGGGCUGGUGACAGGG B CUUCGGGCUGGUGACAGGGTT B 4164
    R-008398548-000R 1622 1114 CUUCGGGCUGGUGACAGGG CCCUGUCACCAGCCCGAAGUU 4165
    R-008398551-000X 2295 1115 UUGAGCUGACCAGCUCUCU AGAGAGCUGGUCAGCUCAAUU 4167
    R-008398551-000X 2295 1115 UUGAGCUGACCAGCUCUCU B UUGAGCUGACCAGCUCUCUTT B 4166
    R-008398554-000Y 2126 1116 GAACUUGCUCAGGACAAGG CCUUGUCCUGAGCAAGUUCUU 4169
    R-008398554-000Y 2126 1116 GAACUUGCUCAGGACAAGG B GAACUUGCUCAGGACAAGGTT B 4168
    R-008398557-000Z 1683 1117 CCAGCCGACACCAAGAAGC GCUUCUUGGUGUCGGCUGGUU 4171
    R-008398557-000Z 1683 1117 CCAGCCGACACCAAGAAGC B CCAGCCGACACCAAGAAGCTT B 4170
    R-008398560-000F 1857 1118 AGGGUGCCAUUCCACGACU AGUCGUGGAAUGGCACCCUUU 4173
    R-008398560-000F 1857 1118 AGGGUGCCAUUCCACGACU B AGGGUGCCAUUCCACGACUTT B 4172
    R-008398563-000G 2064 1119 UUGUGCAGCUGCUUUAUUC GAAUAAAGCAGCUGCACAAUU 4175
    R-008398563-000G 2064 1119 UUGUGCAGCUGCUUUAUUC B UUGUGCAGCUGCUUUAUUCTT B 4174
    R-008398566-000H 1245   31 AUAUAAUGAGGACCUAUAC GUAUAGGUCCUCAUUAUAUUU 4177
    R-008398566-000H 1245   31 AUAUAAUGAGGACCUAUAC B AUAUAAUGAGGACCUAUACTT B 4176
    R-008398569-000J  489 1120 UCACUCAAGAACAAGUAGC B UCACUCAAGAACAAGCAGCTT B 4178
    R-008398569-000J  489 1120 UCACUCAAGAACAAGUAGC GCUACUUGUUCUUGAGUGAUU 4179
    R-008398572-000R 1346 1121 GCUGGUGGAAUGCAAGCUU B CCUGGUGGAAUGCAAGCUUTT B 4180
    R-008398572-000R 1346 1121 GCUGGUGGAAUGCAAGCUU AAGCUUGCAUUCCACCAGCUU 4181
    R-008398575-000S 1442 1122 GCAACUAAACAGGAAGGGA UCCCUUCCUGUUUAGUUGCUU 4183
    R-008398575-000S 1442 1122 GCAACUAAAAGGAAGGGA B GCAACUAAACAGGAAGGGATT B 4182
    R-008398578-000T 1981 1123 AGGUUGUACCGGAGCCCUU B AGGUUGUACCGGAGCCCUUTT B 4184
    R-008398578-000T 1981 1123 AGGUUGUACCGGAGCCCUU AAGGGCUCCGGUACAACCUUU 4185
    R-008398581-000Z  777 1124 AGGCUGCAGUUAUGGUCCA UGGACCAUAACUGCAGCGUUU 4187
    R-008398581-000Z  777 1124 AGGCUGCAGUUAUGGUCCA B AGGCUGCAGUUAUGGUCCATT B 4186
    R-008398584-000A  589 1125 GCAGAUCCCAUCUACACAG CUGUGUAGAUGGGAUCUGCUU 4189
    R-008398584-000A  589 1125 GCAGAUCCCAUCUACACAG B GCAGAUCCCAUCUACACAGTT B 4188
    R-008398587-000B 2205 1126 CUAGGAAUGAAGGUGUGGC GCCACACCUUCAUUCCUAGUU 4191
    R-008398587-000B 2205 1126 CUAGGAAUGAAGGUGUGGC B CUAGGAAUGAAGGUGUGGCTT B 4190
    R-008398590-000H  394 1127 AGCUCCUUCUCUGAGUGGU B AGCUCCUUCUCUGAGUGGUTT B 4192
    R-008398590-000H  394 1127 AGCUCCUUCUCUGAGUGGU ACCACUCAGAGAAGGAGCUUU 4193
    R-008398593-000J 1035 1128 UUACAACUCUCCACAACCU B UUACAACUCUCCACAACCUTT B 4194
    R-008398593-000J 1035 1128 UUACAACUCUCCACAACCU AGGUUGUGGAGAGUUGUAAUU 4195
    R-008398605-000E  410 1129 GGUAAAGGCAAUCCUGAGG B GGUAAAGGCAAUCCUGAGGTT B 4196
    R-008398605-000E  410 1129 GGUAAAGGCAAUCCUGAGG CCUCAGGAUUGCCUUUACCUU 4197
    R-008398608-000F 1721 1130 GUUCGCCUUCACUAUGGAC GUCCAUAGUGAAGGCGAACUU 4199
    R-008398608-000F 1721 1130 GUUCGCCUUCACUAUGGAC B GUUCGCCUUCACUAUGGACTT B 4198
    R-008398611-000M 1134 1131 CAAAUGUUAAAUUCUUGGC GCCAAGAAUUUAACAUUUGUU 4201
    R-008398611-000M 1134 1131 CAAAUGUUAAAUUCUUGGC B CAAAUGUUAAAUUCUUGGCTT B 4200
    R-008398614-000N 3182 1132 CUGUGAUACGAUGCUUCAA B CUGUGAUACGAUGCUUCAATT B 4202
    R-008398614-000N 3182 1132 CUGUGAUACGAUGCUUCAA UUGAAGCAUCGUAUCACAGUU 4203
    R-008398617-000P  881 1133 ACAAAUGAUGUAGAAACAG B ACAAAUGAUGUAGAAACAGTT B 4204
    R-008398617-000P  881 1133 ACAAAUGAUGUAGAAACAG CUGUUUCUACAUCAUUUGUUU 4205
    R-008398620-000W  547 1134 GGUACGAGCUGCUAUGUUC GAACAUAGCAGCUCGUACCUU 4207
    R-008398620-000W  547 1134 GGUACGAGCUGCUAUGUUC B GGUACGAGCUGCUAUGUUCTT B 4206
    R-008398623-000X 2028 1135 GAAUUGUUAUCAGAGGACU AGUCCUCUGAUAACAAUUCUU 4209
    R-008398623-000X 2028 1135 GAAUUGUUAUCAGAGGACU B GAAUUGUUAUCAGAGGACUTT B 4208
    R-008398629-000Z 2023 1136 CAACCGAAUUGUUAUCAGA B CAACCGAAUUGUUAUCAGATT B 4210
    R-008398629-000Z 2023 1136 CAACCGAAUUGUUAUCAGA UCUGAUAACAAUUCGGUUGUU 4211
    R-008398632-000F 3184 1137 GUGAUACGAUGCUUCAAGA B GUGAUACGAUGCUUCAAGATT B 4212
    R-008398632-000F 3184 1137 GUGAUACGAUGCUUCAAGA UCUUGAAGCAUCGUAUCACUU 4213
    R-008398635-000G  413 1138 AAAGGCAAUCCUGAGGAAG CUUCCUCAGGAUUGCCUUUUU 4215
    R-008398635-000G  413 1138 AAAGGCAAUCCUGAGGAAG B AAAGGCAAUCCUGAGGAAGTT B 4214
    R-008398638-000H 2178 1139 CAGCUCCUCUGACAGAGUU B CAGCUCCUCUGACAGAGUUTT B 4216
    R-008398638-000H 2178 1139 CAGCUCCUCUGACAGAGUU AACUCUGUCAGAGGAGCUGUU 4217
    R-008398641-000P  618  143 CUCAUCCCACUAAUGUCCA B CUCAUCCCACUAAUGUCCATT B 4218
    R-008398641-000P  618  143 CUCAUCCCACUAAUGUCCA UGGACAUUAGUGGGAUGAGUU 4219
    R-008398644-000R 1577 1140 AUGGUCUGCCAAGUGGGUG B AUGGUCUGCCAAGUGGGUGTT B 4220
    R-008398644-000R 1577 1140 AUGGUCUGCCAAGUGGGUG CACCCACUUGGCAGACCAUUU 4221
    R-008398647-000S 1793 1141 GCUACUGUUGGAUUGAUUC GAAUCAAUCCAACAGUAGCUU 4223
    R-008398647-000S 1793 1141 GCUACUGUUGGAUUGAUUC B GCUACUGUUGGAUUGAUUCTT B 4222
    R-008398650-000Y  526 1142 UGCAAUGACUCGAGCUCAG B UGCAAUGACUCGAGCUCAGTT B 4224
    R-008398650-000Y  526 1142 UGCAAUGACUCGAGCUCAG CUGAGCUCGAGUCAUUGCAUU 4225
    R-008398653-000Z 2358 1143 GACUUGAUAUUGGUGCCCA UGGGCACCAAUAUCAAGUCUU 4227
    R-008398653-000Z 2358 1143 GACUUGAUAUUGGUGCCCA B GACUUGAUAUUGGUGCCCATT B 4226
    R-008398656-000A  852   11 UGUCUGCUAUUGUACGUAC B UGUCUGCUAUUGUACGUACTT B 4228
    R-008398656-000A  852   11 UGUCUGCUAUUGUACGUAC GUACGUACAAUAGCAGACAUU 4229
    R-008398659-000B 1403 1144 CAGAACUGUCUUUGGACUC GAGUCCAAAGACAGUUCUGUU 4231
    R-008398659-000B 1403 1144 CAGAACUGUCUUUGGACUC B CAGAACUGUCUUUGGACUCTT B 4230
    R-008398662-000H 1875 1145 UAGUUCAGUUGCUUGUUCG CGAACAAGCAACUGAACUAUU 4233
    R-008398662-000H 1875 1145 UAGUUCAGUUGCUUGUUCG B UAGUUCAGUUGCUUGUUCGTT B 4232
    R-008398665-000J 1160 1146 ACAGACUGCCUUCAAAUUU B ACAGACUGCCUUCAAAUUUTT B 4234
    R-008398665-000J 1160 1146 ACAGACUGCCUUCAAAUUU AAAUUUGAAGGCAGUCUGUUU 4235
    R-008398668-000K 1591 1147 GGGUGGUAUAGAGGCUCUU AAGAGCCUCUAUACCACCCUU 4237
    R-008398668-000K 1591 1147 GGGUGGUAUAGAGGCUCUU B GGGUGGUAUAGAGGCUCUUTT B 4236
    R-008398671-000S 1734 1148 AUGGACUACCAGUUGUGGU B AUGGACUACCAGUUGUGGUTT B 4238
    R-008398671-000S 1734 1148 AUGGACUACCAGUUGUGGU ACCACAACUGGUAGUCCAUUU 4239
    R-008398674-000T 2030 1149 AUUGUUAUCAGAGGACUAA UUAGUCCUCUGAUAACAAUUU 4241
    R-008398674-000T 2030 1149 AUUGUUAUCAGAGGACUAA B AUUGUUAUCAGAGGACUAATT B 4240
    R-008398677-000U  775 1150 UAAGGCUGCAGUUAUGGUC GACCAUAACUGCAGCCUUAUU 4243
    R-008398677-000U  775 1150 UAAGGCUGCAGUUAUGGUC B UAAGGCUGCAGUUAUGGUCTT B 4242
    R-008398680-000A 1813 1151 AAAUCUUGCCCUUUGUCCC GGGACAAAGGGCAAGAUUUUU 4245
    R-008398680-000A 1813 1151 AAAUCUUGCCCUUUGUCCC B AAAUCUUGCCCUUUGUCCCTT B 4244
    R-008398683-000B 1938 1152 AGCAGCAAUUUGUGGAGGG B AGCAGCAAUUUGUGGAGGGTT B 4246
    R-008398683-000B 1938 1152 AGCAGCAAUUUGUGGAGGG CCCUCCACAAAUUGGUGCUUU 4247
    R-008398686-000C 2039 1153 AGAGGACUAAAUACCAUUC B AGAGGACUAAAUACCAUUCTT B 4248
    R-008398686-000C 2039 1153 AGAGGACUAAAUACCAUUC GAAUGGUAUUUAGUCCUCUUU 4249
    R-008398689-000D 1297 1154 GCUGAAGGUGCUAUCUGUC B GCUGAAGGUGCUAUCUGUCTT B 4250
    R-008398689-000D 1297 1154 GCUGAAGGUGCUAUCUGUC GACAGAUAGCACCUUCAGCUU 4251
    R-008398692-000K  456 1155 UGUAUGAGUGGGAACAGGG CCCUGUUCCCACUCAUACAUU 4253
    R-008398692-000K  456 1155 UGUAUGAGUGGGAACAGGG B UGUAUGAGUGGGAACAGGGTT B 4252
    R-008398695-000L  869   51 ACCAUGCAGAAUACAAAUG B ACCAUGCAGAAUACAAAUGTT B 4254
    R-008398695-000L  869   51 ACCAUGCAGAAUACAAAUG CAUUUGUAUUCUGCAUGGUUU 4255
    R-008398698-000M  590 1156 CAGAUCCCAUCUACACAGU B CAGAUCCCAUCUACACAGUTT B 4256
    R-008398698-000M  590 1156 CAGAUCCCAUCUACACAGU ACUGUGUAGAUGGGAUCUGUU 4257
    R-008398701-000E 1933 1157 GACACAGCAGCAAUUUGUG B GACACAGCAGCAAUUUGUGTT B 4258
    R-008398701-000E 1933 1157 GACACAGCAGCAAUUUGUG CACAAAUUGCUGCUGUGUCUU 4259
    R-008398704-000F  583 1158 GGGCAUGCAGAUCCCAUCU AGAUGGGAUCUGCAUGCCCUU 4261
    R-008398704-000F  583 1158 GGGCAUGCAGAUCCCAUCU B GGGCAUGCAGAUCCCAUCUTT B 4260
    R-008398707-000G 2540 1159 CAUGCCCAGGACCUCAUGG B CAUGCCCAGGACCUCAUGGTT B 4262
    R-008398707-000G 2540 1159 CAUGCCCAGGACCUCAUGG CCAUGAGGUCCUGGGCAUGUU 4263
    R-008398710-000N 2162 1160 GAAGCUGAGGGAGCCACAG B GAAGCUGAGGGAGCCACAGTT B 4264
    R-008398710-000N 2162 1160 GAAGCUGAGGGAGCCACAG CUGUGGCUCCCUCAGCUUCUU 4265
    R-008398713-000P  330 1161 CUGUUAGUCACUGGCAGCA B CUGUUAGUCACUGGCAGCATT B 4266
    R-008398713-000P  330 1161 CUGUUAGUCACUGGCAGCA UGCUGCCAGUGACUAACAGUU 4267
    R-008398716-000R 1481 1162 CUUGUUCAGCUUCUGGGUU B CUUGUUCAGCUUCUGGGUUTT B 4268
    R-008398716-000R 1481 1162 CUUGUUCAGCUUCUGGGUU AACCCAGAAGCUCAACAAGUU 4269
    R-008398719-000S 1612   22 GCGUACUGUCCUUCGGGCU AGCCCGAAGGACAGUACGCUU 4271
    R-008398719-000S 1612   22 GCGUACUGUCCUUCGGGCU B GCGUACUGUCCUUCGGGCUTT B 4270
    R-008398722-000Y 1709    3 GCCCAGAAUGCAGUUCGCC GGCGAACUGCAUUCUGGGCUU 4273
    R-008398722-000Y 1709    3 GCCCAGAAUGCAGUUCGCC B GCCCAGAAUGCAGUUCGCCTT B 4272
    R-008398725-000Z 1344 1163 AAGCUGGUGGAAUGCAAGC GCUUGCAUUCCACCAGCUUUU 4275
    R-008398725-000Z 1344 1163 AAGCUGGUGGAAUGCAAGC B AAGCUGGUGGAAUGCAAGCTT B 4274
    R-008398728-000A  431 1164 GAGGAUGUGGAUACCUCCC GGGAGGUAUCCACAUCCUCUU 4277
    R-008398728-000A  431 1164 GAGGAUGUGGAUACCUCCC B GAGGAUGUGGAUACCUCCCTT B 4276
    R-008398731-000G 1508 1165 AUAAAUGUGGUCACCUGUG CACAGGUGACCACAUUUAUUU 4279
    R-008398731-000G 1508 1165 AUAAAUGUGGUCACCUGUG B AUAAAUGUGGUCACCUGUGTT B 4278
    R-008398734-000H 1918 1166 UACGUCCAUGGGUGGGACA B UACGUCCAUGGGUGGGACATT B 4280
    R-008398734-000H 1918 1166 UACGUCCAUGGGUGGGACA UGUCCCACCCAUGGACGUAUU 4281
    R-008398737-000J  289 1167 GAUGGAGUUGGACAUGGCC UGCCAUGUCCAACUCCAUCUU 4283
    R-008398737-000J  289 1167 GAUGUAGUUGGACAUGGCC B GAUGGAGUUGGACAUGGCCTT B 4282
    R-008398740-000R  631 1168 UGUCCAGCGUUUGGCUGAA B UGUCCAGCGUUUGGCUGAATT B 4284
    R-008398740-000R  631 1168 UGUCCAGCGUUUGGCUGAA UUCAGCCAAACGCUGGACAUU 4285
    R-008398743-000S 1642   60 AGACAUCACUGAGCCUGCC B AGACAUCACUGAGCCUGCUTT B 4286
    R-008398743-000S 1642   60 AGACAUCACUGAGCCUGCC GGCAGGCUCAGUGAUGUCUUU 4287
    R-008398746-000T 1853 1169 GAGCAGGGUGCCAUUCCAC B GAGCAGGGUGCCAUUCCACTT B 4288
    R-008398746-000T 1853 1169 GAGCAGGGUGCCAUUCCAC GUGGAAUGGCACCCUGCUCUU 4289
    R-008398749-000U 1243 1170 AAAUAUAAUGAGGACCUAU AUAGGUCCUCAUUAUAUUUUU 4291
    R-008398749-000U 1243 1170 AAAUAUAAUGAGGACCUAU B AAAUAUAAUGAGGACCUAUTT B 4290
    R-008398752-000A 1212 1171 UACUGGCUAGUGGUGGACC GGUCCACCACUAGCCAGUAUU 4293
    R-008398752-000A 1212 1171 UACUGGCUAGUGGUGGACC B UACUGGCUAGUGGUGGACCTT B 4292
    R-008398755-000B  996 1172 UGCUUGGUUCACCAGUGGA UCCACUGGUGAACCAAGCAUU 4295
    R-008398755-000B  996 1172 UGCUUGGUUCACCAGUGGA B UGCUUGGUUCACCAGUGGATT B 4294
    R-008398758-000C 2256 1173 CUGAGGACAAGCCACAAGA B CUGAGGACAAGCCACAAGATT B 4296
    R-008398758-000C 2256 1173 CUGAGGACAAGCCACAAGA UCUUGUGGCUUGUCCUCAGUU 4297
    R-008398761-000J 1607 1174 CUUGUGCGUACUGUCCUUC GAAGGACAGUACGCACAAGUU 4299
    R-008398761-000J 1607 1174 CUUGUGCGUACUGUCCUUC B CUUGUGCGUACUGUCCUUCTT B 4298
    R-008398764-000K 3116 1175 UGUUAUUUGGAACCUUGUU B UGUUAUUUGGAACCUUGUTTT B 4300
    R-008398764-000K 3116 1175 UGUUAUUUGGAACCUUGUU AACAAGGUUCCAAAUAACAUU 4301
    R-008398767-000L 1179 1176 UAGCUUAUGGCAACCAAGA UCUUGGUUGCCAUAAGCUAUU 4303
    R-008398767-000L 1179 1176 UAGCUUAUGGCAACCAAGA B UAGCUUAUGGCAACCAAGATT B 4302
    R-008398770-000T 3185 1177 UGAUACCAUGCUUCAAGAG CUCUUGAAGCAUCGUAUCAUU 4305
    R-008398770-000T 3185 1177 UGAUACCAUGCUUCAAGAG B UGAUAGCAUGCUUCAAGAGTT B 4304
    R-008398773-000U 1594 1178 UGGUAUAGAGGCUCUUGUG CACAAGAGCCUCUAUACCAUU 4307
    R-008398773-000U 1594 1178 UGGUAUAGAGGCUCUUGUG B UGGUAUAGAGGCUCUUGUGTT B 4306
    R-008398776-000V  887 1179 GAUGUAGAAACAGCUCGUG B GAUGUAGAAACAGCUCGUUTT B 4308
    R-008398776-000V  887 1179 GAUGUAGAAACAGCUCGUG AACGAGCUGUUUCUACAUCUU 4309
    R-008398779-000W  928 1180 CCUUUCCCAUCAUCGUGAG B CCUUUCCCAUCAUCGUGAGTT B 4310
    R-008398779-000W  928 1180 CCUUUCCCAUCAUCGUGAG CUCACGAUGAUGGGAAAGGUU 4311
    R-008398782-000C  835 1181 GCGUUCUCCUCAGAUGGUG CACCAUCUGAGGAGAACGCUU 4313
    R-008398782-000C  835 1181 GCGUUCUCCUCAGAUGGUG B GCGUUCUCCUCAGAUGGUGTT B 4312
    R-008398785-000D 1900 1182 UCAGGAUACCCAGCGCCGU B UCAGGAUACCCAGCGCCGUTT B 4314
    R-008398785-000D 1900 1182 UCAGGAUACCCAGCGCCGU ACGGCGCUGGGUAUCCUGAUU 4315
    R-008398788-000E 2284 1183 ACGGCUUUCAGUUGAGCUG B ACGGCUUUCAGUUGAGCUGTT B 4316
    R-008398788-000E 2284 1183 ACGGCUUUCAGUUGAGCUG CAGCUCAACUGAAAGCCGUUU 4317
    R-008398791-000L 1976 1184 GUUGAAGGUUGUACCGGAG CUCCGGUACAACCUUCAACUU 4319
    R-008398791-000L 1976 1184 GUUGAAGGUUGUACCGGAG B GUUGAAGGUUGUACCGGAGTT B 4318
    R-008398794-000M 2393 1185 UAUCGCCAGGAUGAUCCUA B UAUCGCCAGGAUGAUCCUATT B 4320
    R-008398794-000M 2393 1185 UAUCGCCAGGAUGAUCCUA UAGGAUGCCAGGAUGAUCCUATT B 4321
    R-008398797-000N 1295 1186 GUGCUGAAGGUGCUAUCUG B GUGCUGAAGGUGCUAUCUGTT B 4322
    R-008398797-000N 1295 1186 GUGCUGAAGGUGCUAUCUG CAGAUAGCACCUUCAGCACUU 4323
    R-008398800-000F 1410 1187 GUCUUUGGACUCUCAGGAA UUCCUGAGAGUCCAAAGACUU 4325
    R-008398800-000F 1410 1187 GUCUUUGGACUCUCAGGAA B GUCUUUGGACUCUCAGGAATT B 4324
    R-008398803-000G 1457 1188 GGGAUGGAAGGUCUCCUUG B GGGAUGGAAGGUCUCCUUGTT B 4326
    R-008398803-000G 1457 1188 GGGAUGGAAGGUCUCCUUG CAAGGAGACCUUCCAUCCCUU 4327
    R-008398806-000H 2296 1189 UGAGCUGACCAGCUCUCUC B UGAGCUGACCAGCUCUCUCTT B 4328
    R-008398806-000H 2296 1189 UGAGCUGACCAGCUCUCUC GAGAGAGCUGGUCAGCUCAUU 4329
    R-008398809-000J  929 1190 CUUUCCCAUCAUCGUGAGG CCUCACGAUGAUGGGAAAGUU 4331
    R-008398809-000J  929 1190 CUUUCCCAUCAUCGUGAGG B CUUUCCCAUCAUCGUGAGGTT B 4330
    R-008398812-000R 1359 1191 AAGCUUUAGGACUUCACCU B AAGCUUUAGGACUUCACCUTT B 4332
    R-008398812-000R 1359 1191 AAGCUUUAGGACUUCACCU AGGUGAAGUCCUAAAGCUUUU 4333
    R-008398815-000S 1351 1192 UGGAAUGCAAGCUUUAGGA B UGGAAUGCAAGCUUUAGGATT B 4334
    R-008398815-000S 1351 1192 UGGAAUGCAAGCUUUAGGA UCCUAAAGCUUGCAUUCCAUU 4335
    R-008398818-000T  969 1193 CUGGAGGCAUUCCUGCCCU B CUGGAGGCAUUCCUGCCCUTT B 4336
    R-008398818-000T  969 1193 CUGGAGGCAUUCCUGCCCU AGGGCAGGAAUGCCUCCAGUU 4337
    R-008398821-000Z 1876 1194 AGUUCAGUUGGUUGUUCGU ACGAAGAAGCAACUGAACUUU 4339
    R-008398821-000Z 1876 1194 AGUUCAGUUGCUUGUUCGU B AGUUCAGUUGCUUGUUCGUTT B 4338
    R-008398824-000A  552 1195 GAGCUGCUAUGUUCCCUGA B GAGCUGCUAUGUUCCCUGATT B 4340
    R-008398824-000A  552 1195 GAGCUGCUAUGUUCCCUGA UCAGGGAACAUAGCAGCUCUU 4341
    R-008398827-000B 2441 1196 GGCCAGGAUGCCUUGGGUA B GGCCAGGAUGCCUUGGGUATT B 4342
    R-008398827-000B 2441 1196 GGCCAGGAUGCCUUGGGUA UACCCAAGGCAUCCUGGCCUU 4343
    R-008398830-000H 2402 1197 GAUGAUCCUAGCUAUCGUU B GAUGAUCCUAGGUAUCGUUTT B 4344
    R-008398830-000H 2402 1197 GAUGAUCCUAGCUAUCGUU AACGAUAGCUAGGAUCAUCUU 4345
    R-008398833-000J 1803 1198 GAUUGAUUCGAAAUCUUGC GCAAGAUUUCGAAUCAAUCUU 4347
    R-008398833-000J 1803 1198 GAUUGAUUCGAAAUCUUGC B GAUUGAUUCGAAAUCUUGCTT B 4346
    R-008398836-000K  101 1199 CAGAGAUGGCCCAGAAUGC B CAGAGAUGGCCCAGAAUGCTT B 4348
    R-008398836-000K 1701 1199 CAGAGAUGGCCCAGAAUGC GCAUUCUGGGCCAUCUCUGUU 4349
    R-008398839-000L 1910 1200 CAGCGCCGUACGUCCAUGG CCAUGGACGUAUGGCGCUGUU 4351
    R-008398839-000L 1910 1200 CAGCGCCGUACGUCCAUGG B CAGCGCCGUACGUCCAUGGTT B 4350
    R-008398842-000T  888 1201 AUGUAGAAACAGCUCGUUG CAACGAGCUGUUUCUACAUUU 4353
    R-008398842-000T  888 1201 AUGUAGAAACAGCUCGUUG B AUGUAGAAACAGCUCGUUGTT B 4352
    R-008398845-000U 1294 1202 AGUGCUGAAGGUGCUAUCU AGAUAGCACCUUCAGCACUUU 4355
    R-008398845-000U 1294 1202 AGUGCUGAAGGUGCUAUCU B AGUGCUGAAGGUGCUAUCUTT B 4354
    R-008398898-000V 1737 1203 GACUACCAGUUGUGGUUAA UUAACCACAACUGGUAGUCUU 4357
    R-008398848-000V 1737 1203 GACUACCAGUUGUGGUUAA B GACUACCAGULGUGGUUAATT B 4356
    R-008398851-000B 1450 1204 ACAGGAAGGGAUGGAAGGU B ACAGGAAGGGAUGGAAGGUTT B 4358
    R-008398851-000B 1450 1204 ACAGGAAGGGAUGGAAGGU ACCUUCCAUCCCUUCCUGUUU 4359
    R-008398854-000C  761 1205 CAGGUGGUGGUUAAUAAGG CCUUAUUAACCACCACCUGUU 4361
    R-008398854-000C  761 1205 CAGGUGGUGGUUAAUAAGG B CAGGCUGUGGUUAAUAAGGTT B 4360
    R-008398857-000D  776 1206 AAGGCUGCAGUUAUGGUCC B AAGGCUGCAGUUAUGGUCCTT B 4362
    R-008398857-000D  776 1206 AAGGCUGCAGUUAUGGUCC GGACCAUAACUGCAGCCUUUU 4363
    R-008398860-000K 1509 1207 UAAAUGUGGUCACCUGUGC GCACAGGUGACCACAUUUAUU 4365
    R-008398860-000K 1509 1207 UAAAUGUGGUCACCUGUGC B UAAAUGUGGUCACCUGUGCTT B 4364
    R-008398863-000L 1788 1208 UAAAGGCUACUGUUGGAUU B UAAAGGCUACUGUUGGAUUTT B 4366
    R-008398863-000L 1788 1208 UAAAGGCUACUGUUGGAUU AAUCCAACAGUAGCCUUUAUU 4367
    R-008398866-000M  515 1209 GAUGGACAGUAUGCAAUGA UCAUUGCAUACUGUCCAUCUU 4369
    R-008398866-000M  515 1209 GAUGGACAGUAUGCAAUGA B GAUGGACAGUAUGCAAUGATT B 4368
    R-008398869-000N 1491 1210 UUCUGGGUUCAGAUGAUAU B UUCUGGGUUCAGAUGAUAUTT B 4370
    R-008398869-000N 1491 1210 UUCUGGGUUCAGAUGAUAU AUAUCAUCUGAACCCAGAAUU 4371
    R-008398872-000V 1614 1211 GUACUGUCCUUCGGGCUGG B GUACUGUCCUUCGGGCUGGTT B 4372
    R-008398872-000V 1614 1211 GUACUGUCCUUCGGGCUGG CCAGCCCGAAGGACAGUACUU 4373
    R-008398875-000W  998 1212 CUUGGUUCACCAGUGGAUU B CUUGGUUCACCAGUGGAUUTT B 4374
    R-008398875-000W  998 1212 CUUGGUUCACCAGUGGAUU AAUCCACUGGUGAACCAAGUU 4375
    R-008398878-000X 2158 1213 UAUUGAAGCUGAGGGAGCC B UAUUGAAGCUGAGGGAGCCTT B 4376
    R-008398878-000X 2158 1213 UAUUGAAGCUGAGGGAGCC GGCUCCCUCAGCUUCAAUAUU 4377
    R-008398881-000D 3168 1214 GUUGUUGUAACCUGCUGUG B GUUGUUGUAACCUGCUGUGTT B 4378
    R-008398881-000D 3168 1214 GUUGUUGUAACCUGCUGUG CACAGCAGGUUACAACAACUU 4379
    R-008398884-000E 1854 1215 AGCAGGGUGCCAUUCCACG B AGCAGGGUGCCAUUCCACUTT B 4380
    R-008398884-000E 1854 1215 AGCAGGGUGCCAUUCCACG CGUGGAAUGGCACCCUGCUUU 4381
    R-008398887-000F 2117 1216 GUCCUCUGUGAACUUGCUC GAGCAAGUUCACAGAGGACUU 4383
    R-008398887-000F 2117 1216 GUCCUCUGUGAACUUGCUC B GUCCUCUGUGAACUUGCUCTT B 4382
    R-008398890-000M 1678 1217 UCUGACCAGCCGACACCAA UUGGUGUCGGCUGGUCAGAUU 4385
    R-008398890-000M 1678 1217 UCUGACCAGCCGACACCAA B UCUGACCAGCCGACACCAATT B 4384
    R-008398893-000N 2159   63 AUUGAAGCUGAGGGAGCCA B AUUGAAGCUGAGGGAGCCATT B 4386
    R-008398893-000N 2159   63 AUUGAAGCUGAGGGAGCCA UGGCUCCCUCAGCUUCAAUUU 4387
    R-008398896-000P  305 1218 GCCAUGGAACCAGACAGAA UUCUGUCUGGUUCCAUGGCUU 4389
    R-008398896-000P  305 1218 GCCAUGGAACCAGACAGAA B GCCAUGGAACCAGACAGAATT B 4388
    R-008398899-000R 2154 1219 AAGCUAUUGAAGCUGAGGG B AAGCUAUUGAAGCUGAGGGTT B 4390
    R-008398899-000R 2154 1219 AAGCUAUUGAAGCUGAGGG CCCUCAGCUUCAAUAGCUUUU 4391
    R-008398902-000H 1807 1220 GAUUCGAAAUCUUGCCCUU B GAUUCGAAAUCUUGCCCUUTT B 4392
    R-008398902-000H 1807 1220 GAUUCGAAAUCUUGCCCUU AAGGGCAAGAUUUCGAAUCUU 4393
    R-008398905-000J 1881 1221 AGUUGCUUGUUCGUGCACA B AGUUGCUUGUUCGUGCACATT B 4394
    R-008398905-000J 1881 1221 AGUUGCUUGUUCGUGCACA UGUGCACGAACAAGCAACUUU 4395
    R-008398908-000K 1565 1222 AAGAACAAGAUGAUGGUCU B AAGAACAAGAUGAUGGUCUTT B 4396
    R-008398908-000K 1565 1222 AAGAACAAGAUGAUGGUCU AGACCAUCAUCUUGUUCUUUU 4397
    R-008398911-000S  407 1223 AGUGGUAAAGGCAAUCCUG B AGUGGUAAAGGCAAUCCUGTT B 4398
    R-008398911-000S  407 1223 AGUGGUAAAGGCAAUCCUG CAGGAUUGCCUUUACCACUUU 4399
    R-008398914-000T 1434 1224 CAGAUGCUGCAACUAAACA UGUUUAGUUGCAGCAUCUGUU 4401
    R-008398914-000T 1434 1224 CAGAUGCUGCAACUAAACA B CAGAUGCUGCAACUAAACATT B 4400
    R-008398917-000U  566 1225 CCUGAGACAUUAGAUGAGG B CCUGAGACAUUAGAUGAGGTT B 4402
    R-008398917-000U  566 1225 CCUGAGACAUUAGAUGAGG CCUCAUCUAAUGUCUCAGGUU 4403
    R-008398920-000A 3161 1226 UCCCAAAGUUGUUGUAACC GGUUACAACAACUUUGGGAUU 4405
    R-008398920-000A 3161 1226 UCCCAAAGUUGUUGUAACC B UCCCAAAGUUGUUGUAACCTT B 4404
    R-008398923-000B  666  117 AACAUGCAGUUGUAAACUU AAGUUUACAACUGCAUGUUUU 4407
    R-008398923-000B  666  117 AACAUGCAGUUGUAAACUU B AACAUGCAGUUGUAAACUUTT B 4406
    R-008398926-000C  848   98 AUGGUGUCUGCUAUUGUAC GUACAAUAGCAGACACCAUUU 4409
    R-008398926-000C  848   98 AUGGUGUCUGCUAUUGUAC B AUGGUGUCUGCUAUUGUACTT B 4408
    R-008398929-000D 1679 1227 CUGACCAGCCGACACCAAG B CUGACCAGCCGACACCAAGTT B 4410
    R-008398929-000D 1679 1227 CUGACCAGCCGACACCAAG CUUGGUGUCGGCUGGUCAGUU 4411
    R-008398932-000K 2096 1228 AUCCAAAGAGUAGCUGCAG B AUCCAAAGAGUAGCUGCAGTT B 4412
    R-008398932-000K 2096 1228 AUCCAAAGAGUAGCUGCAG CUGCAGCUACUCUUUGGAUUU 4413
    R-008398935-000L  630 1229 AUGUCCAGCGUUUGGCUGA B AUGUCCAGCGUUUGGCUGATT B 4414
    R-008398935-000L  630 1229 AUGUCCAGCGUUUGGCUGA UCAGCCAAACGCUGGACAUUU 4415
    R-008398938-000M 1606 1230 UCUUGUGCGUACUGUCCUU AAGGACAGUACGCACAAGAUU 4417
    R-008398938-000M 1606 1230 UCUUGUGCGUACUGUCCUU B UCUUGUGCGUACUGUCCUUTT B 4416
    R-008398941-000U  432 1231 AGGAUGUGGAUACCUCCCA UGGGAGGUAUCCACAUCCUUU 4419
    R-008398941-000U  432 1231 AGGAUGUGGAUACCUCCCA B AGGAUGUGGAUACCUCCCATT B 4418
    R-008398994-000V  778 1232 GGCUGCAGUUAUGGUCCAU B GGCUGCAGUUAUGGUCCAUTT B 4420
    R-008398944-000V  778 1232 GGCUGCAGUUAUGGUCCAU AUGGACCAUAALUGCAGCCUU 4421
    R-008398947-000W 1999 1233 UCACAUCCUAGCUCGGGAU B UCACAUCCUAGCUCGGGAUTT B 4422
    R-008398947-000W 1999 1233 UCACAUCCUAGCUCGGGAU AGCCCGAGCUAGGAUGUGAUU 4423
    R-008398950-000C 1692 1234 ACCAAGAAGCAGAGAUGGC GCCAUCUCUGCUUCUUGGUUU 4425
    R-008398950-000C 1692 1234 ACCAAGAAGCAGAGAUGGC B ACCAAGAAGCAGAGAUGGCTT B 4424
    R-008398953-000D 2490 1235 GCCACCACCGUGGUGCUGA B GCCACCACCCUGGUGCUGATT B 4426
    R-008398953-000D 2490 1235 GCCACCACCCUGGUGGUGA UCAGCACCAGGGUGGUGGCUU 4427
    R-008398956-000E  623 1236 CCCACUAAUGUCCAGCGUU AACGCUGGACAUUAGUGGGUU 4429
    R-008398956-000E  623 1236 CCCACUAAUGUCCAGCGUU B CCCACUAAUGUCCAGCGUUTT B 4428
    R-008398959-000F  339 1237 ACUGGCAGCAACAGUCUUA B ACUGGCAGCAACAGUCUUATT B 4430
    R-008398959-000F  339 1237 ACUGGCAGCAACAGUCUUA UAAGACUGUUGCUGCCAGUUU 4431
    R-008398962-000M 2471  166 AUGGAACAUGAGAUGGGUG CACCCAUCUCAUGUUCCAUUU 4433
    R-008398962-000M 2471  166 AUGGAACAUGAGAUGGGUG B AUGGAACAUGAGAUGGGUGTT B 4432
    R-008398965-000N 2037  164 UCAGAGGACUAAAUACCAU AUGGUAUUUAGUCCUCUGAUU 4435
    R-008398965-000N 2037  164 UCAGAGGACUAAAUACCAU B UCAGAGGACUAAAUACCAUTT B 4434
    R-008398968-000P  912  179 CUGGGACCUUGCAUAACCU AGGUUAUGCAAGGUCCCAGUU 4437
    R-008398968-000P  912  179 CUGGGACCUUGCAUAACCU B CUGGGACCUUGCAUAACCUTT B 4436
    R-008398971-000W 2946 1238 AUCUGAAUAAAGUGUAACA B AUCUGAAUAAAGUGUAACATT B 4438
    R-008398971-000W 2946 1238 AUCUGAAUAAAGUGUAACA UGUUACACUUUAUUCAGAUUU 4439
    R-008398974-000X 1654 1239 GCCUGCCAUCUGUGCUCUU AAGAGCACAGAUGGCAGGCUU 4441
    R-008398974-000X 1654 1239 GCCUGCCAUCUGUGCUCUU B GCCUGCCAUCUGUGCUCUUTT B 4440
    R-008398977-000Y 1033 1240 CAUUACAACUCUCCACAAC B CAUUACAACUCUCCACAACTT B 4442
    R-008398977-000Y 1033 1240 CAUUACAACUCUCCACAAC GUUGUGGAGAGUUGUAAUGUU 4443
    R-008398980-000E  840 1241 CUCCUCAGAUGGUGUCUGC GCAGACACCAUCUGAGGAGUU 4445
    R-008398980-000E  840 1241 CUCCUCAGAUGGUGUCUGC B CUCCUCAGAUGGUGUCUGCTT B 4444
    R-008398983-000F 1880 1242 CAGUUGCUUGUUCGUGCAC GUGCACGAACAAGCAACUGUU 4447
    R-008398983-000F 1880 1242 CAGUUGCUUGUUCGUGCAC B CAGUUGCUUGUUCGUGCACTT B 4446
    R-008398986-000G  420 1243 AUCCUGAGGAAGAGGAUGU B AUCCUGAGGAAGAGGAUGUTT B 4448
    R-008398986-000G  420 1243 AUCCUGAGGAAGAGGAUGU ACAUCCUCUUCCUCAGGAUUU 4449
    R-008398989-000H 1005 1244 CACCAGUGGAUUCUGUGUU B CACCAGUGGAUUCUGUGUUTT B 4450
    R-008398989-000H 1005 1244 CACCAGUGGAUUCUGUGUU AACACAGAAUCCACUGGUGUU 4451
    R-008398992-000P 1193 1245 CAAGAAAGCAAGCUCAUCA B CAAGAAAGCAAGCUCAUCATT B 4452
    R-008398992-000P 1193 1245 CAAGAAAGCAAGCUCAUCA UGAUGAGCUUGCUUUCUUGUU 4453
    R-008398995-000R  919 1246 CUUGCAUAACCUUUCCCAU AUGGGAAAGGUUAUGCAAGUU 4455
    R-008398995-000R  919 1246 CUUGCAUAACCUUUCCCAU B CUUGCAUAACCUUUCCCAUTT B 4454
    R-008399001-000F 1727 1247 CUUCACUAUGGACUACCAG CUGGUAGUCCAUAGUGAAGUU 4457
    R-008399001-000F 1727 1247 CUUCACUAUGGACUACCAG B CUUCACUAUGGACUACCAGTT B 4456
    R-008399004-000G 1883 1248 UUGCUUGUUCGUGCACAUC B UUGCUUGUUCGUGCACAUCTT B 4458
    R-008399004-000G 1883 1248 UUGCUUGUUCGUGCACAUC GAUGUGCACGAACAAGCAAUU 4459
    R-008399007-000H  859 1249 UAUUGUACGUACCAUGCAG B UAUUGUACGUACCAUGCAGTT B 4460
    R-008399007-000H  859 1249 UAUUGUACGUACCAUGCAG CUGCAUGGUACGUACAAUAUU 4461
    R-008399010-000P  870   57 CCAUGCAGAAUACAAAUGA B CCAUGCAGAAUACAAAUGATT B 4462
    R-008399010-000P  870   57 CCAUGCAGAAUACAAAUGA UCAUUUGUAUUCUGCAUGGUU 4463
    R-008399013-000R 1812 1250 GAAAUCUUGCCCUUUGUCC GGACAAAGGGCAAGAUUUCUU 4465
    R-008399013-000R 1812 1250 GAAAUCUUGCCCUUUGUCC B GAAAUCUUGCCCUUUGUCCTT B 4464
    R-008399016-000S 1605 1251 CUCUUGUGCGUACUGUCCU AGGACAGUACGCACAAGAGUU 4467
    R-008399016-000S 1605 1251 CUCUUGUGCGUACUGUCCU B CUCUUGUGCGUACUGUCCUTT B 4466
    R-008399019-000T 2021 1252 CACAACCGAAUUGUUAUCA UGAUAACAAUUCGGUUGUGUU 4469
    R-008399019-000T 2021 1252 CACAACCGAAUUGUUAUCA B CACAACCGAAUUGUUAUCATT B 4468
    R-008399022-000Z 2180 1253 GCUCCUCUGACAGAGUUAC GUAACUCUGUCAGAGGAGCUU 4471
    R-008399022-000Z 2180 1253 GCUCCUCUGACAGAGUUAC B GCUCCUCUGACAGAGUUACTT B 4470
    R-008399025-000A  636 1254 AGCGUUUGGCUGAACCAUC B AGCGUUUGGCUGAACCAUCTT B 4472
    R-008399025-000A  636 1254 AGCGUUUGGCUGAACCAUC GAUGGUUCAGCCAAACGCUUU 4473
    R-008399031-000H  871   48 CAUGCAGAAUACAAAUGAU B CAUGCAGAAUACAAAUGAUTT B 4474
    R-008399031-000H  871   48 CAUGCAGAAUACAAAUGAU AUCAUUUGUAUUCUGCAUGUU 4475
    R-008399034-000J 1801   96 UGGAUUGAUUCGAAAUCUU B UGGAUUGAUUCGAAAUCUUTT B 4476
    R-008399034-000J 1801   96 UGGAUUGAUUCGAAAUCUU AAGAUUUCGAAUCAAUCCAUU 4477
    R-008399037-000K 2282 1255 AAACGGCUUUCAGUUGAGC GCUCAACUGAAAGCCGUUUUU 4479
    R-008399037-000K 2282 1255 AAACGGCUUUCAGUUGAGC B AAACGGCUUUCAGUUGAGCTT B 4478
    R-008399040-000S 1824 1256 UUUGUCCCGCAAAUCAUGC GCAUGAUUUGCGGGACAAAUU 4481
    R-008399040-000S 1824 1256 UUUGUCCCGCAAAUCAUGC B UUUGUCCCGCAAAUCAUGCTT B 4480
    R-008399043-000T 2204 1257 UCUAGGAAUGAAGGUGUGG CCACACCUUCAUUCCUAGAUU 4483
    R-008399043-000T 2204 1257 UCUAGGAAUGAAGGUGUGG B UCUAGGAAUGAAGGUGUGGTT B 4482
    R-008399046-000U  450 1258 AAGUCCUGUAUGAGUGGGA B AAGUCCUGUAUGAGUGGGATT B 4484
    R-008399046-000U  450 1258 AAGUCCUGUAUGAGUGGGA UCCCACUCAUACAGGACUUUU 4485
    R-008399049-000V 1001 1259 GGUUCACCAGUGGAUUCUG B GGUUCACCAGUGGAUUCUGTT B 4486
    R-008399049-000V 1001 1259 GGUUCACCAGUGGAUUCUG CAGAAUCCACUGGUGAACCUU 4487
    R-008399052-000B 1579 1260 GGUCUGCCAAGUGGGUGGU ACCACCCACUUGGCAGACCUU 4489
    R-008399052-000B 1579 1260 GGUCUGCCAAGUGGGUGGU B GGUCUGCCAAGUGGGUGGUTT B 4488
    R-008399055-000C 2179 1261 AGCUCCUCUGACAGAGUUA UAACUCUGUCAGAGGAGCUUU 4491
    R-008399055-000C 2179 1261 AGCUCCUCUGACAGAGUUA B AGCUCCUCUGACAGAGUUATT B 4490
    R-008399058-000D  376 1262 UUCUGGUGCCACUACCACA B UUCUGGUGCCACUACCACATT B 4492
    R-008399058-000D  376 1262 UUCUGGUGCCACUACCACA UGUGGUAGUGGCACCAGAAUU 4493
    R-008399061-000K  556 1263 UGCUAUGUUCCCUGAGACA B UGCUAUGUUCCCUGAGACATT B 4494
    R-008399061-000K  556 1263 UGCUAUGUUCCCUGAGACA UGUCUCAGGGAACAUAGCAUU 4495
    R-008399064-000L 1804 1264 AUUGAUUCGAAAUCUUGCC B AUUGAUUCGAAAUCUUGCCTT B 4496
    R-008399064-000L 1804 1264 AUUGAUUCGAAAUCUUGCC GGCAAGAUUUCGAAUCAAUUU 4497
    R-008399067-000M 2552 1265 CUCAUGGAUGGGCUGCCUC B CUCAUGGAUGGGCUGCCUCTT B 4498
    R-008399067-000M 2552 1265 CUCAUGGAUGGGCUGCCUC GAGGCAGCCCAUCCAUGAGUU 4499
    R-008399070-000U 2071 1266 GCUGCUUUAUUCUCCCAUU B GCUGCUUUAUUCUCCCAUUTT B 4500
    R-008399070-000U 2071 1266 GCUGCUUUAUUCUCCCAUU AAUGGGAGAAUAAAGCAGCUU 4501
    R-008399073-000V 1145   16 UUCUUGGCUAUUACGACAG B UUCUUGGCUAUUACGACAGTT B 4502
    R-008399073-000V 1145   16 UUCUUGGCUAUUACGACAG CUGUCGUAAUAGCCAAGAAUU 4503
    R-008399076-000W 1836 1267 AUCAUGCACCUUUGCGUGA UCACGCAAAGGUGCAUGAUUU 4505
    R-008399076-000W 1836 1267 AUCAUGCACCUUUGCGUGA B AUCAUGCACCUUUGCGUGATT B 4504
    R-008399079-000X  336 1268 GUCACUGGCAGCAACAGUC B GUCACUGGCAGCAACAGUCTT B 4506
    R-008399079-000X  336 1268 GUCACUGGCAGCAACAGUC GACUGUUGCUGCCAGUGACUU 4507
    R-008399082-000D  460 1269 UGAGUGGGAACAGGGAUUU AAAUCCCUGUUCCCACUCAUU 4509
    R-008399082-000D  460 1269 UGAGUGGGAACAGGGAUUU B UGAGUGGGAACAGGGAUUUTT B 4508
    R-008399085-000E 1559 1270 AAUUAUAAGAACAAGAUGA B AAUUAUAAGAACAAGAUGATT B 4510
    R-008399085-000E 1559 1270 AAUUAUAAGAACAAGAUGA UCAUCUUGUUCUUAUAAUUUU 4511
    R-008399091-000M 3136 1271 UGGACAGUUUACCAGUUGC B UGGACAGUUUACCAGUUGCTT B 4512
    R-008399091-000M 3136 1271 UGGACAGUUUACCAGUUGC GCAACUGGUAAACUGUCCAUU 4513
    R-008399097-000P 1250 1272 AUGAGGACCUAUACUUACG B AUGAGGACCUAUACUUACGTT B 4514
    R-008399097-000P 1250 1272 AUGAGGACCUAUACUUACG CGUAAGUAUAGGUCCUCAUUU 4515
    R-008399100-000G 1462 1273  GGAAGGUCUCCUUGGGACU B GGAAGGUCUCCUUGGGACUTT B 4516
    R-008399100-000G 1462 1273 GGAAGGUCUCCUUGGGACU AGUCCCAAGGAGACCUUCCUU 4517
    R-008399103-000H 1965 1274 UGGAAGAAAUAGUUGAAGG B UGGAAGAAAUAGUUGAAGGTT B 4518
    R-008399103-000H 1965 1274 UGGAAGAAAUAGUUGAAGG CCUUCAACUAUUUCUUCCAUU 4519
    R-008399109-000K 3114 1275 GGUGUUAUUUGGAACCUUG CAAGGUUCCAAAUAACACCUU 4521
    R-008399109-000K 3114 1275 GGUGUUAUUUGGAACCUUG B GGUGUUAUUUGGAACCUUGTT B 4520
    R-008399112-000S 1665 1276 GUGCUVUUCGUCAUCUGAC B GUGCUCUUCGUCAUCUGACTT B 4522
    R-008399112-000S 1665 1276 GUGCUVUUCGUCAUCUGAC GUCAGAUGACGAAGAGCACUU 4523
    R-008399115-000T  304 1277 GGCCAUGGAACCAGACAGA UCUGUCUGGUUCCAUGGCCUU 4525
    R-008399115-000T  304 1277 GGCCAUGGAACCAGACAGA B GGCCAUGGAACCAGACAGATT B 4524
    R-008399118-000U  327 1278 CGGCUGUUAGUCACUGGCA UGCCAGUGACUAACAGCCGUU 4527
    R-008399118-000U  327 1278 CGGCUGUUAGUCACUGGCA B CGGCUGUUAGUCACUGGCATT B 4526
    R-008399121-000A 1866 1279 UUCCACGACUAGUUCAGUU B UUCCACGACUAGUUCAGUUTT B 4528
    R-008399121-000A 1866 1279 UUCCACGACUAGUUCAGUU AACUGAACUAGUCGUGGAAUU 4529
    R-008399124-000B 1699 1280 AGCAGAGAUGGCCCAGAAU AUUCUGGGCCAUCUCUGCUUU 4531
    R-008399124-000B 1699 1280 AGCAGAGAUGGCCCAGAAU B AGCAGAGAUGGCCCAGAAUTT B 4530
    R-008399127-000C 2397 1281 GCCAGGAUGAUCCUAGCUA UAGCUAGGAUCAUCCUGGCUU 4533
    R-008399127-000C 2397 1281 GCCAGGAUGAUCCUAGCUA B GCCAGGAUGAUCCUAGCUATT B 4532
    R-008399130-000J 1658 1282 GCCAUCUGUGCUCUUCGUC B GCCAUCUGUGCUCUUCGUCTT B 4534
    R-008399130-000J 1658 1282 GCCAUCUGUGCUCUUCGUC GACGAAGAGCACAGAUGGCUU 4535
    R-008399133-000K  891 1283 UAGAAACAGCUCGUUGUAC GUACAACGAGCUGUUUCUAUU 4537
    R-008399133-000K  891 1283 UAGAAACAGCUCGUUGUAC B UAGAAACAGCUCGUUGUACTT B 4536
    R-008399136-000L 1572 1284 AGAUGAUGGUCUGCCAAGU B AGAUGAUGGUCUGCCAAGUTT B 4538
    R-008399136-000L 1572 1284 AGAUGAUGGUCUGCCAAGU ACUUGGCAGACCAUCAUCUUU 4539
    R-008399139-000M  927 1285 ACCUUUCCCAUCAUCCUGA B ACCUUUCCCAUCAUCGUGATT B 4540
    R-008399139-000M  927 1285 ACCUUUCCCAUCAUCGUGA UCACGAUGAUGGGAAAGGUUU 4541
    R-008399142-000U  290 1286 AUGGAGUUGGACAUGGCCA UGGCCAUGUCCAACUCCAUUU 4543
    R-008399142-000U  290 1286 AUGGAGUUGGACAUGGCCA B AUGGAGUUGGACAUGGCCATT B 4542
    R-008399145-000V 1663 1287 CUGUGCUCUUCGUCAUCUG CAGAUGACGAAGAGCACAGUU 4545
    R-0083991454000V 1663 1287 CUGUGCUCUUCGUCAUCUG B CUGUGCUCUUCGUCAUCUGTT B 4544
    R-008399198-000W 1562 1288 UAUAAGAACAAGAUGAUGG B UAUAAGAACAAGAUGAUGGTT B 4546
    R-008399148-000W 1562 1288 UAUAAGAACAAGAUGAUGG CCAUCAUCUUGUUCUUAUAUU 4547
    R-008399154-000D 2947 1289 UCUGAAUAAAGUGUAACAA UUGUUACACUUUAUUCAGAUU 4549
    R-008399159-000D 2947 1289 UCUGAAUAAAGUGUAACAA B UCUGAAUAAAGUGUAACAATT B 4548
    R-008399157-000E 1711 1290 CCAGAAUGCAGUUCGCCUU AAGGCGAACUGCAUUCUGGUU 4551
    R-008399157-000E 1711 1290 CCAGAAUGCAGUUCGCCUU B CCAGAAUGCAGUUCGCCUUTT B 4550
    R-008399160-000L 1566 1291 AGAACAAGAUGAUGGUCUG B AGAACAAGAUGAUGGUCUGTT B 4552
    R-008399160-000L 1566 1291 AGAACAAGAUGAUGGUCUG CAGACCAUCAUCUUGUUCUUU 4553
    R-008399163-000M 1815 1292 AUCUUGCCCUUUGUCCCGC GCGGGACAAAGGGCAAGAUUU 4555
    R-008399163-000M 1815 1292 AUCUUGCCCUUUGUCCCGC B AUCUUGCCCUUUGUCCCGCTT B 4554
    R-008399166-000N 1087 1293 GCCUUUAGCUGGUGGGCUG CAGCCCACCAGCUAAACGCUU 4557
    R-008399166-000N 1087 1293 GCCUUUAGCUGGUGGGCUG B GCGUUUAGCUGGUGGGCUGTT B 4556
    R-008399169-000P 1495 1294 GGGUUCAGAUGAUAUAAAU B GGGUUCAGAUGAUAUAAAUTT B 4558
    R-008399169-000P 1495 1294 GGGUUCAGAUGAUAUAAAU AUUUAUAUCAUCUGAACCCUU 4559
    R-008399172-000W 1363 1295 UUUAGGACUUCACCUGACA B UUUAGGACUUCACCUGACATT B 4560
    R-008399172-000W 1363 1295 UUUAGGACUUCACCUGACA UGUCAGGUGAAGUCCUAAAUU 4561
    R-008399175-000X  391 1296 CACAGCUCCUUCUCUGAGU ACUCAGAGAAGGAGCUGUGUU 4563
    R-008399175-000X  391 1296 CACAGCUCCUUCUCUGAGU B CACAGCUCCUUCUCUGAGUTT B 4562
    R-008399178-000Y 1392 1297 AACGUCUUGUUCAGAACUG CAGUUCUGAACAAGACGUUUU 4565
    R-008399178-000Y 1392 1297 AACGUCUUGUUCAGAACUG B AACGUCUUGUUCAGAACUGTT B 4564
    R-008399181-000E 1935 1298 CACAGCAGCAAUUUGUGGA B CACAGCAGCAAUUUGUGCATT B 4566
    R-008399181-000E 1935 1298 CACAGCAGCAAUUUGUGUA UCCACAAAUUGCUGCUGUGUU 4567
    R-008399184-000F 1872 1299 GACUAGUUCAGUUGCUUGU B GACUAGUUCAGUUGCUUGUTT B 4568
    R-008399184-000F 1872 1299 GACUAGUUCAGUUGCUUGU ACAAGCAACUGAACUAGUCUU 4569
    R-008399187-000G 1159 1300 GACAGACUGCCUUCAAAUU AAUUUGAAGGCAGUCUGUCUU 4571
    R-008399187-000G 1159 1300 GACAGACUGCCUUCAAAUU B GACAGACUGCCUUCAAAUUTT B 4570
    R-008399190-000N 2308 1301 CUCUCUCUUCAGAACAGAG CUCUGUUCUGAAGAGAGAGUU 4573
    R-008399190-000N 2308 1301 CUCUCUCUUCAGAACAGAG B CUCUCUCUUCAGAACAGAGTT B 4572
    R-008399193-000P  632 1302 GUCCAGCGUUUGGCUGAAC GUUCAGCCAAACGCUGGACUU 4575
    R-008399193-000P  632 1302 GUCCAGCGUUUGGCUGAAC B GUCCAGCGUUUGGCUGAACTT B 4574
    R-008399196-000R  580  173 UGAGGGCAUGCAGAUCCCA B UGAGGGCAUGCAGAUCCCATT B 4576
    R-008399196-000R  580  173 UGAGGGCAUGCAGAUCCCA UGGGAUCUGCAUGCCCUCAUU 4577
    R-008399199-000S 1564 1303 UAAGAACAAGAUGAUGGUC B UAAGAACAAGAUGAUGGUCTT B 4578
    R-008399199-000S 1564 1303 UAAGAACAAGAUGAUGGUC GACCAUCAUCUUGUUCUUAUU 4579
    R-008399202-000J 1384 1304 UCCAAGUCAACGUCUUGUU B UCCAAGUCAACGUCUUGUUTT B 4580
    R-008399202-000J 1384 1304 UCCAAGUCAACGUCUUGUU AACAAGACGUUGACUUGGAUU 4581
    R-008399205-000K 1690 1305 ACACCAAGAAGCAGAGAUG B ACACCAAGAAGCAGAGAUGTT B 4582
    R-008399205-000K 1690 1305 ACACCAAGAAGCAGAGAUG CAUCUCUGCUUCUUGGUGUUU 4583
    R-008399208-000L 1421 1306 CUCAGGAAUCUUUCAGAUG B CUCAGGAAUCUUUCAGAUGTT B 4584
    R-008399208-000L 1421 1306 CUCAGGAAUCUUUCAGAUG CAUCUGAAAGAUUCCUGAGUU 4585
    R-008399211-000T 1141 1307 UAAAUUCUUGGCUAUUACG B UAAAUUCUUGGCUAUUACGTT B 4586
    R-008399211-000T 1141 1307 UAAAUUCUUGGCUAUUACG CGUAAUAGCCAAGAAUUUAUU 4587
    R-008399214-000U 1732 1308 CUAUGGACUACCAGUUGUG B CUAUGGACUACCAGUUGUGTT B 4588
    R-008399214-000U 1732 1308 CUAUGGACUACCAGUUGUG CACAACUGGUAGUCCAUAGUU 4589
    R-008399217-000V  634 1309 CCAGCGUUUGGCUGAACCA B CCAGCGUUUGGCUGAACCATT B 4590
    R-008399217-000V  634 1309 CCAGCGUUUGGCUGAACCA UGGUUCAGCCAAACGCUGGUU 4591
    R-008399220-000B  932 1310 UCCCAUCAUCGUGAGGGCU B UCCCAUCAUCGUGAGGGCUTT B 4592
    R-008399220-000B  932 1310 UCCCAUCAUCGUGAGGGCU AGCCCUCACGAUGAUGGGAUU 4593
    R-008399223-000C  579  171 AUGAGGGCAUGCAGAUCCC GGGAUCUGCAUGCCCUCAUUU 4595
    R-008399223-000C  579  171 AUGAGGGCAUGCAGAUCCC B AUGAGGGCAUGCAGAUCCCTT B 4594
    R-008399226-000D 1366 1311 AGGACUUCACCUGACAGAU AUCUGUCAGGUGAAGUCCUUU 4597
    R-008399226-000D 1366 1311 AGGAGUUCACCUGACAGAU B AGGACUUCACCUGACAGAUTT B 4596
    R-008399229-000E 1608 1312 UUGUGCGUACUGUCCUUCG B UUGUGCGUACUGUCCUUCGTT B 4598
    R-008399229-000E 1608 1312 UUGUGCGUACUGUCCUUCG CGAAGGACAGUACGCACAAUU 4599
    R-008399232-000L  814   10 AGCUUCCAGACACGCUAUC GAUAGCGUGUCUGGAAGCUUU 4601
    R-008399232-000L  814   10 AGCUUCCAGACACGCUAUC B AGCUUCCAGACACGCUAUCTT B 4600
    R-008399235-000M 1923 1313 CCAUGGGUGGGACACAGCA B CCAUGGGUGGGACACAGCATT B 4602
    R-008399235-000M 1923 1313 CCAUGGGUGGGACACAGCA UGCUGUGUCCCACCCAUGGUU 4603
    R-008399238-000N 1458 1314 GGAUGGAAGGUCUCCUUGG CCAAGGAGACCUUCCAUCCUU 4605
    R-008399238-000N 1458 1314 GGAUGGAAGGUCUCCUUGG B GGAUGGAAGGUCUCCUUGGTT B 4604
    R-008399241-000V 1908 1315 CCCAGCGCCGUACGUCCAU B CCCAGCGCCGUACGUCCAUTT B 4606
    R-008399241-000V 1908 1315 CCCAGCGCCGUACGUCCAU AUGGACGUACGGCGCUGGGUU 4607
    R-008399244-000W  539 1316 GCUCAGAGGGUACGAGCUG CAGCUCGUACCCUCUGAGCUU 4609
    R-008399244-000W  539 1316 GCUCAGAGGGUACGAGCUG B GCUCAGAGGGUACGAGCUGTT B 4608
    R-008399247-000X 2016 1317 AUGUUCACAACCGAAUUGU ACAAUUCGGUUGUGAACAUUU 4611
    R-008399247-000X 2016 1317 AUGUUCACAACCGAAUUGU B AUGUUCACAACCGAAUUGUTT B 4610
    R-008399250-000D 1884 1318 UGCUUGUUCGUGCACAUCA B UGCUUGUUCGUGCACAUCATT B 4612
    R-008399250-000D 1884 1318 UGCUUGUUCGUGCACAUCA UGAUGUGCACGAACAAGCAUU 4613
    R-008399253-000E  560 1319 AUGUUCCCUGAGACAUUAG B AUGUUCCCUGAGACAUUAGTT B 4614
    R-008399253-000E  560 1319 AUGUUCCCUGAGACAUUAG CUAAUGUCUCAGGGAACAUUU 4615
    R-008399256-000F  411 1320 GUAAAGGCAAUCCUGAGGA UCCUCAGGAUUGCCUUUACUU 4617
    R-008399256-000F  411 1320 GUAAAGGCAAUCCUGAGGA B GUAAAGGCAAUCCUGAGGATT B 4616
    R-008399259-000G  338 1321 CACUGGCAGCAACAGUCUU AAGACUGUUGCUGCCAGUGUU 4619
    R-008399259-000G  338 1321 CACUGGCAGCAACAGUCUU B CACUGGCAGCAACAGUCUUTT B 4618
    R-008399262-000N  830 1322 AUCAUGCGUUCUCCUCAGA UCUGAGGAGAACGCAUGAUUU 4621
    R-008399262-000N  830 1322 AUCAUGCGUUCUCCUCAGA B AUCAUGCGUUGUCCUCAGATT B 4620
    R-008399265-000P 3086 1323 UAUGUAUGGGUAGGGUAAA B UAUGUAUGGGUAGGGUAAATT B 4622
    R-008399265-000P 3086 1323 UAUGUAUGGGUAGGGUAAA UUUACCCUACCCAUACAUAUU 4623
    R-008399268-000R 3115 1324 GUGUUAUUUGGAACCUUGU ACAAGGUUCCAAAUAACACUU 4625
    R-008399268-000R 3115 1324 GUGUUAUUUGGAACCUUGU B GUGUUAUUUGGAACCUUGUTT B 4624
    R-008399271-000X 2177 1325 ACAGCUCCUCUGACAGAGU B ACAGCUCCUCUGACAGAGUTT B 4626
    R-008399271-000X 2177 1325 ACAGCUCCUCUGACAGAGU ACUCUGUCAGAGGAGCUGUUU 4627
    R-008399274-000Y 1733 1326 UAUGGACUACCAGUUGUGG B UAUGGACUACCAGUUGUGGTT B 4628
    R-008399274-000Y 1733 1326 UAUGGACUACCAGUUGUGG CCACAACUGGUAGUCCAUAUU 4629
    R-008399277-000Z  375 1327 AUUCUGGUGCCACUACCAC GUGGUAGUGGCACCAGAAUUU 4631
    R-008399277-000Z  375 1327 AUUCUGGUGCCACUACCAC B AUUCUGGUGCCACUACCACTT B 4630
    R-008399280-000F 2565 1328 UGCCUCCAGGUGACAGCAA B UGCCUCCAGGUGACAGCAATT B 4632
    R-008399280-000F 2565 1328 UGCCUCCAGGUGACAGCAA UUGCUGUCACCUGGAGGCAUU 4633
    R-008399283-000G  442 1329 UACCUCCCAAGUCCUGUAU AUACAGGACUUGGGAGGUAUU 4635
    R-008399283-000G  442 1329 UACCUCCCAAGUCCUGUAU B UACCUCCCAAGUCCUGUAUTT B 4634
    R-008399286-000H  819 1330 CCAGACACGCUAUCAUGCG CGCAUGAUAGCGUGUCUGGUU 4637
    R-008399286-000H  819 1330 CCAGACACGCUAUCAUGCG B CCAGACACGCUAUCAUGCGTT B 4636
    R-008399289-000J  700 1331 UGAUGCAGAACUUGCCACA B UGAUGCAGAACUUGCCACATT B 4638
    R-008399289-000J  700 1331 UGAUGCAGAACUUGCCACA UGUGGCAAGUUCUGCAUCAUU 4639
    R-008399292-000R 1089 1332 GUUUAGCUGGUGGGCUGCA B GUUUAGCUGGUGGGCUGCATT B 4640
    R-008399292-000R 1089 1332 GUUUAGCUGGUGGGCUGCA UGCAGCCCACCAGCUAAACUU 4641
    R-008399295-000S 1580 1333 GUCUGCCAAGUGGGUGGUA UACCACCCACUUGGCAGACUU 4643
    R-008399295-000S 1580 1333 GUCUGCCAAGUGGGUGGUA B GUCUGCCAAGUGGGUGGUATT B 4642
    R-008399298-000T 1982 1334 GGUUGUACCGGAGCCCUUC GAAGGGCUCCGGUACAACCUU 4645
    R-008399298-000T 1982 1334 GGUUGUACCGGAGCCCUUC B GGUUGUACCGGAGCCCUUCTT B 4644
    R-008399301-000K 1986 1335 GUACCGGAGCCCUUCACAU B GUACCGGAGCCCUUCACAUTT B 4646
    R-008399301-000K 1986 1335 GUACCGGAGCCCUUCACAU AUGUGAAGGGCUCCGGUACUU 4647
    R-008399304-000L  418 1336 CAAUCCUGAGGAAGAGGAU AUCCUCUUCCUCAGGAUUGUU 4649
    R-008399304-000L  418 1336 CAAUCCUGAGGAAGAGGAU B CAAUCCUGAGGAAGAGGAUTT B 4648
    R-008399307-000M 1306 1337 GCUAUCUGUCUGCUCUAGU ACUAGAGCAGACAGAUAGCUU 4651
    R-008399307-000M 1306 1337 GCUAUCUGUCUGCUCUAGU B GCUAUCUGUCUGCUCUAGUTT B 4650
    R-008399310-000U 1377 1338 UGACAGAUCCAAGUCAACG CGUUGACUUGGAUCUGUCAUU 4653
    R-008399310-000U 1377 1338 UGACAGAUCCAAGUCAACG B UGACAGAUCCAAGUCAACGTT B 4652
    R-008399313-000V 2467 1339 CAUGAUGGAACAUGAGAUG CAUCUCAUGUUCCAUCAUGUU 4655
    R-008399313-000V 2467 1339 CAUGAUGGAACAUGAGAUG B CAUGAUGGAACAUGAGAUGTT B 4654
    R-008399316-000W 1414 1340 UUGGACUCUCAGGAAUCUU B UUGGACUCUCAGGAAUCUUTT B 4656
    R-008399316-000W 1414 1340 UUGGACUCUCAGGAAUCUU AAGAUUCCUGAGAGUCCAAUU 4657
    R-008399319-000X 1668 1341 CUCUUCGUCAUCUGACCAG B CUCUUCGUCAUCUGACCAGTT B 4658
    R-008399319-000X 1668 1341 CUCUUCGUCAUCUGACCAG CUGGUCAGAUGACGAAGAGUU 4659
    R-008399322-000D 1818 1342 UUGCCCUUUGUCCCGCAAA B UUGCCCUUUGUCCCGCAAATT B 4660
    R-008399322-000D 1818 1342 UUGCCCUUUGUCCCGCAAA UUUGCGGGACAAAGGGCAAUU 4661
    R-008399325-000E 1697 1343 GAAGCAGAGAUGGCCCAGA B GAAGCAGAGAUGGCCCAGATT B 4662
    R-008399325-000E 1697 1343 GAAGCAGAGAUGGCCCAGA UCUGGGCCAUCUCUGCUUCUU 4663
    R-008399328-000F  918 1344 CCUUGCAUAACCUUUCCCA B CCUUGCAUAACCUUUCCCATT B 4664
    R-008399328-000F  918 1344 CCUUGCAUAACCUUUCCCA UGGGAAAGGUUAUGCAAGGUU 4665
    R-008399331-000M  605 1345 CAGUUUGAUGCUGCUCAUC GAUGAGCAGCAUCAAACUGUU 4667
    R-008399331-000M  605 1345 CAGUUUGAUGCUGCUCAUC B CAGUUUGAUGCUGCUCAUCTT B 4666
    R-008399334-000N 1374 1346 ACCUGACAGAUCCAAGUCA B ACCUGACAGAUCCAAGUCATT B 4668
    R-008399334-000N 1374 1346 ACCUGACAGAUCCAAGUCA UGACUUGGAUCUGUCAGGUUU 4669
    R-008399337-000P 1430 1347 CUUUCAGAUGCUGCAACUA UAGUUGCAGCAUCUGAAAGUU 4671
    R-008399337-000P 1430 1347 CUUUCAGAUGCUGCAACUA B CUUUCAGAUGCUGCAACUATT B 4670
    R-008399340-000W 3186 1348 GAUACGAUGCCUCAAGAGA UCUCUUGAAGCAUCGUAUCUU 4673
    R-008399340-000W 3186 1348 GAUACGAUGCUUCAAGAGA B GAUACGAUGCUUCAAGAGATT B 4672
    R-008399343-000X 1355 1349 AUGCAAGCUUUAGGACUUC B AUGCAAGCUUUAGGACUUCTT B 4674
    R-008399343-000X 1355 1349 AUGCAAGCUUUAGGACUUC GAAGUCCUAAAGCUUGCAUUU 4675
    R-008399346-000Y  433 1350 GGAUGUGGAUACCUCCCAA UUGGGAGGUAUCCACAUCCUU 4677
    R-008399346-000Y  433 1350 GGAUGUGGAUACCUCCCAA B GGAUGUGGAUACCUCCCAATT B 4676
    R-008399349-000Z 1901   13 CAGGAUACCCAGCGCCGUA B CAGGAUACCCAGCGCCGUATT B 4678
    R-008399349-000Z 1901   13 CAGGAUACCCAGCGCCGUA UACGGCGCUGGGUAUCCUGUU 4679
    R-008399352-000F 1713 1351 AGAAUGCAGUUCGCCUUCA UGAAGGCGAACUGCAUUCUUU 4681
    R-008399352-000F 1713 1351 AGAAUGCAGUUCGCCUUCA B AGAAUGCAGUUCGCCUUCATT B 4680
    R-008399355-000G  823   17 ACACGCUAUCAUGCGUUCU AGAACGCAUGAUAGCGUGUUU 4683
    R-008399355-000G  823   17 ACACGCUAUCAUGCGUUCU B ACACGCUAUCAUGCGUUCUTT B 4682
    R-008399358-000H 1811 1352 CGAAAUCUUGCCCUUUGUC B CGAAAUCUUGCCCUUUGUCTT B 4684
    R-008399358-000H 1811 1352 CGAAAUCUUGCCCUUUGUC GACAAAGGGCAAGAUUUCGUU 4685
    R-008399361-000P  491 1353 ACCCAAGAACAAGUAGCUG B ACUCAAGAACAAGUAGCUGTT B 4686
    R-008399361-000P  491 1353 ACCCAAGAACAAGUAGCUG CAGCUACUUGUUCUUGAGUUU 4687
    R-008399364-000R 2209 1354 GAAUGAAGGUGUGGCGACA UGUCGCCACACCUUCAUUCUU 4689
    R-008399364-000R 2209 1354 GAAUGAAGGUGUGGCGACA B GAAUGAAGGUGUGGCGACATT B 4688
    R-008399367-000S 1840 1355 UGCACCCUUGCGUGAGCAG B UGCACCUUUGCGUGAGCAGTT B 4690
    R-008399367-000S 1840 1355 UGCACCCUUGCGUGAGCAG CUGCUCACGCAAAGGUGCAUU 4691
    R-008399370-000Y  550 1356 ACGAGCUGCUAUGUUCCCU AGGGAACAUAGCAGCUCGUUU 4693
    R-008399370-000Y  550 1356 ACGAGCUGCUAUGUUCCCU B ACGAGCUGCUAUGUUCCCUTT B 4692
    R-008399373-000Z  429 1357 AAGAGGAUGUGGAUACCUC GAGGUAUCCACAUCCUCUUUU 4695
    R-008399373-000Z  429 1357 AAGAGGAUGUGGAUACCUC B AAGAGGAUGUGGACACCUCTT B 4694
    R-008399376-000A 2436 1358 GAUAUGGCCAGGAUGCCUU AAGGCAUCCUGGCCAUAUCUU 4697
    R-008399376-000A 2436 1358 GAUAUGGCCAGGAUGCCUU B GAUAUGGCCAGGAUGCCUUTT B 4696
    R-008399379-000B 1597 1359 UAUAGAGGCUCUUGUGCGC B UAUAGAGGCUCUUGUGCGUTT B 4698
    R-008399379-000B 1597 1359 UAUAGAGGCUCUUGUGCGC ACGCACAAGAGCCUCUAUAUU 4699
    R-008399382-000H 1496 1360 GGUUCAGAUGAUAUAAAUG B GGUUCAGAUGAUAUAAAUGTT B 4700
    R-008399382-000H 1496 1360 GGUUCAGAUGAUAUAAAUG CAUUUAUAUCAUCUGAACCUU 4701
    R-008399385-000J 1456 1361 AGGGAUGGAAGGUCUCCUU AAGGAGACCUUCCAUCCCUUU 4703
    R-008399385-000J 1456 1361 AGGGAUGGAAGGUCUCCUU B AGGGAUGGAAGGUCUCCUUTT B 4702
    R-008399388-000K 3159 1362 UAUCCCAAAGUUGUUGUAA UUACAACAACUUUGGGAUAUU 4705
    R-008399388-000K 3159 1362 UAUCCCAAAGUUGUUGUAA B UAUCCCAAAGUUGUUGUAATT B 4704
    R-008399391-000S 2309 1363 UCUCUCUUCAGAACAGAGC B UCUCUCUUCAGAACAGAGCTT B 4706
    R-008399391-000S 2309 1363 UCUCUCUUCAGAACAGAGC GCUCUGUUCUGAAGAGAGAUU 4707
    R-008399394-000T 2300 1364 CUGACCAGCUCUCUCUUCA B CUGACCAGCUCUCUCUUCATT B 4708
    R-008399394-000T 2300 1364 CUGACCAGCUCUCUCUUCA UGAAGAGAGAGCUGGUCAGUU 4709
    R-008399397-000U 3177 1365 ACCUGCUGUGAUACGAUGC B ACCUGCUGUGAUACGAUGCTT B 4710
    R-008399397-000U 3177 1365 ACCUGCUGUGAUACGAUGC GCAUCGUAUCACAGCAGGUUU 4711
    R-008399400-000L 1079 1366 AUGGCAGUGCGUUUAGCUG B AUGGCAGUGCGUUUAGCUGTT B 4712
    R-008399400-000L 1079 1366 AUGGCAGUGCGUUUAGCUG CAGCUAAACGCACUGCCAUUU 4713
    R-008399403-000M 1383 1367 AUCCAAGUCAACGUCUUGU ACAAGACGUUGACUUGGAUUU 4715
    R-008399403-000M 1383 1367 AUCCAAGUCAACGUCUUGU B AUCCAAGUCAACGUCUUGUTT B 4714
    R-008399406-000N 2563 1368 GCUGCCUCCAGGUGACAGC GCUGUCACCUGGAGGCAGCUU 4717
    R-008399406-000N 2563 1368 GCUGCCUCCAGGUGACAGC B GCUGCCUCCAGGUGACAGCTT B 4716
    R-008399409-000P 1084 1369 AGUGCGUUUAGCUGGUGGG B AGUGCGUUUAGCUGGGUGGTT B 4718
    R-008399409-000P 1084 1369 AGUGCGUUUAGCUGGUGGG CCCACCAGCUAAACGCACUUU 4719
    R-008399412-000W 1329 1370 AGCCGGCUAUUGUAGAAGC B AGCCGGCUAUUGUAGAAGCTT B 4720
    R-008399412-000W 1329 1370 AGCCGGCUAUUGUAGAAGC GCUUCUACAAUAGCCGGCUUU 4721
    R-008399415-000X 1662  169 UCUGUGCUCUUCGUCAUCU AGAUGACGAAGAGCACAGAUU 4723
    R-008399415-000X 1662  169 UCUGUGCUCUUCGUCAUCU B UCUGUGCUCUUCGUCAUCUTT B 4722
    R-008399418-000Y 2268   99 CACAAGAUUACAAGAAACG CGUUUCUUGUAAUCUUGUGUU 4725
    R-008399418-000Y 2268   99 CACAAGAUUACAAGAAACG B CACAAGAUUACAAGAAACGTT B 4724
    R-008399421-000E 2470  108 GAUGGAACAUGAGAUGGGU B GAUGGAACAUGAGAUGGGUTT B 4726
    R-008399421-000E 2470  108 GAUGGAACAUGAGAUGGGU ACCCAUCUCAUGUUCCAUCUU 4727
    R-008399424-000F  573 1371 CAUUAGAUGAGGGCAUGCA B CAUUAGAUGAGGGCAUGCATT B 4728
    R-008399424-000F  573 1371 CAUUAGAUGAGGGCAUGCA UGCAUGCCCUCAUCUAAUGUU 4729
    R-008399427-000G 2213 1372 GAAGGUGUGGCGACAUAUG B GAAGGUGUGGCGACAUAUGTT B 4730
    R-008399427-000G 2213 1372 GAAGGUGUGGCGACAUAUG CAUAUGUCGCCACACCUUCUU 4731
    R-008399430-000N 1587 1373 AAGUGGGUGGUAUAGAGGC B AAGUGGGUGGUAUAGAGGCTT B 4732
    R-008399430-000N 1587 1373 AAGUGGGUGGUAUAGAGGC GCCUCUAUACCACCCACUUUU 4733
    R-008399433-000P 2166 1374 CUGAGGGAGCCACAGCUCC B CUGAGGGAGCCACAGCUCCTT B 4734
    R-008399433-000P 2166 1374 CUGAGGGAGCCACAGCUCC GGAGCUGUGGCUCCCUCAGUU 4735
    R-008399436-000R  637 1375 GCGUUUGGCUGAACCAUCA UGAUGGUUCAGCCAAACGCUU 4737
    R-008399436-000R  637 1375 GCGUUUGGCUGAACCAUCA B GCGUUUGGCUGAACCAUCATT B 4736
    R-008399439-000S  397 1376 UCCUUCUCUGAGUGGUAAA B UCCUUCUCUGAGUGGUAAATT B 4738
    R-008399439-000S  397 1376 UCCUUCUCUGAGUGGUAAA UUUACCACUCAGAGAAGGAUU 4739
    R-008399442-000Y 1718 1377 GCAGUUCGCCUUCACUAUG B GCAGUUCGCCUUCACUAUGTT B 4740
    R-008399442-000Y 1718 1377 GCAGUUCGCCUUCACUAUG CAUAGUGAAGGCGAACUGCUU 4741
    R-008399445-000Z 1415  111 UGGACUCUCAGGAAUCUUU B UGGACUCUCAGGAAUCUUUTT B 4742
    R-008399445-000Z 1415  111 UGGACUCUCAGGAAUCUUU AAAGAUUCCUGAGAGUCCAUU 4743
    R-008399448-000A 1413  162 UUUGGACUCUCAGGAAUCU B UUUGGACUCUCAGGAAUCUTT B 4744
    R-008399448-000A 1413  162 UUUGGACUCUCAGGAAUCU AGAUUCCUGAGAGUCCAAAUU 4745
    R-008399451-000G 2445  160 AGGAUGCCUUGGGUAUGGA B AGGAUGCCUUGGGUAUGGATT B 4746
    R-008399451-000G 2445  160 AGGAUGCCUUGGGUAUGGA UCCAUACCCAAGGCAUCCUUU 4747
    R-008399454-000H  567  157 CUGAGACAUUAGAUGAGGG B CUGAGACAUUAGAUGAGGGTT B 4748
    R-008399454-000H  567  157 CUGAGACAUUAGAUGAGGG CCCUCAUCUAAUGUCUCAGUU 4749
    R-008399457-000J 1498   86 UUCAGAUGAUAUAAAUGUG CACAUUUAUAUCAUCUGAAUU 4751
    R-008399457-000J 1498   86 UUCAGAUGAUAUAAAUGUG B UUCAGAUGAUAUAAAUGUGTT B 4750
    R-008399460-000R 2357 1378 GGACUUGAUAUUGGUGCCC B GGACUUUGAAUUGGUGCCCTT B 4752
    R-008399460-000R 2357 1378 GGACUUGAUAUUGGUGCCC GGGCACCAAUAUCAAGUCCUU 4753
    R-008399463-000S  639 1379 GUUUGGCUGAACCAUCACA UGUGAUGGUUCAGCCAAACUU 4755
    R-008399463-000S  639 1379 GUUUGGCUGAACCAUCACA B GUUUGGCUGAACCAUCACATT B 4754
    R-008399466-000T  585 1380 GCAUGCAGAUCCCAUCUAC GUAGAUGGGAUCUGCAUGCUU 4757
    R-008399466-000T  585 1380 GCAUGCAGAUCCCAUCUAC B GCAUGCAGAUCCCAUCUACTT B 4756
    R-008399469-000U 2519 1381 GAUGGGCUGCCAGAUCUGG B GAUGGGCUGCCAGAUCUGGTT B 4758
    R-008399469-000U 2519 1381 GAUGGGCUGCCAGAUCUGG CCAGAUCUGGCAGCCCAUCUU 4759
    R-008399472-000A 1367 1382 GGACUUCACCUGACAGAUC B GGACUUCACCUGACAGAUCTT B 4760
    R-008399472-000A 1367 1382 GGACUUCACCUGACAGAUC GAUCUGUCAGGUGAAGUCCUU 4761
    R-008399475-000B 1391 1383 CAACGUCUUGUUCAGAACU B CAACGUCUUGUUCAGAACUTT B 4762
    R-008399475-000B 1391 1383 CAACGUCUUGUUCAGAACU AGUUCUGAACAAGACGUUGUU 4763
    R-008399478-000C  509 1384 GAUAUUGAUGUACAGUAUG B GAUAUUGAUGGACAGUAUGTT B 4764
    R-008399478-000C  509 1384 GAUAUUGAUGUACAGUAUG CAUACUGUCCAUCAAUAUCUU 4765
    R-008399481-000J  303 1385 UGGCCAUGGAACCAGACAG B UGGCCAUGGAACCAGACAGTT B 4766
    R-008399481-000J  303 1385 UGGCCAUGGAACCAGACAG CUGUCUGGUUCCAUGGCCAUU 4767
    R-008399484-000K  494 1386 CAAGAACAAGUAGCUGAUA UAUCAGCUACUUGUUCUUGUU 4769
    R-008399484-000K  494 1386 CAAGAACAAGUAGCUGAUA B CAAGAACAAGUAGCUGAUATT B 4768
    R-008399487-000L  328 1387 GGCUGUUAGUCACUGGCAG CUGCCAGUGACUAACAGCCUU 4771
    R-008399487-000L  328 1387 GGCUGUUAGUCACUGGCAG B GGCUGUUAGUCACUGGCAGTT B 4770
    R-008399490-000T 2058 1388 CAUUGUUUGUGCAGCUGCU AGCAGCUGCACAAACAAUGUU 4773
    R-008399490-000T 2058 1388 CAUUGUUUGUGCAGCUGCU B CAUUGUUUGUGCAGUUGCUTT B 4772
    R-008399493-000U 1447 1389 UAAACAGGAAGGGAUGGAA B UAAACAGGAAGGGAUGGAATT B 4774
    R-008399493-000U 1447 1389 UAAACAGGAAGGGAUGGAA UUCCAUCCCUUCCUGUUUAUU 4775
    R-008399496-000V 1563 1390 AUAAGAACAAGAUGAUGGU ACCAUCAUCUUGUUCUUAUUU 4777
    R-008399496-000V 1563 1390 AUAAGAACAAGAUGAUGGU B AUAAGAACAAGAUGAUGGUTT B 4776
    R-008399499-000W 1350 1391 GUGGAAUGCAAGCUUUAGG CCUAAAGUTUGCAUUCCACUU 4779
    R-008399499-000W 1350 1391 GUGGAAUGCAAGCUUUAGG B GUGGAAUGCAAGUTUUAGGTT B 4778
    R-008399502-000N 2208 1392 GGAAUGAAGGUGUGGCGAC GUCGCCACACCUUCAUUCCUU 4781
    R-008399502-000N 2208 1392 GGAAUGAAGGUGUGGCGAC B GGAAUGAAGGUGUGGCGACTT B 4780
    R-008399505-000P 1689 1393 GACACCAAGAAGCAGAGAU AUCUCUGUTUCUUGGUGUCUU 4783
    R-008399505-000P 1689 1393 GACACCAAGAAGCAGAGAU B GACACCAAGAAGCAGAGAUTT B 4782
    R-008399508-000R 1407 1394 ACUGUCUUUGGACUCUCAG B ACUGUCUUUGGACUCUCAGTT B 4784
    R-008399508-000R 1407 1394 ACUGUCUUUGGACUCUCAG CUGAGAGUCCAAAGACAGUUU 4785
    R-008399511-000X 2137 1395 GGACAAGGAAGCUGCAGAA B GGACAAGGAAGCUGCAGAATT B 4786
    R-008399511-000X 2137 1395 GGACAAGGAAGCUGCAGAA UUCUGCAGCUUCCUUGUCCUU 4787
    R-008399519-000Y  854 1396 UCUGCUAUUGUACGUACCA B UCUGCUAUUGUACGUACCATT B 4788
    R-008399514-000Y  854 1396 UCUGCUAUUGUACGUACCA UGGUACGUACAAUAGGAGAUU 4789
    R-008399517-000Z 2070 1397 AGCUGCUUUAUUCUCCCAU AUGGGAGAAUAAAGCAGCUUU 4791
    R-008399517-000Z 2070 1397 AGCUGCUUUAUUCUCCCAU B AGCUGCUUUAUUCUCCCAUTT B 4790
    R-008399520-000F  545 1398 AGGGUACGAGCUGCUAUGU ACAUAGCAGCUCGUACCCUUU 4793
    R-008399520-000F  545 1398 AGGGUACGAGCUGCUAUGU B AGGGUACGAGCUGCUAUGUTT B 4792
    R-008399523-000G 1640 1399 GAAGACAUCACUGAGCCUG B GAAGACAUCAGUGAGCCUGTT B 4794
    R-008399523-000G 1640 1399 GAAGACAUCACUGAGCCUG CAGGCUCAGUGAUGUCUUCUU 4795
    R-008399526-000H 2012 1400 CGGGAUGUUCACAACCGAA UUCGGUUGUGAACAUCCCGUU 4797
    R-008399526-000H 2012 1400 CGGGAUGUUCACAACCGAA B CGGGAUGUUCACAAGGGAATT B 4796
    R-008399529-000J 1684 1401 CAGCCGACACCAAGAAGCA B CAGCCGACACCAAGAAGCATT B 4798
    R-008399529-000J 1684 1401 CAGCCGACACCAAGAAGCA UGGUUCUUGGUGUCGGCUGUU 4799
    R-008399535-000S  520    9 ACAGUAUGCAAUGAGUCGA UCGAGUCAUUGCAUACUGUUU 4801
    R-008399535-000S  520    9 ACAGUAUGCAAUGACUCGA B AGAGUAUGCAAUGACUCGATT B 4800
    R-008399538-000T 1969  182 AGAAAUAGUUGAAGGUUGU B AGAAAUAGUUGAAGGUUGUTT B 4802
    R-008399538-000T 1969  182 AGAAAUAGUUGAAGGUUGU ACAACCUUCAACUAUUUCUUU 4803
    R-008399541-000Z 2017 1402 UGUUCACAACCGAAUUGUU B UGUUCACAACCGAAUUGUUTT B 4804
    R-008399591-000Z 2017 1402 UGUUCACAACCGAAUUGUU AACAAUUCGGUUGUGAACAUU 4805
    R-008399544-000A 2307 1403 GCUCUCUCUUCAGAACAGA B GCUCUCUCUUCAGAACAGATT B 4806
    R-008399544-000A 2307 1403 GCUCUCUCUUCAGAACAGA UCUGUUCUGAAGAGAGAGGUU 4807
    R-008399547-000B  844 1404 UCAGAUGGUGUCUGCUAUU B UCAGAUGGUGUCUGCUAUUTT B 4808
    R-008399597-000B  844 1404 UCAGAUGGUGUCUGCUAUU AAUAGCAGACACCAUCUGAUU 4809
    R-008399550-000H  405 1405 UGAGUGGUAAAGGCAAUCC GGAUUGCCUUUACCACUCAUU 4811
    R-008399550-000H  405 1405 UGAGUGGUAAAGGCAAUCC B UGAGUGGUAAAGGCAAUCCTT B 4810
    R-008399553-000J  379 1406 UGGUGCCACUACCACAGCU B UGGUGCCACUACCACAGCUTT B 4812
    R-008399553-000J  379 1406 UGGUGCCACUACCACAGCU AGCUGUGGUAGUGGCACCAUU 4813
    R-008399556-000K 1825 1407 UUGUCCCGCAAAUCAUGCA B UUGUCCCGCAAAUCAUGCATT B 4814
    R-008399556-000K 1825 1407 UUGUCCCGCAAAUCAUGCA UGCAUGAUUUGCGGGACAAUU 4815
    R-008399559-000L 2495 1408 CACCCUGGUGCUGACUAUC GAUAGUCAGCACCAGGGUGUU 4817
    R-008399559-000L 2495 1408 CACCCUGGUGCUGACUAUC B CACCCUGGUGCUGACUAUCTT B 4816
    R-008399562-000T  629 1409 AAUGUCCAGCGUUUGGCUG B AAUGUCCAGCGUUUGGCUGTT B 4818
    R-008399562-000T  629 1409 AAUGUCCAGCGUUUGGCUG CAGCCAAACGCUGGACAUUUU 4819
    R-008399565-000U 2561 1410 GGGCUGCCUCCAGGUGAGA UGUCACCUGGAGGCAGCCCUU 4821
    R-008399565-000U 2561 1410 GGGCUGCCUCCAGGUGACA B GGGCUGCCUCCAGGUGACATT B 4820
    R-008399568-000V 2192 1411 GAGUUACUUCACUCUAGUA B GAGUUACUUCACUCUAGGATT B 4822
    R-008399568-000V 2192 1411 GAGUUACUUCACUCUAGUA UCCUAGAGUGAAGUAACUCUU 4823
    R-008399571-000B 1809 1412 UUCGAAAUCUUGCCCUUUG B UUCGAAAUCUUGCCCUUUGTT B 4824
    R-008399571-000B 1809 1412 UUCGAAAUCUUGCCCUUUG CAAAGGGCAAGAUUUCGAAUU 4825
    R-008399574-000C 1596 1413 GUAUAGAGGCUCUUGUGCG B GUAUAGAGGCUCUUGUGCGTT B 4826
    R-008399574-000C 1596 1413 GUAUAGAGGCUCUUGUGCG CGCACAAGAGCCUCUAUACUU 4827
    R-008399577-000D 2298 1414 AGCUGACCAGCUCUCUCUU AAGAGAGAGCUGGUCAGCUUU 4829
    R-008399577-000D 2298 1414 AGCUGACCAGCUCUCUCUU B AGCUGACCAGCUCUCUCUUTT B 4828
    R-008399580-000K  858 1415 CUAUUGUACGUACCAUGCA UGCAUGGUACGUACAAUAGUU 4831
    R-008399580-000K  858 1415 CUAUUGUACGUACCAUGCA B CUAUUGUACGUACCAUGCATT B 4830
    R-008399583-000L  524 1416 UAUGCAAUGACUCGAGCUC B UAUGCAAUGACUCGAGCUCTT B 4832
    R-008399583-000L  524 1416 UAUGCAAUGACUCGAGCUC GAGCUCGAGUCAUUGCAUAUU 4833
    R-008399586-000M 2542 1417 UGCCCAGGACCUCAUGGAU B UGCCCAGGACCUCAUGGAUTT B 4834
    R-008399586-000M 2542 1417 UGCCCAGGACCUCAUGGAU AUCCAUGAGGUCCUGGGCAUU 4835
    R-008399589-000N  498 1418 AACAAGUAGCUGAUAUUGA B AACAAGUAGCUGAUAUUGATT B 4836
    R-008399589-000N  498 1418 AACAAGUAGCUGAUAUUGA UCAAUAUCAGCUACUUGUUUU 4837
    R-008399592-000V  414 1419 AAGGCAAUCCUGAGGAAGA UCUUCCUCAGGAUUGCCUUUU 4839
    R-008399592-000V  414 1419 AAGGCAAUCCUGAGGAAGA B AAGGCAAUCCUGAGGAAGATT B 4838
    R-008399595-000W 1570 1420 CAAGAUGAUGGUCUGCCAA B CAAGAUGAUGGUCUGCCAATT B 4840
    R-008399595-000W 1570 1420 CAAGAUGAUGGUCUGCCAA UUGGCAGACCAUCAUCUUGUU 4841
    R-008399598-000X 1030 1421 UGCCAUUACAACUCUCCAC GUGGAGAGUUGUAAUGGCAUU 4843
    R-008399598-000X 1030 1421 UGCCAUUACAACUCUCCAC B UGCCAUUACAACUCUCCACTT B 4842
    R-008399601-000P 1380   20 CAGAUCCAAGUCAACGUCU AGACGUUGACUUGGAUCUGUU 4845
    R-008399601-000P 1380   20 CAGAUCCAAGUCAACGUCU B CAGAUCCAAGUCAACGUCUTT B 4844
    R-008399604-000R 3087 1422 AUGUAUGGGUAGGGUAAAU B AUGUAUGGGUAGGGUAAAUTT B 4846
    R-008399604-000R 3087 1422 AUGUAUGGGUAGGGUAAAU AUUUACCCUACCCAUACAUUU 4847
    R-008399607-000S 1664 1423 UGUGCUCUUCGUCAUCUGA B UGUGCUCUUCGUCAUCUGATT B 4848
    R-008399607-000S 1664 1423 UGUGCUCUUCGUCAUCUGA UCAGAUGACGAAGAGCACAUU 4849
    R-008399610-000Y 1790 1424 AAGGCUACUGUUGGAUUGA B AAGGCUACUGUUGGAUUGATT B 4850
    R-008399610-000Y 1790 1424 AAGGCUACUGUUGGAUUGA UCAAUCCAACAGUAGCCUUUU 4851
    R-008399613-000Z 1615 1425 UACUGUCCUUCGGGCUGGU ACCAGCCCGAAGGACAGUAUU 4853
    R-008399613-000Z 1615 1425 UACUGUCCUUCGGGCUGGU B UACUGUCCUUCGGGCUGGUTT B 4852
    R-008399616-000A  774 1426 AUAAGGCUGCAGUUAUGGU ACCAUAACUGCAGCCUUAUUU 4855
    R-008399616-000A  774 1426 AUAAGGCUGCAGUUAUGGU B AUAAGGCUGCAGUUAUGGUTT B 4854
    R-008399619-000B 1672 1427 UCGUCAUCUGACCAGCCGA UCGGCUGGUCAGAUGACGAUU 4857
    R-008399619-000B 1672 1427 UCGUCAUCUGACCAGCCGA B UCGUCAUCUGACCAGCCGATT B 4856
    R-008399625-000J 3171 1428 GUUGUAACCUGCUGUGAUA UAUCACAGCAGGUUACAACUU 4859
    R-008399625-000J 3171 1428 GUUGUAACCUGCUGUGAUA B GUUGUAACCUGCUGUGAUATT B 4858
    R-008399628-000K 2271 1429 AAGAUUACAAGAAACGGCU B AAGAUUACAAGAAACGGCUTT B 4860
    R-008399628-000K 2271 1429 AAGAUUACAAGAAACGGCU AGCCGUUUCUUGUAAUCUUUU 4861
    R-008399631-000S 1183 1430 UUAUGGCAACCAAGAAAGC B UUAUGGCAACCAAGAAAGCTT B 4862
    R-008399631-000S 1183 1430 UUAUGGCAACCAAGAAAGC GCUUUCUUGGUUGCCAUAAUU 4863
    R-008399634-000T 2512 1431 UCCAGUUGAUGGGCUGCCA B UCCAGUUGAUGGGCUGCCATT B 4864
    R-008399634-000T 2512 1431 UCCAGUUGAUGGGCUGCCA UGGCAGCCCAUCAACUGGAUU 4865
    R-008399637-000U 1521  132 CCUGUGGAGCUGGAAUUCU AGAAUUCCAGCUGCACAGGUU 4867
    R-008399637-000U 1521  132 CCUGUGCAGCUGGAAUUCU B CCUGUGCAGCUGGAAUUCUTT B 4866
    R-008399640-000A 1931 1432 GGGACACAGCAGCAAUUUG CAAAUUGCUGCUGUGUCCCUU 4869
    R-008399640-000A 1931 1432 GGGACACAGCAGCAAUUUG B GGGACACAGCAGCAAUUUGTT B 4868
    R-008399643-000B 2468 1433 AUGAUGGAACAUGAGAUGG B AUGAUGGAACAUGAGAUGGTT B 4870
    R-008399643-000B 2468 1433 AUGAUGGAACAUGAGAUGG CCAUCUCAUGAUCCAUCAUUU 4871
    R-008399646-000C 3077 1434 UAUUUGGGAUAUGUAUGGG B UAUUUGGGAUAUGUAUGGGTT B 4872
    R-008399646-000C 3077 1434 UAUUUGGGAUAUGUAUGGG CCCAUACAUAUCCCAAAUAUU 4873
    R-008399649-000D 2069 1435 CAGCUGCUUUAUUCUCCCA UGGGAGAAUAAAUCAGCUGUU 4875
    R-008399649-000D 2069 1435 CAGCUGCUUUAUUCUCCCA B CAGCUGCUUUAUUCUCCCATT B 4874
    R-008399652-000K  272 1436 GCUACUCAAGCUGAUUUGA B GCUACUCAAGCUGAUUUGATT B 4876
    R-008399652-000K  272 1436 GCUACUCAAGCUGAUUUGA UCAAAUCAGCUUGAGUAGCUU 4877
    R-008399655-000L  564 1437 UCCCUGAGACAUUAGAUGA UCAUCUAAUGUCUCAGGGAUU 4879
    R-008399655-000L  564 1437 UCCCUGAGACAUUAGAUGA B UCCCUGAGACAUUAGAUGATT B 4878
    R-008399658-000M  437 1438 GUGGAUACCUCCCAAGUCC GGACUUGGGAGGUAUCCACUU 4881
    R-008399658-000M  437 1438 GUGGAUACCUCCCAAGUCC B GUGGAUACCUCCCAAGUCCTT B 4880
    R-008399661-000U 2206 1439 UAGGAAUGAAGGUGUGGCG B UAGGAAUGAAGGUGUGGCGTT B 4882
    R-008399661-000U 2206 1439 UAGGAAUGAAGGUGUGGCG CGCCACACCUUCAUUCCUAUU 4883
    R-008399664-000V 2187 1440 UGACAGAGUUACUUCACUC GAGUGAAGUAACUCUGUCAUU 4885
    R-008399664-000V 2187 1440 UGACAGAGUUACUUCACUC B UGACAGAGUUACUUCACUCTT B 4884
    R-008399667-000W  325 1441 AGCGGCUGUUAGUCACUGG CCAGUGACUAACAGCCGCUUU 4887
    R-008399667-000W  325 1441 AGCGGCUGUUAGUCACUGG B AGCGGCUGUUAGUCACUGGTT B 4886
    R-008399670-000C 3222 1442 AUGGUUCAGAAUUAAACUU B AUGGUUCAGAAUUAAACUUTT B 4888
    R-008399670-000C 3222 1442 AUGGUUCAGAAUUAAACUU AAGUUUAAUUCUGAACCAUUU 4889
    R-008399673-000D 2024 1443 AACCGAAUUGUUAUCAGAG B AACCGAAUUGUUAUCAGAGTT B 4890
    R-008399673-000D 2024 1443 AACCGAAUUGUUAUCAGAG CUCUGAUAACAAUUCGGUUUU 4891
    R-008399676-000E 1858 1444 GGGUGCCAUUCCACGACUA B GGGUGCCAUUCCACGACUATT B 4892
    R-008399676-000E 1858 1444 GGGUGCCAUUCCACGACUA UAGUCGUGGAAUGGCACCCUU 4893
    R-008399679-000F 1574 1445 AUGAUGGUCUGCCAAGUGG B AUGAUGGUCUGCCAAGUGGTT B 4894
    R-008399679-000F 1574 1445 AUGAUGGUCUGCCAAGUGG CCACUUGGCAGACCAUCAUUU 4895
    R-008399682-000M 1638   78 GGGAAGACAUCACUGAGCC B GGGAAGACAUCACUGAGCCTT B 4896
    R-008399682-000M 1638   78 GGGAAGACAUCACUGAGCC GGCUCAGUGAUGUCUUCCCUU 4897
    R-008399685-000N 1896 1446 CACAUCAGGAUACCCAGCG B CACAUCAGGAUACCCAGCGTT B 4898
    R-008399685-000N 1896 1446 CACAUCAGGAUACCCAGCG CGCUGGGUAUCCUGAUGUGUU 4899
    R-008399688-000P 2207 1447 AGGAAUGAAGGUGUGGCGA B AGGAAUGAAGGUGUGGCGATT B 4900
    R-008399688-000P 2207 1447 AGGAAUGAAGGUGUGGCGA UCGCCACACCUUCAUUCCUUU 4901
    R-008399691-000W 1300 1448 GAAGGUGCUAUCUGUCUGC B GAAGGUGCUAUCUGUCUGCTT B 4902
    R-008399691-000W 1300 1448 GAAGGUGCUAUCUGUCUGC GCAGACAGAUAGCACCUUCUU 4903
    R-008399694-000X 1192 1449 CCAAGAAAGCAAGCUCAUC GAUGAGCUUGCUUUCUUGGUU 4905
    R-008399694-000X 1192 1449 CCAAGAAAGCAAGCUCAUC B CCAAGAAAGCAAGCUCAUCTT B 4904
    R-008399697-000Y  551 1450 CGAGCUGCUAUGUUCCCUG B CGAGCUGCUAUGUUCCCUGTT B 4906
    R-008399697-000Y  551 1450 CGAGCUGCUAUGUUCCCUG CAGGGAACAUAGCAGCUCGUU 4907
    R-008399700-000R 2498 1451 CCUGGUGCUGACUAUCCAG B CCUGGUGCUGACUAUCCAGTT B 4908
    R-008399700-000R 2498 1451 CCUGGUGCUGACUAUCCAG CUGGAUAGUCAGCACCAGGUU 4909
    R-008399703-000S 1305 1452 UGCUAUCUGUCUGCUCUAG B UGCUAUCUGUCUGCUCUAGTT B 4910
    R-008399703-000S 1305 1452 UGCUAUCUGUCUGCUCUAG CUAGAGCAGACAGAUAGCAUU 4911
    R-008399706-000T 1337 1453 AUUGUAGAAGCUGGUGGAA B AUUGUAGAAGCUGGUGGAATT B 4912
    R-008399706-000T 1337 1153 AUUGUAGAAGCUGGUGGAA UUCCACCAGCUUCUACAAUUU 4913
    R-008472717-000G 1870  194 ACGACUAGUUCAGUUGCUU B aCgaC UAguUCAGUUGCU U UsU B 2147
    R-008472717-000G 1870  194 ACGACUAGUUCAGUUGCUU aaGCAAcUgAAcuagUCGUUsU 6367
    R-008472765-000B 1870  194 ACGACUAGUUCAGUUGCUU aaGCaAcUGAAcuaGUCGUUsU 6368
    R-008472765-000B 1870  194 ACGACUAGUUCAGUUGCUU B aCgaC UAguUCAGUUGCU U UsU B 2147
    R-008488882-000B 1797    5 CUGUUGGAUUGAUUCGAAA B CUGUUGGAUUGAUUCGAAAUU B 6370
    R-008488882-000B 1797    5 CUGUUGGAUUGAUUCGAAA uuucGAauCaAUCcAaCaGUU 6369
    R-008488887-000V 1870  194 ACGACUAGUUCAGUUGCUU aaGCAAcUgAaCuagUcGUUU 6371
    R-008488887-000V 1870  194 ACGACUAGUUCAGUUGCUU B aCgaC UAguUCAGUUGCU U UU B 6372
    R-008488885-000C 1870  194 ACGACUAGUUCAGUUGCUU aaGCAAcUgAAcuagUCGUUU 6373
    R-008488885-000C 1870  194 ACGACUAGUUCAGUUGCUU B aCgaC UAguUCAGUUGCU U UU B 6372
    R-008488889-000M 1870  194 ACGACUAGUUCAGUUGCUU B aCgaC UAguUCAGUUGCU U UU B 6372
    R-008488889-000M 1870  194 ACGACUAGUUCAGUUGCUU aaGCaAcUGAAcuaGUCGUUU 6374
    wherein:
    A, C, G, and U = ribose A, C, G or U
    a, g, c and u = 2′-deoxy-2′-fluoro A, G, C or U
    A, U, C and G = 2′-O-methyl (2′-OMe) A, U, C, or G
    A, U, C, and G = deoxy A, U, C, or G
    B = inverted abasic
    T = thymidine
    I = inosine
    s = phosphorothioate linkage
  • Further Synthesis Steps for Commercial Preparation
  • Once analysis indicates that the target product purity has been achieved after the annealing step, the material is transferred to the tangential flow filtration (TFF) system for concentration and desalting, as opposed to doing this prior to the annealing step.
  • Ultrafiltration: The annealed product solution is concentrated using a TFF system containing an appropriate molecular weight cut-off membrane. Following concentration, the product solution is desalted via diafiltration using water until the conductivity of the filtrate is that of water.
  • Lyophilization: The concentrated solution is transferred to a bottle, flash frozen and attached to a lyophilizer. The product is then freeze-dried to a powder. The bottle is removed from the lyophilizer and is now ready for use.
  • Initial Screening Protocol (96-Well Plate Transfections)
  • Cell Culture Preparation:
  • Human hepatoma cell line, HepG2, rhesus kidney epithelial cell line, LLC-MK2 Derivative, and the Huh7 cell line, were grown in modified Eagle's medium. All the culture media were supplemented with 10% fetal bovine serum, 100 μg/ML streptomycin, 100 U/ml, penicillin, and 1% sodium bicarbonate.
  • Transfection and Screening
  • Cells were plated in all wells of tissue-culture treated, plates at a final count of 3500 (HepG2 find LLC-MK2 Derivative and Huh7) cells/well in 100 μL of the appropriate culture media. The cells were cultured for overnight after plating at 37° C. in the presence of 5% CO2.
  • On the next day, complexes containing siNA and RNAiMax (invitrogen) were created as follows. A solution of RNAiMax diluted 33-fold in OPTI-MEM was prepared. In parallel, solutions of the siNAs for testing were prepared to a final concentration of 120 nM in OPTI-MEM. After incubation of RNAiMax/OPTI-MEM solution at room temperature for 5 ruin, an equal volume of the siNA solution and the RNAiMax solution were added together for each of the siNAs.
  • Mixing resulted in a solution of siNA/RNAiMax where the concentration of siNA was 60 nM. This solution was incubated at room temperature for 20 minutes. After incubation, 20 μK of the solution was added to each of the relevant wells. The final concentration of siNA in each well was 10 nM and the final volume of RNAiMax in each well was 0.3 ul.
  • For low concentration screens, siNAs were transfected at 200, 150, 100 or 75 pM per well. For 12-point dose response curve studies, the siNA series are 6-fold serial dilution starting at 300 nM or 4-fold serial dilution starting at 40 nM. All transfections were set up as multiple biological replicates.
  • The time of incubation with the RNAiMax-siNA complexes was 24 hours and there was no change in media between transfection and harvesting for screening and dose response curve studies. For duration assays, the time of incubation with the RNAiMax-siNA complexes was 24, 72, and 120 hours. There was no change in media between transfection and harvesting for 24- and 72-hour time points. Media was replaced with fresh media 72 hours after transfection for 120-hour time point.
  • Cells-to-Ct and Reverse Transcription Reactions
  • The culture medium was aspirated and discarded from the wells of the culture plates at the desired time points. The transfected cells were washed once with 50 uL DPBS solution per well. Fifty microliters per well of the Lysis Solution from the TaqMan® Gene Expression Cells-to-CT™ Kit (Applied Biosystems, Cat #4399002) supplemented with DNase I was added directly to the plates to lyse the cells. Five microliters per well of Stop Solution from the same kit was added to the plates to inactivate DNase I 5 minutes later. The lysis plates were incubated for at least 2 minutes at room temperature. The plates can be stored for 2 hours at 4° C., or −80° C. tor two months.
  • Each well of the reverse transcription plate required 10 uL of 2× reverse transcriptase buffer, 1 uL of 20× reverse transcription enzyme and 2 uL of nuclease-free water. The reverse transcription master mix was prepared by mixing 2× reverse transcription buffer, 20× reverse transcription enzyme mix, and nuclease-free water. 13 uL of the reverse transcription master mix was dispensed into each well of the reverse transcription plate (semi-skirted). A separate reverse transcription plate was prepared for each cell plate. A separate reverse transcription plate was prepared for each cell plate. Seven microliters per lysate from the cell lysis procedure described above was added into each well of the reverse transcription plate. The plate was sealed and spun on a centrifuge (1000 rpm for 30 seconds) to settle the contents to the bottom of the reverse transcription plate. The plate was placed in a thermocycler at 37° C. for 60 min, 95° C. for 5 min, and 4° C. until the plate is removed from the thermocycler. Upon removal, if not used immediately, the plate was frozen at −20° C.
  • For duration assays, a similar protocol was followed, however, the cells were lysed 1, 3, or 5 days after transfection. cDNA was generated using Cells-to-Ct™ Kit (Applied Biosystems).
  • Quantitative RT-PCR (Taqman)
  • A series of probes and primers were used to detect the various mRNA transcripts of the genes of CTNNB1 and GAPDH. All Taqman probes and primers for the experiments here-in described were supplied as pre-validated sets by Applied Biosystems, Inc. (see Table 2).
  • TABLE 2
    Probes and primers used to carry out
    Real-Time RT/PCR (Taqman) reactions
    for CTNNB1 mRNA analysis.
    Species Gene ABI Cat. #
    Human CTNNB1 Hs00355045_m1
    Human GAPDH 4310884E
    Rhesus GAPDH Rh02621745_g1
    Mouse CTNNB1 Mm00483033_m1
    Mouse GAPDH 4352339E
  • The assays were performed on an ABI 7900 instrument, according to the manufacturer's instructions. A TagMan Gene Expression Master Mix (provided in the Cells-to-CT™ Kit, Applied Biosystems, Cat #4399002) was used. The PCR reactions were carried out at 50° C. for 2 min, 95° C. for 10 min followed by 40 cycles at 95° C. for 15 sees and 60° C. for 1 minute.
  • Within each experiment, the baseline was set in the exponential phase of the amplification curve, and based on the intersection point of the baselines with the amplification curve, a Ct value was assigned by the instrument.
  • Calculations
  • The expression level of the gene of interest and % inhibition of gene expression (% KD) was calculated using Comparative Ct method:

  • ΔCt=Ct Target −Ct GAPDH

  • ΔΔCt(Log 2(fold change))=ΔCt (Target siNA) −ΔCt (NTC)

  • Relative expression level=−ΔΔCt

  • % KD=100×(1−2−ΔΔCt)
  • The non-targeting control siNA was, unless otherwise indicated, chosen as the value against which to calculate the percent inhibition (knockdown) of gene expression, because it is the most relevant control.
  • Additionally, only normalized data, which reflects the general health of the cell and quality of the RNA extraction, was examined. This was done by looking at the level of two different mRNAs in the treated cells, the first being the target LANA and the second being the normalizer mRNA. This allowed for elimination of siNAs that might be potentially toxic to cells rather than solely knocking down the gene of interest. This was done by comparing the Ct for GAPDH in each well relative to the GAPDH Ct for the entire plate.
  • All calculations of IC50s were performed using R.2.9.2 software. The data were analyzed using the sigmoidal dose-response (variable slope) equation for simple ligand binding. In all of the calculations of the percent inhibition (knock-down), the calculation was made relative to the normalized level of expression of the gene of interest in the samples treated with the non-targeting control (Ctrl siNA) unless otherwise indicated.
  • The level of protein was quantified using the Bio-Rad VersaDoc Imager according to the protocols of that piece of equipment. A pixel count was performed in each lane using an area of identical size. Each sample was then compared to the appropriate control treated sample and converted to a percent of protein remaining compared to control.
  • The effects of lead siNAs on CTNNB1 protein level were compared to the effects of the universal control using a two tail Student's T-test to obtain a P value. P<0.05 was considered significant.
  • Results:
  • The CTNNB1 siNAs were designed and synthesized as described previously. Various siNAs were screened in HepG2, MK2D and Huh7 cells. The log 2 (fold change) in CTNNB1 gene expression data upon treatment with various modified CTNNB1 siNAs in human cells is shown in Table 3a. Each screen was performed at 24 hrs. Quantitative RT-PCR was used to assess the level of CTNNB1 mRNA and the data were normalized to the expression level of GAPDH (an ubiquitously expressed ‘house-keeping’ gene). Each treatment was then normalized against the non-CTNNB1 targeting control.
  • TABLE 3a
    Primary screening data in HepG2 Cells, MK2D Cells and Huh7 Cells
    (n = 2), recorded as log 2(fold change) in CTNNB1 gene expression.
    HEPG2 HEPG2 MK2D MK2D Huh7 Huh7
    Mean SD Mean SD Mean SD
    siNA Duplex ID ΔΔCt ΔΔCt ΔΔCt ΔΔCt ΔΔCt ΔΔCt
    R-008362875-000L 5.06 0.28 5.05 0.05 4.10 0.12
    R-008362785-000U 4.92 0.24 4.98 0.05 4.05 0.14
    R-008362959-000W 4.76 0.11 4.90 0.14 3.99 0.05
    R-008363073-000K 4.54 0.16 5.15 0.14 3.98 0.60
    R-008308997-000F 4.27 0.32 4.86 0.17 3.97 0.16
    R-008362932-000A 4.57 0.50 5.13 0.13 3.97 0.11
    R-008362713-000E 4.52 0.02 4.56 0.00 3.96 0.20
    R-008362791-000B 5.14 0.21 5.96 0.04 3.94 0.06
    R-008362689-000U 5.16 0.20 5.24 0.04 3.94 0.08
    R-008362692-000A 0.84 0.06 4.30 0.09 3.94 0.00
    R-008363055-000T 4.87 0.16 5.19 0.11 3.86 0.13
    R-008309033-000Y 4.39 0.08 5.35 0.15 3.83 0.04
    R-008363058-000U 4.20 0.23 4.68 0.22 3.83 0.43
    R-008362755-000S 4.18 0.21 4.37 0.08 3.83 0.10
    R-008362821-000P 4.29 0.53 4.95 0.11 3.83 0.09
    R-008362722-000N 5.37 0.36 5.27 0.19 3.82 0.25
    R-008362824-000R 4.36 0.23 4.92 0.06 3.80 0.05
    R-008363070-000J 4.51 0.03 4.54 0.01 3.79 0.14
    R-008362686-000T 4.84 0.26 5.03 0.08 3.79 0.34
    R-008362947-000L 4.45 0.25 4.74 0.04 3.79 0.44
    R-008362728-000R 4.66 0.15 4.47 0.12 3.77 0.15
    R-008363019-000H 4.75 0.08 5.06 0.05 3.77 0.21
    R-008362833-000Z 4.26 0.11 4.61 0.15 3.75 0.09
    R-008362812-000F 4.79 0.14 4.93 0.17 3.75 0.37
    R-008363064-000B 4.54 0.11 4.87 0.16 3.75 0.49
    R-008362980-000V 1.07 0.02 4.48 0.13 3.73 0.09
    R-008362992-000E 0.35 0.09 4.24 0.04 3.72 0.00
    R-008362872-000K 4.28 0.26 4.77 0.11 3.70 0.02
    R-008362677-000J 4.37 0.06 4.60 0.01 3.68 0.08
    R-008362878-000M 3.85 0.09 4.54 0.06 3.67 0.01
    R-008363031-000Y 4.82 0.26 5.19 0.14 3.65 0.00
    R-008363043-000H 4.89 0.27 5.61 0.03 3.65 0.04
    R-008362797-000D 4.77 0.03 4.31 0.09 3.63 0.09
    R-008362842-000H 3.92 0.00 4.71 0.09 3.63 0.26
    R-008362704-000W 4.11 0.16 4.38 0.12 3.60 0.17
    R-008362740-000F 0.66 0.11 4.74 0.10 3.60 0.00
    R-008362839-000B 4.10 0.22 4.43 0.16 3.57 0.40
    R-008362950-000T 4.73 0.08 4.80 0.21 3.55 0.03
    R-008363010-000E 4.28 0.12 4.44 0.09 3.51 0.40
    R-008362752-000R 3.42 0.03 2.93 0.04 3.50 0.33
    R-008362854-000T 0.72 0.26 3.93 0.09 3.49 0.00
    R-008362830-000Y 4.59 0.12 4.90 0.04 3.48 0.03
    R-008363016-000G 4.14 0.09 4.35 0.02 3.45 0.05
    R-008362998-000G 4.29 0.18 4.05 0.12 3.45 0.01
    R-008362674-000H 4.55 0.14 4.55 0.01 3.45 0.32
    R-008362938-000C 4.27 0.10 5.01 0.22 3.44 0.27
    R-008362788-000V 4.11 0.21 4.48 0.09 3.44 0.11
    R-008362884-000V 4.11 0.08 4.90 0.13 3.44 0.11
    R-008362896-000E 3.91 0.18 3.86 0.06 3.44 0.29
    R-008363061-000A 3.84 0.17 4.34 0.01 3.43 0.14
    R-008362782-000T 3.73 0.60 5.27 0.13 3.43 0.43
    R-008362776-000K 4.08 0.15 4.33 0.15 3.43 0.12
    R-008362764-000A 1.00 0.02 4.82 0.14 3.40 0.31
    R-008362683-000S 0.85 0.00 4.80 0.12 3.39 0.32
    R-008362869-000D 4.65 0.02 4.57 0.06 3.36 0.24
    R-008309054-000S 0.88 0.01 4.27 0.08 3.36 0.12
    R-008362746-000H 4.22 0.08 4.85 0.07 3.35 0.47
    R-008362935-000B 4.51 0.01 5.00 0.14 3.33 0.15
    R-008362995-000F 3.52 0.02 4.80 0.02 3.31 0.25
    R-008362923-000S 4.16 0.16 4.15 0.08 3.31 0.09
    R-008309099-000E 3.72 0.38 4.49 0.03 3.30 0.23
    R-008362794-000C 3.97 0.05 3.81 0.05 3.30 0.12
    R-008308556-000N 4.54 0.04 4.69 0.19 3.29 0.13
    R-008309087-000V 4.04 0.06 4.19 0.14 3.28 0.01
    R-008362893-000D 0.66 0.15 4.31 0.05 3.27 0.20
    R-008362725-000P 4.20 0.22 4.54 0.23 3.26 0.05
    R-008362863-000B 1.04 0.13 4.27 0.09 3.26 0.20
    R-008362941-000J 3.93 0.42 4.38 0.16 3.24 0.34
    R-008362929-000U 1.45 0.05 3.98 0.08 3.23 0.04
    R-008363052-000S 0.43 0.13 4.30 0.07 3.23 0.03
    R-008362857-000U 1.73 0.12 3.70 0.08 3.23 0.37
    R-008362758-000T 0.70 0.16 4.19 0.10 3.22 0.41
    R-008309048-000J 4.21 0.15 4.23 0.09 3.21 0.14
    R-008363004-000X 3.76 0.12 4.55 0.07 3.20 0.43
    R-008362719-000G 3.88 0.16 4.61 0.31 3.20 0.09
    R-008362671-000G 4.56 0.19 4.71 0.19 3.20 0.06
    R-008363049-000K 3.40 0.08 3.01 0.01 3.19 0.22
    R-008362902-000Y 3.79 0.29 3.92 0.12 3.19 0.07
    R-008363022-000P 4.32 0.21 4.06 0.12 3.14 0.43
    R-008362848-000K 3.83 0.04 4.04 0.18 3.09 0.08
    R-008362743-000G 4.46 0.16 5.28 0.10 3.09 0.69
    R-008362737-000Z 4.41 0.09 4.88 0.24 3.09 0.19
    R-008362881-000U 0.77 0.02 4.08 0.10 3.09 0.05
    R-008308601-000T 4.21 0.54 4.56 0.02 3.08 0.17
    R-008362983-000W 4.09 0.03 4.38 0.00 3.04 0.12
    R-008362800-000W 4.42 0.15 4.69 0.06 3.02 0.38
    R-008362971-000L 4.10 0.14 4.48 0.05 3.02 0.01
    R-008308661-000X 3.68 0.27 4.68 0.21 3.00 0.09
    R-008362956-000V 3.89 0.10 3.97 0.19 3.00 0.05
    R-008363001-00W 3.97 0.05 4.25 0.06 2.99 0.02
    R-008362680-000R 4.22 0.16 4.33 0.12 2.99 0.31
    R-008309081-000T 3.97 0.11 4.21 0.01 2.99 0.35
    R-008362860-000A 3.39 0.49 3.39 0.01 2.98 0.19
    R-008362716-000F 3.87 0.10 4.27 0.19 2.96 0.20
    R-008362809-000Z 0.82 0.00 3.79 0.06 2.95 0.18
    R-008308562-000W 3.85 0.14 4.09 0.09 2.94 0.01
    R-008362989-000Y 4.11 0.07 4.27 0.01 2.94 0.01
    R-008309102-000X 3.95 0.05 3.89 0.20 2.90 0.11
    R-008362773-000J 3.92 0.23 3.99 0.02 2.89 0.06
    R-008362779-000L 4.30 0.20 4.46 0.02 2.85 0.86
    R-008362962-000C 3.67 0.08 3.59 0.09 2.82 0.00
    R-008362905-000Z 3.33 0.22 3.81 0.08 2.78 0.14
    R-008362707-000X 3.53 0.49 4.13 0.15 2.78 0.03
    R-008362977-000N 3.29 0.34 4.18 0.01 2.76 0.27
    R-008362944-000K 3.56 0.19 3.31 0.13 2.75 0.19
    R-008309018-000G 3.53 0.13 4.22 0.07 2.72 0.16
    R-008362770-000H 3.92 0.15 3.97 0.01 2.72 0.12
    R-008362749-000J 3.29 0.13 3.60 0.02 2.68 0.09
    R-008308496-000Y 3.83 0.21 4.49 0.11 2.67 0.41
    R-008362836-000A 0.49 0.02 3.94 0.05 2.67 0.81
    R-008308667-000Z 4.42 0.01 4.60 0.03 2.65 0.45
    R-008362926-000T 4.22 0.08 5.81 0.12 2.60 0.18
    R-008362851-000S 4.01 0.80 4.57 0.01 2.53 0.95
    R-008363007-000Y 3.23 0.05 2.93 0.15 2.51 0.19
    R-008362701-000V 3.94 0.09 4.32 0.13 2.51 0.48
    R-008362698-000C 4.10 0.03 4.15 0.13 2.50 0.24
    R-008308625-000M 3.77 0.09 3.42 0.24 2.46 0.03
    R-008362815-000G 4.27 0.20 4.14 0.09 2.46 0.51
    R-008363067-000C 4.14 0.27 5.42 0.16 2.46 0.06
    R-008362914-000H 3.78 0.03 3.66 0.06 2.41 0.25
    R-008363028-000S 0.86 0.01 4.10 0.07 2.39 0.09
    R-008362866-000C 3.42 0.03 3.68 0.01 2.38 0.07
    R-008362695-000B 3.06 0.18 2.78 0.06 2.37 0.27
    R-008363013-000F 3.56 0.24 3.93 0.11 2.37 0.16
    R-008362908-000A 3.20 0.11 2.63 0.01 2.35 0.09
    R-008362917-000J 3.01 0.04 3.23 0.05 2.34 0.15
    R-008308508-000U 4.18 0.04 4.17 0.02 2.29 0.58
    R-008308526-000L 0.59 0.04 3.87 0.09 2.27 0.15
    R-008363034-000Z 0.78 0.17 3.95 0.02 2.27 0.30
    R-008362827-000S 3.74 0.00 3.12 0.05 2.25 0.09
    R-008362968-000E 4.00 0.02 3.46 0.12 2.24 0.62
    R-008309006-000X 2.95 0.26 2.59 0.04 2.24 0.07
    R-008362734-000Y 4.06 0.02 4.33 0.15 2.21 0.41
    R-008362767-000B 4.22 0.05 4.19 0.13 2.13 0.41
    R-008362806-000Y 0.73 0.04 2.89 0.02 2.08 0.56
    R-008308724-000N 3.34 0.05 3.55 0.01 2.06 0.04
    R-008362818-000H 1.49 0.14 3.44 0.05 2.05 0.18
    R-008309051-000R 2.38 0.12 2.71 0.06 2.04 0.30
    R-008362920-000R 2.82 0.31 3.00 0.13 1.98 0.03
    R-008362965-000D 1.24 0.07 2.76 0.00 1.98 0.05
    R-008308544-000D 0.53 0.03 3.67 0.07 1.97 0.04
    R-008308523-000K 3.15 0.01 3.69 0.12 1.94 0.17
    R-008362986-000X 3.24 0.08 3.50 0.13 1.92 0.01
    R-008362731-000X 3.62 0.04 2.96 0.09 1.77 1.24
    R-008363046-000J 2.67 0.02 3.94 0.05 1.75 0.07
    R-008308733-000X 3.32 0.16 2.63 0.08 1.74 0.15
    R-008362911-000G 0.75 0.04 2.74 0.10 1.73 0.26
    R-008308706-000W 3.31 0.01 4.09 0.17 1.61 0.09
    R-008308709-000X 3.29 0.13 3.95 0.00 1.54 0.30
    R-008362890-000C 0.90 0.03 1.03 0.22 1.35 0.34
    R-008363025-000R 2.95 0.06 3.05 0.08 1.32 0.81
    R-008362953-000U 2.33 0.03 2.67 0.10 1.24 0.10
    R-008362899-000F 1.50 0.17 2.77 0.03 1.24 0.13
    R-008308697-000B 2.18 0.11 2.19 0.04 1.17 0.02
    R-008308589-000S 2.17 0.22 3.42 0.03 1.12 0.08
    R-008308634-000W 2.41 0.11 2.66 0.01 1.09 0.11
    R-008362710-000D 0.71 0.10 2.17 0.11 1.06 0.18
    R-008308493-000X 0.55 0.03 2.12 0.24 1.00 0.05
    R-008308703-000V 0.87 0.02 1.69 0.02 0.95 0.13
    R-008308568-000Y 2.84 0.14 2.85 0.23 0.63 0.41
    R-008362887-000W 0.83 0.14 0.93 0.09 0.33 0.07
    R-008362974-000M 0.80 0.07 0.96 0.02 0.23 0.02
    R-008363037-000A 0.69 0.09 0.85 0.05 0.12 0.03
    R-008363040-000G −0.07 0.02 −0.22 0.05 −0.19 0.09
    R-008362845-000J −4.37 0.21 −1.50 0.07 −1.25 0.33
    R-008362761-000Z −2.03 0.11 −3.54 0.05 −1.88 0.24
    R-008308586-000R −1.64 0.18 −1.83 0.01 −2.27 0.31
    R-008362803-000X −4.04 0.51 −4.61 0.01 −4.03 0.44
  • A subset of siNAs from Table 3a having a large log 2 (fold change in the primary screen were rescreened in Huh7 cells. The results are shown in Table 3b.
  • TABLE 3b
    Primary screening data in Huh7 Cells (n = 2), recorded as log
    2(fold change) in CTNNB1 gene expression.
    Huh7 Huh7
    Mean SD
    siNA Duplex ID ΔΔCt ΔΔCt
    R-008362791-000B 4.24 0.05
    R-008362812-000F 4.17 0.02
    R-008362689-000U 4.17 0.01
    R-008362722-000N 4.17 0.04
    R-008362932-000A 4.07 0.17
    R-008363043-000H 4.05 0.02
    R-008362875-000L 4.03 0.12
    R-008308997-000F 3.99 0.35
    R-008362947-000L 3.99 0.18
    R-008362821-000P 3.95 0.11
    R-008362686-000T 3.94 0.13
    R-008363070-000J 3.91 0.08
    R-008362824-000R 3.91 0.16
    R-008362785-000U 3.88 0.06
    R-008363031-000Y 3.88 0.10
    R-008363073-000K 3.87 0.19
    R-008362782-000T 3.86 0.04
    R-008309033-000Y 3.85 0.00
    R-008363064-000B 3.84 0.08
    R-008362950-000T 3.84 0.05
    R-008362959-000W 3.83 0.28
    R-008363019-000H 3.82 0.02
    R-008362842-000H 3.82 0.14
    R-008363058-000U 3.75 0.11
    R-008362713-000E 3.73 0.08
    R-008362938-000C 3.72 0.05
    R-008362755-000S 3.71 0.16
    R-008362746-000H 3.59 0.22
    R-008362830-000Y 3.56 0.16
    R-008362704-000W 3.55 0.11
    R-008362839-000B 3.48 0.23
    R-008362992-000E 3.45 0.04
    R-008363055-000T 3.44 0.26
    R-008363061-000A 3.38 0.07
    R-008362995-000F 3.35 0.01
  • The CTNNB1 siNAs were designed and synthesized as described previously. Various siNAs were screened in M1K2D cells. The log 2 (fold change) in CTNNB1 gene expression data upon treatment with various modified CTNNB1 siNAs in human cells is shown in Table 3c. Each screen was performed at 24 hrs. Quantitative RT-PCR was used to assess the level of CTNNB1 mRNA and the data were normalized to the expression level of GAPDH (a ubiquitously expressed ‘house-keeping’ gene). Each treatment was then normalized against the non-CTNNB1 targeting control.
  • TABLE 3c
    Primary screening data in MK2D Cells (n = 2), recorded
    as log 2(fold change) CTNNB1 gene expression.
    MK2D MK2D
    MEAN SD
    siNA Duplex ID ΔΔCT ΔΔCT
    R-008395722-000P 4.06 0.06
    R-008395725-000R 3.78 0.08
    R-008395749-000K 4.20 0.02
    R-008395752-000S 5.53 0.06
    R-008395758-000U 2.41 0.01
    R-008395761-000A 5.61 0.08
    R-008395767-000C 3.00 0.00
    R-008395770-000J 5.53 0.18
    R-008395779-000M 4.93 0.16
    R-008395785-000V 2.56 0.19
    R-008395791-000C 6.76 0.23
    R-008395800-000X 2.87 0.07
    R-008395827-000T 2.89 0.14
    R-008395863-000C 1.65 0.22
    R-008395881-000V 3.94 0.05
    R-008395887-000X 4.54 0.24
    R-00839.5977-000P 5.63 0.47
    R-008395980-000W 4.31 0.27
    R-008395995-000G 4.83 0.12
    R-008396004-000Y 3.16 0.01
    R-008396022-000R 4.83 0.13
    R-008396052-000T 4.08 0.08
    R-008396061-000B −0.99 0.08
    R-008396067-000D 3.52 0.39
    R-008396070-000K 4.84 0.03
    R-008396079-000N 4.32 0.04
    R-008396103-000Z 3.67 0.07
    R-008396106-000A 5.34 0.03
    R-008396109-000B −1.10 0.03
    R-008396112-000H 5.19 0.26
    R-008396118-000K 3.23 0.01
    R-008396136-000C −2.56
    R-008396142-000K −0.95 0.10
    R-008396148-000M 3.84 0.24
    R-008396151-000U 4.60 0.08
    R-008396154-000V 4.77 0.07
    R-008396172-000M 6.28 0.06
    R-008396214-000K 2.82 0.29
    R-008396220-000T 5.40 0.05
    R-008396223-000U 4.57 0.06
    R-008396226-000V 2.27 0.12
    R-008396247-000N 3.32 0.08
    R-008396250-000V 3.79 1.00
    R-008396253-000W 6.42 0.03
    R-008396259-000Y 2.14 0.03
    R-008396274-000P 5.39 0.18
    R-008396292-000G 3.85 0.05
    R-008396295-000H 2.57 0.08
    R-008396298-000J 3.00 0.22
    R-008396301-000B 2.10 0.24
    R-008396304-000C 3.24 0.04
    R-008396343-000N 2.49 0.07
    R-008396349-000R 4.00 0.08
    R-008396379-000T 4.29 0.22
    R-008396382-000Z −0.44 0.02
    R-008396388-000B 3.90 0.18
    R-008396391-000H 2.23 0.05
    R-008396409-000F 3.96 0.26
    R-008396415-000N 4.72 0.00
    R-008396418-000P 4.48 0.20
    R-008396421-000W 3.78 0.14
    R-008396457-000A 3.89 0.01
    R-008396478-000U 4.62 0.03
    R-008396481-000A 4.29 0.14
    R-008396529-000A 4.69 0.10
    R-008396532-000G 4.46 0.05
    R-008396538-000J 5.59 0.05
    R-008396544-000S 5.04 0.20
    R-008396550-000Z 3.79 0.18
    R-008396553-000A 2.32 0.01
    R-008396556-000B 2.85 0.07
    R-008396559-000C 5.20 0.12
    R-008396613-000R 4.92 0.10
    R-008396616-000S 2.90 0.01
    R-008396619-000T 4.67 0.37
    R-008396622-000Z 4.09 0.08
    R-008396631-000H 4.28 0.13
    R-008396685-000E 4.01 0.10
    R-008396694-000N 4.73 0.12
    R-008396697-000P 1.56 0.16
    R-008396730-000J 2.19 0.02
    R-008396730-000J 3.24 0.03
    R-008396733-000K 1.43 0.10
    R-008396736-000L 5.14 0.04
    R-008396742-000U 0.78 0.28
    R-008396751-000C 3.62 0.13
    R-008396754-000D 4.17 0.05
    R-008396793-000P 2.68 0.01
    R-008396796-000R 4.94 0.03
    R-008396820-000B 4.70 0.08
    R-008396826-000D 4.73 0.20
    R-008396832-000L 3.63 0.10
    R-008396835-000M 2.84 0.85
    R-008396838-000N 3.40 0.20
    R-008396868-000R 3.99 0.14
    R-008396871-000X 4.62 0.12
    R-008396874-000Y 4.01 0.02
    R-008396898-000T 3.11 0.32
    R-008396904-000L 2.46 0.06
    R-008396910-000U 2.30 0.03
    R-008396919-000X 4.06 0.23
    R-008396934-000N 3.37 0.18
    R-008396943-000X 3.77 0.01
    R-008396949-000Z 3.40 0.07
    R-008396958-000H 5.29 0.05
    R-008396985-000J 5.25 0.09
    R-008396994-000T 3.08 0.40
    R-008397015-000U 4.41 0.08
    R-008397018-000V 1.73 0.03
    R-008397021-000B 5.50 0.05
    R-008397024-000C 3.45 0.27
    R-008397039-000N 4.21 0.04
    R-008397060-000M 1.76 0.08
    R-008397069-000R 3.16 0.14
    R-008397072-000X 3.94 0.17
    R-008397081-000F 3.02 0.02
    R-008397108-000M 5.62 0.08
    R-008397111-000U 4.08 0.10
    R-008397114-000V 3.50 0.03
    R-008397132-000M 3.97 0.16
    R-008397138-000P 6.60 0.17
    R-008397141-000W 4.58 0.02
    R-008397147-000Y 3.73 0.00
    R-008397150-000E 6.44 0.11
    R-008397153-000F 2.43 0.03
    R-008397156-000G 4.04 0.31
    R-008397165-000R 3.44 0.01
    R-008397168-000S 3.29 0.15
    R-008397180-000G 4.46 0.02
    R-008397186-000J 5.22 0.06
    R-008397237-000R 2.77 0.04
    R-008397243-000Y 3.31 0.23
    R-008397246-000Z 3.21 0.21
    R-008397255-000H 3.77 0.05
    R-008397258-000J 1.91 0.02
    R-008397306-000P 3.04 0.05
    R-008397309-000R 3.16 0.05
    R-008397312-000X 5.97 0.13
    R-008397315-000Y 4.19 0.33
    R-008397342-000Z 3.04 0.06
    R-008397345-000A 4.87 0.03
    R-008397348-000B 3.62 0.04
    R-008397351-000H 2.29 0.15
    R-008397354-000J 4.81 0.09
    R-008397372-000B 4.40 0.10
    R-008397381-000K 3.38 0.08
    R-008397384-000L 3.95 0.14
    R-008397387-000M 6.11 0.04
    R-008397390-000U 3.84 0.16
    R-008397396-000W 6.69 0.24
    R-008397408-000S 5.61 0.05
    R-008397417-000A 3.92 0.49
    R-008397420-000G 4.53 0.02
    R-008397429-000K 2.91 0.05
    R-008397450-000J 2.53 0.05
    R-008397459-000M 4.75 0.00
    R-008397462-000U 5.28 0.17
    R-008397465-000V 4.45 0.18
    R-008397468-000W 4.05 0.09
    R-008397471-000C 3.22 0.12
    R-008397474-000D 4.06 0.21
    R-008397519-000C 3.67 0.03
    R-008397531-000T 5.94 0.10
    R-008397537-000V 4.20 0.07
    R-008397540-000B 5.04 0.12
    R-008397564-000W 5.95 0.12
    R-008397576-000F 3.39 0.05
    R-008397579-000G 2.94 0.02
    R-008397582-000N 3.95 0.12
    R-008397588-000R 4.25 0.07
    R-008397591-000X 5.25 0.06
    R-008397594-000Y 3.81 0.00
    R-008397618-000D 4.58 0.03
    R-008397630-000U 3.46 0.15
    R-008397645-000E 3.71 0.07
    R-008397657-000P −1.50 0.14
    R-008397660-000W 4.85 0.04
    R-008397663-000X 2.62 0.03
    R-008397666-000Y 3.68 0.09
    R-008397669-000Z 2.80 0.78
    R-008397702-000U 2.34 0.78
    R-008397705-000V 5.13 0.20
    R-008397732-000W 3.27 0.01
    R-008397735-000X 2.92 0.03
    R-008397738-000Y 3.97 0.06
    R-008397768-000A 1.62 0.05
    R-008397771-000G 4.45 0.17
    R-008397774-000H −1.15 0.02
    R-008397777-000J −1.16 0.09
    R-008397783-000S −1.16 0.03
    R-008397807-000X 2.52 0.05
    R-008397828-000R 4.36 0.27
    R-008397855-000S 1.94 0.01
    R-008397858-000T 4.43 0.17
    R-008397882-000T 5.26 0.10
    R-008397885-000U 2.53 0.01
    R-008397888-000V 3.55 0.03
    R-008397933-000Z 4.19 0.22
    R-008397966-000C 5.19 0.17
    R-008397969-000D 3.35 0.11
    R-008397987-000W 4.95 0.16
    R-008397990-000C 4.69 0.09
    R-008397993-000D 2.17 0.01
    R-008397996-000E −1.14 002
    R-008398002-000V 3.74 0.10
    R-008398020-000M 3.51 0.06
    R-008398026-000P 5.64 0.06
    R-008398050-000P 3.57 0.10
    R-008398056-000S 4.46 0.13
    R-008398086-000U 3.65 0.18
    R-008398098-000D 3.93 0.04
    R-008398119-000H 2.68 0.25
    R-008398137-000A 5.16 0.02
    R-008398140-000G 3.87 0.14
    R-008398140-000G 4.86 0.03
    R-008398143-000H 1.74 0.05
    R-008398146-000J 3.95 0.12
    R-008398149-000K 4.45 0.03
    R-008398155-000T 4.37 0.25
    R-008398161-000A 3.82 0.05
    R-008398176-000L 3.83 0.14
    R-008398182-000U 4.52 0.06
    R-008398227-000T 6.28 0.06
    R-008398239-000C 2.48 0.02
    R-008398242-000J 3.81 0.03
    R-008398245-000K 5.34 0.23
    R-008398275-000M 1.53 0.08
    R-008398278-000N 2.71 0.07
    R-008398281-000V 4.31 0.14
    R-008398326-000U 5.66 0.09
    R-008398329-000V 3.83 0.26
    R-008398332-000B 4.63 0.02
    R-008398362-000D 2.98 0.17
    R-008398365-000E 5.06 0.06
    R-008398368-000F 4.37 0.03
    R-008398374-000N 3.66 0.03
    R-008398377-000P −1.12 0.02
    R-008398401-000A 4.57 0.18
    R-008398413-000K 3.23 0.07
    R-008398419-000M 3.78 0.10
    R-008398422-000U 2.63 0.05
    R-008398425-000V 3.31 0.02
    R-008398428-000W 4.20 0.05
    R-008398431-000C 4.82 0.02
    R-008398434-000D 2.54 0.06
    R-008398437-000E 5.38 0.09
    R-008398479-000S 5.16 0.41
    R-008398482-000Y 1.55 0.01
    R-008398533-000E 3.60 0.01
    R-008398539-000G 4.85 0.07
    R-008398542-000N 3.64 0.01
    R-008398563-000G 5.22 0.27
    R-008398566-000H 2.69 0.13
    R-008398575-000S 4.79 0.03
    R-008398584-000A 2.92 0.04
    R-008398590-000H 4.97 0.13
    R-008398593-000J 4.52 0.03
    R-008398617-000P 3.50 0.01
    R-008398647-000S 4.34 0.23
    R-008398650-000Y 4.26 0.01
    R-008398653-000Z 3.27 0.22
    R-008398656-000A 5.36 0.15
    R-008398662-000H 5.03 0.42
    R-008398665-000J 3.28 0.08
    R-008398668-000K 5.53 0.41
    R-008398677-000U 4.94 0.03
    R-008398686-000C 1.43 0.14
    R-008398701-000E 4.38 0.10
    R-008398740-000R 3.54 0.04
    R-008398749-000U 2.72 0.18
    R-008398782-000C 2.87 0.02
    R-008398785-000D −1.10 0.05
    R-008398788-000E 5.61 0.09
    R-008398815-000S 3.68 0.14
    R-008398821-000Z 5.75 0.00
    R-008398830-000H 4.45 0.21
    R-008398833-000J 4.61 0.05
    R-008398836-000K 3.83 0.01
    R-008398863-000L −1.22 0.03
    R-008398866-000M 3.99 0.02
    R-008398869-000N 4.06 0.32
    R-008398872-000V 4.32 0.18
    R-008398875-000W 3.28 0.08
    R-008398902-000H 5.58 0.03
    R-008398917-000U 2.05 0.13
    R-008398923-000B 5.33 0.13
    R-008398926-000C 2.22 0.07
    R-008398956-000E 3.78 0.15
    R-008398962-000M 1.67 0.04
    R-008398965-000N 4.87 0.13
    R-008398968-000P 3.76 0.21
    R-008399031-000H 4.84 0.16
    R-008399034-000J 5.71 0.05
    R-008399037-000K 2.86 0.08
    R-008399049-000V 3.77 0.01
    R-008399058-000D 3.88 0.26
    R-008399070-000U 5.31 0.00
    R-008399091-000M 4.67 0.01
    R-008399103-000H 3.75 0.18
    R-008399109-000K 5.39 0.14
    R-008399133-000K 3.73 0.05
    R-008399145-000V 4.27 0.01
    R-008399172-000W 3.39 0.07
    R-008399175-000X 3.44 0.11
    R-008399181-000E 3.37 0.06
    R-008399184-000F 6.50 0.11
    R-008399187-000G 4.29 0.10
    R-008399202-000J 4.09 0.44
    R-008399205-000K 2.85 0.21
    R-008399208-000L 4.45 0.00
    R-008399211-000T 4.08 0.08
    R-008399214-000U 4.54 0.01
    R-008399226-000D 2.02 0.05
    R-008399262-000N 4.13 0.06
    R-008399265-000P 3.87 0.03
    R-008399268-000R 5.89 0.30
    R-008399271-000X 4.44 0.18
    R-008399274-000Y 1.24 0.07
    R-008399334-000N 2.96 0.22
    R-008399343-000X 3.86 0.02
    R-008399370-000Y 1.45 0.92
    R-008399373-000Z 3.64 0.17
    R-008399376-000A 4.79 0.22
    R-008399382-000H 4.33 0.06
    R-008399394-000T 4.40 0.09
    R-008399415-000X 3.21 0.15
    R-008399418-000Y 3.33 0.13
    R-008399421-000E 3.57 0.21
    R-008399436-000R −1.18 0.08
    R-008399439-000S 3.23 0.13
    R-008399442-000Y 4.12 0.04
    R-008399445-000Z −0.90 0.12
    R-008399451-000G 2.57 0.66
    R-008399454-000H 1.55 0.01
    R-008399457-000J 2.95 0.00
    R-008399481-000J 2.30 0.08
    R-008399487-000L 2.81 0.26
    R-008399526-000H 5.38 0.35
    R-008399535-000S 3.24 0.04
    R-008399538-000T 4.18 0.28
    R-008399568-000V 3.85 0.13
    R-008399571-000B 4.51 0.28
    R-008399589-000N 2.43 0.07
    R-008399592-000V 5.11 0.02
    R-008399604-000R −1.15 0.03
    R-008399610-000Y 4.97 0.16
    R-008399616-000A 2.18 0.03
    R-008399628-000K 4.04 0.00
    R-008399634-000T 3.53 0.23
    R-008399640-000A 3.90 0.16
    R-008399652-000K 4.94 0.03
    R-008399655-000L 3.57 0.14
    R-008399658-000M 3.74 0.42
    R-008399661-000U 3.01 0.06
    R-008399664-000V 3.84 0.16
    R-008399670-000C 5.25 0.09
    R-008399679-000F 3.51 0.29
    R-008399682-000M 1.20 0.08
  • Select high ranking siNAs from Tables 3a & 3b were further analyzed for efficacy and potency in Huh7 cells use dose response curves. The results for these siNAs are shown in Table 4. The potency 50 is the calculated siNA transfection concentration that produces 50% target mRNA knockdown. The IC50 was determined after 24 hour exposure time.
  • TABLE 4
    Dose response data for various siNAs in Huh 7
    cells. Calculated maximum ΔΔCt is
    determined from the dose response curve.
    Mean SD POTENCY IC50
    siNA Duplex ID ΔΔCt ΔΔCt 50 (nM) (nM)
    R-008362824-000R 4.18 0.09 0.02 0.02
    R-008362821-000P 4.16 0.01 0.02 0.02
    R-008363031-000Y 4.10 0.24 0.01 0.01
    R-008362785-000U 4.00 0.31 0.03 0.03
    R-008362686-000T 3.98 0.18 0.07 0.06
    R-008362782-000T 3.95 0.55 0.05 0.04
    R-008362875-000L 3.61 036 0.02 0.02
    R-008308997-000F 3.59 0.14 0.02 0.02
    R-008362722-000N 3.58 0.23 0.03 0.02
    R-008362791-000B 3.51 0.89 0.02 0.01
    R-008362932-000A 3.48 0.46 0.02 0.02
    R-008362689-000U 3.39 0.81 0.02 0.02
    R-008363043-000H 3.29 0.01 0.02 0.02
    R-008363073-000K 3.21 0.45 0.10 0.08
    R-008362812-000F 3.07 0.40 0.03 0.03
    R-008362947-000L 3.07 0.28 0.02 0.01
    R-008363070-000J 2.91 0.10 0.01 0.01
  • Additional siNAs from Tables 3a & 3b were farther analyzed for efficacy and potency in MK2D cells using dose response curves. The results for these siNAs are shown in Table 5. The potency 50 is the calculated siNA transfection concentration that produces 50% target mRNA knockdown. The IC50 was determined after 24 hour exposure time.
  • TABLE 5
    Dose response data for various siNAs in MK2D
    cells. Calculated maximum ΔΔCt is
    determined from the dose response curve.
    Mean SD IC50
    siNA Duplex ID ΔΔCt ΔΔCt (nM)
    R-008380929-000H002 6.8 0.03 0.004
    R-008488882-000B001 5.8 0.01 0.004
    R-008488885-000C001 6.1 0.03 0.007
    R-008488887-000V001 6.6 0.02 0.004
    R-008488889-000M001 6.4 0.23 0.005
  • Example 2: Determining In Vitro Serum Stability of siNAs
  • siNAs are reconstituted as 50 μM to 100 μM stock solution with H2O and added to human serum pre-warmed to 37° C. to a final concentration of 20 μg/mL. The mixture is then incubated at 37° C. for 0, 1 and 2 hours. At the end of each time point, the reactions are stopped by mixing with equal volume of Phenomenex Lysis-Loading Buffer. Oligotrucleotides are purified in 96-well format by Phenomenex Solid Phase Extraction and lyophilized until dry with Labconco Triad Lyo-00417. The lyophilized samples are reconstituted in 150 μL, of 1 mM EDTA prepared with RNase-free H2O. The sample solutions re then diluted 5 fold with 1 mM EDTA for liquid chromatography/mass spectrometry (LC/MS) analysis on ThermoFisher Orbitrap. Scrum metabolites of the siNAs were determined based on the measured molecular weights.
  • Example 3: Testing of Cytokine Induction
  • To assess immunostimulative effects of various siNAs of the invention loaded in lipid nanoparticles (DLinDMA/Cholesterol/S-PEG-C-DMA/DSPC in a 40/48/2/10 ratio), C57Bl/6 mice are dosed with a single 3 mpk dose of LNP formulated siNAs through tail vein injection. Serum or plasma samples are collected at 3 and 24 hours post-dose. The cytokine and chemokine levels in these samples is measured with the SearchLight IR Cytokine Array from Aushon Biosciences according to the manufacturer's instruction. The cytokines and chemokines measured are IL-1α, IL-1β, IL-6, KC, IL-10, IFNγ, TNF, GMCSF, MIP-1β, MCP-1/JE, and RANTES.
  • Example 4: Efficacy Studies in Mouse
  • Mice are dosed IV via tail vein injections with LNP encapsulated siNAs or vehicle control using 2 different 3-week dosing schemes: one 1 mg/kg dose for 3 consecutive days or a single 6 mg/kg does per week. In some experiments, the mice are co-dosed with sorafertib at a dose of 100 mg/kg BID every day for 3 weeks. Total tumor burden is measured by micro-CT scan imaging. The animals are sacrificed 5 days after the last siNA dose (Day 23), and normal liver and tumor tissues from each animal is collected for RNA purification. Total RNA is purified using RNeasy 96 kit (Qiagen, Cat #74182), cDNA is generated from total RNA using High Capacity cDNA Reverse Transcription Kit (Cat #: 4368813). Quantitative PCR reactions are performed with TaqMan. Universal PCR Master Mix (Cat #:4304437). Human CTNNB1 TaqMan Gene Expression Assay (Hs00355045_m1) and human GAPDH TaqMan. Gene Expression Assay is used to monitor the mRNA level of both transcripts in tumor tissue. Mouse CTNNB1 TaqMan. Gene Expression Assay (Mm00483033_m1) and mouse GAPDH TaqMan Gene Expression Assay is used to monitor the mRNA level of both transcripts in liver tissue. The expression level of CTNNB1 is normalized against GAPDH to minimize technical variations.
  • Example 5: Pharmacodynamic Study in Non-Human Primates
  • Rhesus macaque monkeys are dosed with a single 2.5 mpk dose of siNA loaded lipid nanoparticles through intravenous infusion. To monitor target mRNA knockdown, liver biopsies are performed at various time points pre- and post-dose with 16T gauge Menghini needles for about 20 mg tissue per animal. Whole blood and serum/plasma is also collected at different time points pre- and post-dose to monitor potential toxicity associated with the treatments. All procedures adhere to the regulations outlined in the USDA Animal Welfare Act (9 CFR, Parts 1, 2 and 3) and the conditions specified in The Guide for Care and Use of Laboratory Animals (ILAR publication, 1996, National Academy Press). Total RNA from the liver biopsy tissue was purified using RNeasy 96 kit (Qiagen, Cat; 74182). cDNA was generated from total RNA using High Capacity cDNA Reverse Transcription Kit (Cat #: 4368813). Quantitative PCR reactions were performed with TagMan Universal PCR Master Mix (Cat #: 4304437), Human CTNNB1 TaqMan Gene Expression Assay (Hs00355045_ml) and rhesus GAPDH TagMan Gene Expression Assay (Rh02621745_g1) is used to monitor the mRNA level of both transcripts in liver biopsy tissue. The expression level of CTNNB1 is normalized against GAPDH to minimize technical variations.
  • LNP formulations (DLinDMA/Cholesterol/S-PEG-C-DMA/DSPC in a 40/48/2/10 ratio) comprising the siNA are tested. Log 2 (fold change) in CTNNB1 gene expression is determined on days 3, 7, 11, and 28 days post-dosing. Pre-dose CTNNB1 expression levels for the monkey is measured 7 days before the first dosing.
  • Example 6: Pharmacodynamic Studies in Mouse
  • Mice were dosed IV via tail vein injections with LNP encapsulated siNAs or vehicle control using a single 0.33 mg/kg. Five animals which received each treatment were sacrificed 2, 7, 14 and 21 days after the siNA dose, and liver tissues from each animal was collected for RNA purification. Total RNA was purified using RNeasy 96 kit (Qiagen, Cat #74182). cDNA was generated from total RNA using High Capacity cDNA Reverse Transcription Kit (Cat #: 4368813). Quantitative PCR reactions were performed with TagMan Universal PCR Master Mix (Cat #: 4304437). Mouse CTNNB1 TaqMan Gene Expression Assay (Mm00483033_ml) and mouse GAPDH TaqMan Gene Expression Assay was used to monitor the mRNA level of both transcripts. The expression level of CTNNB1 was normalized against GAPDH to minimize technical variations. Data is shown in Table 6.
  • TABLE 6
    In vivo screening data in C57Bl/6 mice, recorded as log 2(fold change)
    in CTNNB1 gene expression.
    Day 2 Day 7 Day 14 Day 21
    Mouse Mouse Mouse Mouse Mouse Mouse Mouse Mouse
    Mean SD Mean SD Mean SD Mean SD
    ΔΔCT ΔΔCT ΔΔCT ΔΔCT ΔΔCT ΔΔCT ΔΔCT ΔΔCT
    PBS 0.00 0.23 0.00 0.21 0.00 0.16 0.00 0.15
    R-008380929-000H 2.95 0.27 2.76 0.14 2.33 0.09 1.95 0.33
    R-008381104-000W 2.90 0.21 2.43 0.26 1.77 0.30 1.32 0.23
    R-008488882-000B 3.21 0.37 2.86 0.33 2.34 0.14 1.93 0.18
    R-008488885-000C 2.44 0.13 1.35 0.22 0.59 0.17 0.58 0.31
    R-008488887-000V 2.11 0.31 1.76 0.14 0.94 0.42 1.05 0.32
    R-008488889-000M 2.31 0.22 1.87 0.35 1.30 0.10 0.86 0.17
  • Example 7: Pharmacodynamic Study in Non-Human Primates
  • Rhesus macaque monkeys were dosed with a single 3.34 mg/m2 of body surface area dose of siNA loaded lipid nanoparticles through intravenous infusion. To monitor target snRNA knockdown, liver biopsies were performed at various time points pre- and post-dose with 16T gauge Menghini needles for about 20 mg tissue per animal. Whole blood and serum/plasma is also collected at different time points pre- and post-dose to monitor potential toxicity associated with the treatments. All procedures adhered to the regulations outlined in the USDA Animal Welfare Act (9 CFR, Parts 1, 2 and 3) and the conditions specified in The Guide for Care and Use of Laboratory Animals (ILAR publication, 1996, National Academy Press). Total RNA from the liver biopsy tissue was purified using RNeasy 96 kit (Qiagen, Cat #74182), cDNA was generated from total RNA using High Capacity cDNA Reverse Transcription Kit (Cat #: 4368813). Quantitative PCR reactions were, performed with TaqMan Universal PCR Master Mix (Cat #: 4304437). Human CTNNB1 TaqMan Gene Expression Assay (Hs00355045_m1) and rhesus GAPDH TaqMan Gene Expression Assay (Rh02621745_g1) was used to monitor the mRNA level of both transcripts in liver biopsy tissue. The expression level of CTNNB1 was normalized against GAPDH to minimize technical variations. Data is shown in Table 7. LNP formulations (DLinDMA/Cholesterol/S-PEG-C-DMA/DSPC in a 40/48/2/10 ratio) comprising the siNA were tested. Log 2 (fold change) in CTNNB1 gene expression was determined on days 2 and 7 days post-dosing. Pre-dose CTNNB1 expression levels for the monkey is measured 6 days before the first dosing.
  • TABLE 7
    In vivo screening data in rhesus, recorded as log 2(fold change)
    in CTNNB1 gene expression.
    Day −6 Day 2 Day 7
    Rhesus Rhesus Rhesus Rhesus Rhesus Rhesus
    Mean SD Mean SD Mean SD
    LNP siNA duplex ΔΔCT ΔΔCT ΔΔCT ΔΔCT ΔΔCT ΔΔCT
    PBS 0.00 0.37 0.00 0.24 0.00 0.25
    LNP-2 R-008488882-000B −0.11 0.20 1.41 0.35 0.73 0.56
    LNP-4 R-008488885-000C −0.15 0.13 1.79 0.46 1.64 0.59
    LNP-1 R-008488889-000M 0.02 0.29 1.59 0.43 1.44 0.60
    LNP-3 R-008380929-000H −0.10 0.25 1.89 0.17 1.60 0.04
  • Example 8: Short interfering nucleic acid Lipid Nanoparticle (LNP) Formulations A. General LNP Process Description for LAP Formulations:
  • The lipid nanoparticles were prepared by an impinging jet process. The particles were formed by mixing lipids dissolved in alcohol with siNA dissolved in a citrate buffer. The lipid solution contained a cationic lipid, a helper lipid (cholesterol), PEG (e.g. PEG-C-DMA, PEG-DMG) lipid, and DSPC at a concentration of 5-15 mg/mL with a target of 9-12 mg/mL in an alcohol (for example ethanol). The ratio of the lipids had a mole percent range of 25-98 for the cationic lipid with a target of 35-65, the helper lipid had a mole percent range from 0-75 with a target of 30-50, the PEG lipid has a mole percent range from 1-15 with a target of 1-6, and the DSPC had a mole percent range of 0-15 with a target of 0-12. The siNA solution contained one or more siNA sequences at a concentration range from 0.3 to 0.6 mg/mL with a target of 0.3-0.9 mg/mL in a sodium citrate buffered salt solution with pH in the range of 3.5-5. The two solutions were heated to a temperature in the range of 15-40° C., targeting 30-40° C., and then mixed in an impinging jet mixer instantly forming the LNP. The teeID had a range from 0.25 to 1.0 mm and a total flow rate from 10-600 mL/minute. The combination of flow rate and tubing ID had the effect of controlling the particle size of the LNPs between 30 and 200 inn. The LNP suspension was then mixed with a buffered solution at a higher pH with a mixing ratio in the range of 1:1 to 1:3 vol:vol, but targeting 1:2 vol:vol. This buffered solution was at a temperature in the range of 15-40° C., targeting 30-40° C. This LNP suspension was further mixed with a buffered solution at a higher pH and with a mixing ratio in the range of 1:1 to 1:3 vol:vol, but targeting 1:2 vol:vol. The buffered solution was at a temperature in the range of 15-40° C., targeting 30-40° C. The mixed LNPs were held from 30 minutes to 2 hrs prior to an anion exchange filtration step. The temperature during incubating was in the range of 15−40° C., targeting 30-40° C. After incubating, the LNP suspension was filtered through a 0.8 um filter containing an anion exchange separation step. This process used tubing IDs ranging from 1 mm ID to 5 mm ID and a flow rate from 10 to 2000 mL/minute The LNPs were concentrated and diafiltered via an ultrafiltration process where the alcohol was removed and the citrate buffer was exchanged for the final buffer solution such as phosphate buffered saline. The ultrafiltration process used a tangential flow filtration format (TFF). This process used a membrane nominal molecular weight cutoff range from 30-500 KD. The membrane format was hollow fiber or flat sheet cassette. The TFF processes with the proper molecular weight cutoff retained the LNP in the retentate and the filtrate or permeate contained the alcohol; citrate buffer; and final buffer wastes. The TFF process is a multiple step process with an initial concentration to a siNA concentration of 1-3 mg/mL. Following concentration, the LNP suspension was diafiltered against the final buffer for 10-20 volumes to remove the alcohol and perform buffer exchange. The material was then concentrated an additional 1-3 fold. The final steps of the LNP process were to sterile filter the concentrated LNP solution and vial the product.
  • Analytical Procedure:
  • 1) siNA Concentration
  • The siNA duplex concentrations were determined by Strong Anion-Exchange High-Performance Liquid Chromatography (SAX-H PLC) using Waters 2695 Alliance system (Water Corporation, Milford Mass.) with a 2996 PDA detector. The LNPs, otherwise referred to as RNAi Delivery Vehicles (RDVs), were treated with 0.5% Triton X-100 to free total siNA and analyzed by SAX separation using a Dionex BioLC DNAPac PA 200 (4×250 mm) column with UV detection at 254 nm. Mobile phase was composed of A: 25 mM NaClO4, 10 mM Tris, 20% EtOH, pH 7.0 and B: 250 mM. NaClO4, 10 mM Tris, 20% EtOH, pH 7.0 with a liner gradient from 0-15 min and a flow rate of 1 ml/minute. The siNA amount was determined by comparing to the siNA standard curve.
  • 2) Encapsulation Rate
  • Fluorescence reagent SYBR Gold was employed for RNA quantitation to monitor the encapsulation rate of RDVs. RDVs with or without Triton X-100 were used to determine the free siNA and total siNA amount. The assay is performed using a SpectraMax M5e microplate spectrophotometer from Molecular Devices (Sunnyvale, Calif.). Samples were excited at 485 nm and fluorescence emission was measured at 530 nm. The siNA amount is determined by comparing to an siNA standard curve.

  • Encapsulation rate=(1−free siNA/total SiNA)×00%
  • 3) Particle Size and Polydispersity
  • RDVs containing 1 μg siNA were diluted to a final volume of 3 ml with 1×PBS. The particle size and polydispersity of the samples was measured by a dynamic light scattering method using ZetaPALS instrument (Brookhaven instruments Corporation, Holtsville, N.Y.). The scattered intensity was measured with He—Ne laser at 25° C. with a scattering angle of 90°.
  • 4) Zeta Potential Analysis
  • RDVs containing 1 μg siNA were diluted to a final volume of 2 ml with 1 mM Tris buffer (pH 7.4). Electrophoretic mobility of samples was determined using ZetaPALS instrument (Brookhaven instruments Corporation, Holtsville, N.Y.) with electrode and He—Ne laser as a light source. The Smoluchowski limit was assumed in the calculation of zeta potentials,
  • 5) Lipid Analysis
  • Individual lipid concentrations were determined by Reverse Phase High-Performance Liquid Chromatography (RP-HPLC) using Waters 2695 Alliance system (Water Corporation, Milford Mass.) with a Corona charged aerosol detector (CAD) (ESA Biosciences, Inc, Chelmsford, Mass.). Individual lipids in RDVs were analyzed using an Agilent Zorbax SB-C18 (50×4.6 runt, 1.8 μm particle size) column with CAD at 60° C. The mobile phase was composed of A: 0.1% TEA in H2O and B: 0.1% TEA in IPA. The gradient changed from 60% mobile phase A and 40% mobile phase B from time 0 to 40% mobile phase A and 60% mobile phase B at 1.00 min; 40% mobile phase A and 60% mobile phase B from 1.00 to 5.00 min; 40% mobile phase A and 60% mobile phase B from 5.00 min to 25% mobile phase A and 75% mobile phase B at 10.00 min; 25% mobile phase A and 75% mobile phase B from 10.00 min to 5% mobile phase A and 95% mobile phase B at 15.00 min and 5% mobile phase A and 95% mobile phase B from 15.00 to 60% mobile phase A and 40% mobile phase B at 20.00 min with a flow rate of 1 ml/minute. The individual lipid concentration was determined by comparing to the standard curve with all the lipid components in the RDVs with a quadratic curve fit. The molar percentage of each lipid was calculated based on its molecular weight.
  • B. General LNP Preparation For Various Formulations in Table 11
  • siNA nanoparticle suspensions in Table 11 were prepared by dissolving siNAs and/or carrier molecules in 20 mM sodium citrate buffer (pH 5.0) at a concentration of about 0.40 mg/mL. Lipid solutions were prepared by dissolving a mixture of cationic lipid (e.g., (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine, see structure in Table 12), DSPC, Cholesterol, and PEG-DMG (ratios shown in Table 11) in absolute ethanol at a concentration of about 8 mg/mL. The nitrogen to phosphate ratio was approximated to 6:1.
  • Nearly equal volumes of siNA/carrier and lipid solutions were delivered with two FPLC pumps at the same flow rates to a mixing T connector. A back pressure valve wais used to adjust to the desired particle size. The resulting milky mixture was collected in a sterile glass bottle. This mixture was then diluted with an equal volume of citrate buffer, followed by equal volume of PBS (pH 7.4), and filtered through an ion-exchange membrane to remove any free siNA/carrier in the mixture. Ultra filtration against PBS (7.4)) was employed to remove ethanol and to exchange buffer. The final LNP was obtained by concentrating to the desired volume and sterile filtered through a 0.2 μm filter. The obtained LNPs were characterized in term of particle size, Zeta potential, alcohol content, total lipid content, nucleic acid encapsulated, and total nucleic acid concentration.
  • LNP Manufacture Process
  • In a non-limiting example, LNPs were prepared in bulk as follows. The process consisted of (1) preparing a lipid solution; (2) preparing an siNA/carrier solution; (3) mixing/particle formation; (4) incubation; (5) dilution; (6) ultrafiltration and concentration.
  • 1. Preparation of Lipid Solution
  • 2 L glass reagent bottles and measuring cylinders were depyrogenated. The lipids were warmed to room temperature. Into the glass reagent bottle was transferred 8.0 g of (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine with a pipette and 1.2 g of DSPC, 3.5 g of Cholesterol, 0.9 g of PEG-DMG were added. To the mixture is added 1 L of ethanol. The reagent bottle was placed in heated water bath, at a temperature not exceeding 50° C. The lipid suspension was stirred with a stir bar. A thermocouple probe was put into the suspension through one neck of the round bottom flask with a sealed adapter. The suspension was heated at 30-40° C. until it became clear. The solution was allowed to cool to room temperature.
  • 2. Preparation of siNA/Carrier Solution
  • Into a sterile container (Corning storage bottle) was weighed 0.4 g times the water correction factor (approximately 1.2) of siNA powder. The siNA was transferred to a depyrogenated 2 L glass reagent bottle. The weighing container was rinsed 3× with citrate buffer (20 mM, pH 5.0) and the rinses were placed into the 2 L glass bottle, QS with citrate buffer to 1 L. The concentration of the siNA solution was determined with a UV spectrometer using the following procedure. 20 μL at was removed from the solution, diluted 50 times to 1000 μL, and the UV reading recorded at A260 nm after blanking with citrate buffer. This was repeated. Note, if the readings for the two samples are consistent, an average can be taken and the concentration calculated based on the extinction coefficients of the siNAs. If the final concentration is out of the range of 0.40±0.01 mg/mL, the concentration can be adjusted by adding more siNA/carrier powder, or adding more citrate buffer. This process can be repeated for the second siNA, if applicable
  • When the siNA/carrier solution comprised a single siNA duplex instead of a cocktail of two or more siNA duplexes and/or carriers, then the siNA/carrier was dissolved in 20 mM citrate buffer (pH 5.0) to give a final concentration of 0.4 mg/mL.
  • The lipid and ethanol solutions were then sterile filtered through a Pall Acropak 20 0.8/0.2 μm sterile filter PN 12203 into a depyrogenated glass vessel using a Master Flex Peristaltic Pump Model 7520-40 to provide a sterile starting material for the encapsulation process. The filtration process was run at an 80 ml, scale with membrane area of 20 cm2. The flow rate was 280 mL/minute. This process can be scaled by increasing the tubing diameter and the filtration area.
  • 3. Particle Formation—Mixing Step
  • Using a two-barrel syringe driven pump (Harvard 33 Twin Syringe), the sterile lipid/ethanol solution and the sterile siNA/carrier or siNA/carrier cocktail/citrate buffer (20 mM citrate buffer, pH 5.0) solutions were mixed in a 0.5 mm ID T-mixer (Mixing Stage 1) at equal, or nearly equal, flow rates. The resulting outlet LNP suspension contained 40-50 vol % ethanol. To obtain a 45 vol % ethanol outlet suspension, the sterile lipid/ethanol and the sterile siNA/carrier or siNA/carrier cocktail/citrate buffer solutions were mixed at flow rates of 54 mL/min and 66 mL/min, respectively, such that the total flow rate of the mixing outlet is 120 mL/min.
  • 4. Dilution
  • The outlet stream of Mixing Stage I was fed directly into a 4 mm ID T-mixer (Mixing Stage II), where it was diluted with a buffered solution at higher pH (20 mM sodium citrate, 300 mM sodium chloride, pH 6.0) at a ratio of 1:1 vol:vol 1%. This buffered solution was at a temperature in the range of 30-40′C, and was delivered to the 4 mm T-mixer via a peristaltic pump (Cole Parmer Masterflex L/S 600 RPM) at a flow rate of 120 mL/min.
  • The outlet stream of Mixing Stage II was fed directly into a 6 min ID T-mixer (Mixing Stage III), where it was diluted with a buffered solution at higher pH (PBS, pH 7.4) at a ratio of 1:1 vol:vol %. This buffered solution was at a temperature in the range of 15-25° C., and was delivered to the 6 mm T-mixer via peristaltic pump (Cole Parmer MasterFlex L/S 600 RPM) at a flow rate of 240 mil min.
  • 5. Incubation Free siNA Removal
  • The outlet stream of Mixing Stage III was held after mixing for 30 minute incubation. The incubation was conducted at temperature of 35-40° C. and the in-process suspension was protected from light. Following incubation, free (un-encapsulated) siNA was removed via anion exchange with Mustang Q chromatography filters (capsules). Prior to use, the chromatography filters were pre-treated sequentially with flushes of 1N Na0H, 1M NaCl, and a final solution of 12.5 vol % ethanol in PBS. The pH of the final flush was checked to ensure pH <8. The incubated LNP stream was then filtered via Mustang Q filters via peristaltic pump (Cole Partner MasterFlex L/S 600 RPM) at flow rate of approximately 100 mL/min. The filtered stream was received into a sterile glass container for ultrafiltration and concentration as follows.
  • 6. Ultrafiltration, Concentration and Sterile Filtration
  • The ultrafiltration process is a timed process and the flow rates must be monitored carefully. This is a two step process; the first is a concentration step taking the diluted material and concentrating approximately 8-fold, to a concentration of approximately 0.3-0.6 mg/mL siNA.
  • In the first step, a ring-stand with a ultrafiltration membrane 100 kDa PES (Spectrum Labs) installed was attached to a peristaltic pump (Spectrum KrosFloII System). 9.2 L of sterile distilled water was added to the reservoir; 3 L was drained to waste and the remainder was drained through permeate to waste. 5.3 L of 0.25 N sodium hydroxide was added to the reservoir with 1.5 L drained to waste and 3.1 L drained through permeate to waste. The remaining sodium hydroxide was held in the system for sanitization (at least 10 minutes), and then the pump was drained, 9.2 L of 70 (v/v) % isopropyl alcohol was added to the reservoir with 1.5 L drained to waste and the remainder drained through permeate to waste. 6 L of conditioning buffer (12.5% ethanol in phosphate buffered saline) was added with 1.5 L drained to waste and the remainder drained though the permeate until the waste was of neutral pH (7-8). A membrane flux value was recorded, and the pump was then drained.
  • The diluted LNP solution was placed into the reservoir to the 1.1 L mark. The pump was turned on at 2.3 L/min. After 5 minutes of recirculation, the permeate pump was turned on at 62.5 mL/min and the liquid level was constant at approximately 950 mL in the reservoir. The diluted LNP solution was concentrated from 9.8 L to 1.1 L in 140 minutes, and the pump was paused when all the diluted LNP solution has been transferred to the reservoir.
  • The second step was a diafiltration step exchanging the ethanol/aqueous buffer to phosphate buffered saline. During this step, approximately 10-20 diafiltration volumes of phosphate buffered saline were used. Following diafiltration, a second concentration was undertaken to concentrate the LNP suspension 3-fold to approximately 1-1.5 mg/mL siRNA. The concentrated suspension was collected into sterile, plastic PETG bottles. The final suspension was then filtered sequentially via Pall 0.45 um PES and Pall 0.2 um PES titters for terminal sterilization prior to vial filling.
  • The obtained LNPs were characterized in terms of particle size, Zeta potential, alcohol content, total lipid content, nucleic acid encapsulated, and total nucleic acid concentration.
  • C. Synthesis of Novel Cationic Lipids
  • Synthesis of the novel cationic lipids is a linear process starting from lipid acid (i). Coupling to N,O-dimethyl hydroxylamine gives the Weinreb amide ii. Grignard addition generates ketone iii. Titanium mediated reductive amination gives final products of type iv.
  • Figure US20230030119A1-20230202-C00003
  • Synthesis of the single carbon homologated cationic lipids v is a linear process starting from lipid ketone (iii). Conversion of the ketone to the nitrile (iv) is accomplished via treatment with TOSMIC and potassium tert-butoxide. Reduction of the nitrite to the primary amine followed by reductive amination provides final cationic lipids v.
  • Figure US20230030119A1-20230202-C00004
  • Synthesis of two carbon homologated cationic lipids vii is a linear process starting from lipid ketone (iii). Conversion of the ketone to the α,β-unsaturated amide vi is accomplished under Peterson conditions. Conjugate reduction of the α,β-unsaturation is performed using LS-Selectride to give amide vii. Reduction of the amide with lithium aluminum hydride provides final cationic lipids viii.
  • Figure US20230030119A1-20230202-C00005
  • Cyclopropyl containing lipids are prepared according to General Scheme 4. Unsaturated Weinreb amides ii are subjected to Simmons-Smith cyclopropanation conditions to give cyclopropyl containing Weinreb amides ix. These are carried on to final products as outlined in General Schemes 1-3.
  • Figure US20230030119A1-20230202-C00006
  • Synthesis of allylic amine cationic lipids xv is a linear process starting with aldehyde x. Addition of t-butyl acetate generates P-hydroxy ester xi. Conversion of the hydroxyl functionality to a fluoro group followed by acid treatment generates β-fluoro acid xii. Conversion of the acid to the Weinreb amide followed by Grignard addition gives the β-fluoro ketone xiv. Reductive amination results in simultaneous elimination to generate the desired allylic amine xv.
  • Figure US20230030119A1-20230202-C00007
  • 20,23-nonacosadien-10-amine, N,N-dimethyl-, (20Z,23Z) (Compound 1)
  • Figure US20230030119A1-20230202-C00008
  • 11,14-Eicosadienoic acid, (11Z,14Z)— (50 g, 162 mmol), N,O-Dimethythydroxylamine hydrochloride (31.6 g, 324 mmol), HOAt (44.1 g, 324 mmol), Et3N (45.2 mL, 324 mmol), and EDC (62.1 g, 324 mmol) were mixed in DCM (810 mL) and stirred overnight at ambient temperature. Reaction was then washed 5×700 mL water, then washed 1×600 mL, 1 M NaOH, dried with sodium sulfate, filtered through celite and evaporated to obtain 53.06 g (93%) 11,14-eicosadienamide, N-methoxy-N-methyl-, (11Z,14Z) as a clear golden oil.
  • 1H NMR (400 MHz, CDCl3) δ 5.35 (m, 4H), 3.68 (s, 3H), 3.18 (s, 3H), 2.77 (m, 2H), 2.41 (t, J=7 Hz, 2H), 2.05 (m, 4H), 1.63 (m, 2H), 1.40-1.26 (m, 18H), 0.89 (t, J=7 Hz, 3H).
  • Figure US20230030119A1-20230202-C00009
  • 11,14-eicosadienamide, N-methoxy-N-methyl-, (11Z,14Z)-1 (4 g, 11.38 mmol) was dissolved in dry THF (50.0 ml) in a 250 mL flask then 1 M nonylmagnesium bromide (22.76 22.76 mmol) was added under nitrogen at ambient temperature. After 10 min, the reaction was slowly quenched with excess sat. aq NH4Cl. The reaction was washed into a separator), funnel with hexane and water, shaken, the lower aqueous layer discarded, the upper layer dried with sodium sulfate, filtered, and evaporated to give crude ketone as a golden oil. To the above crude ketone was added dimethylamine (2 M in THF) (14.22 ml, 28.4 mmol) followed by Ti(O-i-Pr)4 (6.67 ml, 22.76 mmol) and let stir overnight. The next day, added EtOH (50 ml) followed by NaBH4 (0.646 g, 17.07 mmol). After 5 min of stirring, directly injected entire reaction onto a 40 g silica column that was in hue with a 330 g silica column. Eluted 10 min 100% DCM, then 30 min 0-15% MeOH/DCM, collected 20,23-nonacosadien-10-amine, N,N-dimenthyl, (20Z,23Z) (1) (2.45 g, 5.47 mmol, 48.1% yield) as a faintly golden oil. 1H NMR (400 MHz, CDCl3) δ 5.35 (m, 4H), 2.78 (m, 2H), 2.23 (m, 1H), 2.21 (s, 6H), 2.05 (m, 4H), 1.45-1.16 (n, 38H), 0.89 (m, 6H), HRMS calcd for C31H61N, 448.4877, found 448.4872.
  • Compounds 2-30 are novel cationic lipids and were prepared according to the General Scheme 1 above.
  • Compound Structure HRMS
     2
    Figure US20230030119A1-20230202-C00010
    calcd C28H56N 406.4407, found 406.4405.
     3
    Figure US20230030119A1-20230202-C00011
    calcd C27H54N 392.4251, found 392.4250.
     4
    Figure US20230030119A1-20230202-C00012
    calcd C24H48N 350.3781, found 350.3770.
     5
    Figure US20230030119A1-20230202-C00013
    calcd C23H46N 336.3625, found 336.3613.
     6
    Figure US20230030119A1-20230202-C00014
    calcd C25H50N 364.3938, found 364.3941.
     7
    Figure US20230030119A1-20230202-C00015
    calcd C26H52N 378.4094, found 378.4081.
     8
    Figure US20230030119A1-20230202-C00016
    calcd C29H58N 420.4564, found 420.4562.
     9
    Figure US20230030119A1-20230202-C00017
    calcd C26H52N 378.4094, found 378.4089.
    10
    Figure US20230030119A1-20230202-C00018
    calcd C25H50N 364.3938, found 364.3931.
    11
    Figure US20230030119A1-20230202-C00019
    calcd C30H60N 434.4720, found 434.4717.
    12
    Figure US20230030119A1-20230202-C00020
    calcd C29H58N 420.4564, found 420.4561.
    13
    Figure US20230030119A1-20230202-C00021
    calcd C28H56N 406.4407, found 406.4404.
    14
    Figure US20230030119A1-20230202-C00022
    calcd C27H54N 392.4251, found 392.4245.
    15
    Figure US20230030119A1-20230202-C00023
    calcd C33H66N 476.5190, found 476.5196.
    16
    Figure US20230030119A1-20230202-C00024
    calcd C32H64N 462.5033, found 462.5045.
    17
    Figure US20230030119A1-20230202-C00025
    calcd C29H59N 422.4720, found 422.4726.
    18
    Figure US20230030119A1-20230202-C00026
    calcd C28H57N 408.4564, found 408.4570.
    19
    Figure US20230030119A1-20230202-C00027
    calcd C30H59N 434.4720, found 434.4729.
    20
    Figure US20230030119A1-20230202-C00028
    calcd C29H61N 424.4877, found 424.4875.
    21
    Figure US20230030119A1-20230202-C00029
    calcd C32H64N 462.5033, found 462.5023.
    22
    Figure US20230030119A1-20230202-C00030
    calcd C33H64N 474.5033, found 474.5033.
    23
    Figure US20230030119A1-20230202-C00031
    calcd C29H60N 422.4720, found 422.4716.
    24
    Figure US20230030119A1-20230202-C00032
    calcd C29H60N 422.4720, found 422.4718.
    25
    Figure US20230030119A1-20230202-C00033
    calcd C31H64N 450.5033, found 450.5031.
    26
    Figure US20230030119A1-20230202-C00034
    calcd C31H64N 450.5033, found 450.5034.
    27
    Figure US20230030119A1-20230202-C00035
    calcd C35H72N 506.5659, found 506.5635.
    28
    Figure US20230030119A1-20230202-C00036
    calcd C31H64N 450.5033, found 450.5037.
    29
    Figure US20230030119A1-20230202-C00037
    calcd C33H68N 478.5346, found 478.5358.
    30
    Figure US20230030119A1-20230202-C00038
    calcd C27H56N 394.4407, found 394.4407.
  • (12Z,15Z)—N,N-dimethyl-2-nonylhenicosa-12,15-dien-1-amine (Compound 31)
  • Figure US20230030119A1-20230202-C00039
  • A solution of keton iii (4.0 g, 9.55 mmol), TOSMIC (2.4 g, 12.4 mmol) in dimethoxyethane (45 mL) was cooled to 0° C. and treated with potassium Cert-butoxide (19.1 mmol, 19.1 mL of a 1M solution in tBuOH). After 90 minutes, the reaction was partitioned between hexanes and water. The organics were washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. This material was purified by flash chromatography (0-5% EtOAc/hexanes) to give desired product (containing ˜20% of s.m.). This mixture was carried into next step as is, LC/MS (M+H)=430.6.
  • Figure US20230030119A1-20230202-C00040
  • Lithium aluminum hydride (23.9 mmol, 23.9 mL of a 1M solution in THF) was added directly to nitrile iv (3.42 g, 8 mmol) at ambient temperature and the reaction was stirred for 20 minutes. The reaction was diluted with 100 mL THF, cooled to 0° C. and carefully quenched with sodium sulfate decahydrate solution. The solids were filtered off and washed with THF. The filtrate was evaporated in vacuo and carried directly into next reaction crude. LC/MS (M+H)=434.6.
  • Figure US20230030119A1-20230202-C00041
  • A solution of primary amine (3.45 g, 6.2 mmol) in dichloroethane (100 mL) was treated with formaldehyde (1.6 mL, 21.7 mmol) followed by sodium triacetoxyborohydride (6.6 g, 31 mmol). After 5 minutes, the reaction was partitioned between dichloromethane and 1N NaOH. The organics were dried over sodium sulfate, filtered and evaporated in vacuo. The crude mixture was purified by reverse phase preparative chromatography (C8 column) to provide (12Z,15Z)—N,N-dimethyl-2-nonylhenicosa-12,15-dien-1-amine. HRMS calc'd 462.5033, found 462.5026. 1H NMR (400 MHz, CDCl3) δ 5.35 (m, 4H), 2.78 (2H, t, J=5.6 Hz), 2.18 (s, 6H), 2.05 (m, 6H), 1.3 (m, 39H), 0.89 (m, 6H).
  • (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine (Compound 32)
  • Figure US20230030119A1-20230202-C00042
  • The silyl amide Peterson reagent (3.1 g, 16.7 mmol) was dissolved in THF (35 mL) and cooled to −63° C. To this solution was added nBuLi (16.7 mmol, 6.7 mL of a 2,5M solution). The reaction was warmed to ambient temperature for 30 minutes. The ketone (5.0 g, 11.9 mmol) was dissolved in THF (25 mL) in a second flask. The Peterson reagent was transferred to the ketone solution at −60 The reaction was warmed to −40° C. for 1 hour, then warmed to 0° C. for 30 minutes. The reaction was quenched with sodium bicarbonate, diluted with additional water and partitioned between water/hexanes. The organics were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (0-40% MTBE/hexanes) gave α,β-unsutured amide vi. 1H NMR (400 MHz, CDCl3) δ 5.75 (s, 1H), 5.36 (m, 4H), 3.01 (s, 3H), 2.99 (s, 3H), 2.78 (t, 2H), 2.28 (t, 2H), 2.05 (m, 6H), 1.35 (m, 34H), 0.89 (m, 6H).
  • Figure US20230030119A1-20230202-C00043
  • α,β-unsatured amide vi (1 g, 2.1 mmol) and LS-Selectride (4.1 mmol, 4.1 mL of a 1M solution) were combined in a sealed tube and heated to 60° C. for 24 hours. The reaction was cooled to ambient temperature and partitioned between ammonium chloride solution and heptane. The organics were dried over sodium sulfate, filtered and evaporated in vacuo to give amide vii. This intermediate was carried directly into next reaction crude.
  • Figure US20230030119A1-20230202-C00044
  • To a solution of amide vii (2.85 g, 5.8 mmol) was added lithium aluminum hydride (8.7 mmol, 8.7 mL of a 1M solution). The reaction was stirred at ambient temperature for 10 minutes then quenched by slow addition of sodium sulfate decahydrate solution. The solids were filtered and washed with THF and the filtrate evaporated in vacuo. The crude mixture was purified by reverse phase preparative chromatography (C8 column) to provide (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine (Compound 32) as an oil. FIRMS (M+H) calc'd 476.5190, found 476.5189. 1H NMR (400 MHz, CDCl3) δ 5.37 (m, 4H), 2.78 (t, 2H), 2.42 (m, 8H), 2.05 (q, 4H), 1.28 (m, 41H), 0.89 (m, 6H).
  • N,N-dimethyl-1-(2-octylcyclopropyl)heptadecan-8-amine (Compound 33)
  • Figure US20230030119A1-20230202-C00045
  • To a solution of oleic acid (1 g, 3.5 mmol) in DCM (500 mL) cooled to 0° C. was added CDI (0.63 g, 3.9 mmol). The reaction was warmed to ambient temperature for 30 minutes before cooling to 0° C. and treating first with triethylamine (0.39 g, 3.9 mmol) and then dimethyl hydroxylamine hydrochloride (0.38 g, 3.9 mmol). After 1 hour the reaction was partitioned between water and heptane. The organics were dried over magnesium sulfate, filtered and evaporate in vacuo to give crude Weinreb amide ii which was carried directly into next reaction.
  • Figure US20230030119A1-20230202-C00046
  • A solution of diethylzine (70.3 mmol, 70.3 mL of a 1M solution) in dichloromethane (130 mL) was cooled to −1° C. and treated dropwise with TEA (8.0 g, 70.3 mmol). After 30 minutes, diiodomethane (18.8 g, 70.3 mmol) was added and this was aged for 30 minutes in the ice bath. To this solution was added Weinreb amide ii (7.6 g, 23.4 mmol). The reaction was warmed to ambient temperature and stirred for 1 hour. The reaction was quenched with ammonium chloride solution (100 mL) and organic layer partitioned off, washed with 10% sodium thiosulfate, dried over magnesium sulfate, filtered and evaporated in vacuo. Purification was flash chromatography (0-30% MTBE/heptane) gave desired product ix. 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3H), 3.22 (s, 3H), 2.48 (t, 2H), 1.65 (m, 2H), 1.39 (m, 22H), 1.18 (m, 2H), 0.91 (t, 3H), 0.68 (m, 21), 0.59 (m, −0.32 (m, 1H).
  • Figure US20230030119A1-20230202-C00047
  • Conversion of Weinreb amide ix to Compound 33 was carried out in a manner analogous to that described for Compound 1 above (nonyl Grignard addition followed by reductive amination). LC/MS (M+H)=436.6. 1H NMR (400 MHz, CDCl3) δ 2.25 (s, 6H), 1.30 (m, 45H), 0.91 (m, 6H), 0.68 (m, 2H), 0.59 (m, 1H), −0.31 (m, 1H).
  • Compounds 34-43 are novel cationic lipids and were prepared according to General Schemes 1-4 above.
  • Compound Structure HRMS
    34
    Figure US20230030119A1-20230202-C00048
    calcd C30H62N 436.4877, found 436.4872.
    35
    Figure US20230030119A1-20230202-C00049
    calcd C32H66N 464.5190, found 464.5186.
    36
    Figure US20230030119A1-20230202-C00050
    calcd C34H70N 492.5503, found 492.5496.
    37
    Figure US20230030119A1-20230202-C00051
    calcd C33H66N 476.5190, found 476.5174.
    38
    Figure US20230030119A1-20230202-C00052
    caled C29H60N 422.4720, found 422.4701.
    39
    Figure US20230030119A1-20230202-C00053
    calcd C30H62N 436.4877, found 436.4880.
    40
    Figure US20230030119A1-20230202-C00054
    calcd C32H66N 464.5190, found 464.5199.
    41
    Figure US20230030119A1-20230202-C00055
    calcd C30H62N 436.4877, found 436.4877.
    42
    Figure US20230030119A1-20230202-C00056
    caled C30H62N 436.4877, found 436.4875.
    43
    Figure US20230030119A1-20230202-C00057
    LC/MS (M + H) 408.6.
  • (11E,20Z,23Z)—N,N-dimethylnonacosa-11,20,23-trien-10-amine (Compound 44)
  • Figure US20230030119A1-20230202-C00058
  • To a solution of LDA (95 mmol, 47.5 mL of a 2M solution) in THF (127 mL) cooled to −78° C. was added t-butyl acetate. The reaction was stirred for 15 minutes followed by addition of aldehyde x. The reaction was immediately quenched with ammonium chloride solution, warmed to ambient temperature and partitioned between water/pentane. The organics were dried over sodium sulfate, filtered and evaporated in vacuo. LC/MS (M+H−tBu)=325.4.
  • Figure US20230030119A1-20230202-C00059
  • Hydroxy ketone xi (7 g, 18.4 mmol) was dissolved in dichloromethane (150 mL) and cooled to 0° C. and treated with deoxofluor (7.3 g, 33.1 mmol). The reaction was warmed to ambient temperature with stirring for 16 hours followed by quenching with sodium bicarbonate solution. The reaction was partitioned and the organics dried over sodium sulfate, filtered and evaporate in vacuo. Flash column chromotagraphy (0-5% ethyl acetate/hexanes) gave the—fluoro ester.
  • Fluoro ester intermediate (6 g, 15.6 mmol) in dichloromethane was treated with hydrogen chloride (157 mmol, 39.2 mL of a 4M solution in dioxane) and the reaction was stirred at ambient temperature for 16 hours. The reaction was evaporated in vacuo to give desired β-fluoro acid xii. LC/MS (M+H)=327.3.
  • Figure US20230030119A1-20230202-C00060
  • Fluoro carboxylic acid xii (5.1 g, 15.7 mmol), EDC (6.0 g, 31.4 mmol), N,O-dimethylhydroxylamine hydrochloride (3.1 g, 31.4 mmol), trimethylamine (4.0 g, 39.2 mmol), and HOAt (4.3 g, 31.4 mmol) were combined in DCM (78 mL) and stirred at ambient temperature for 16 hours. The reaction was partitioned between water/DCM and the organics were washed with water (3×) and NaOH solution (1×), dried over sodium sulfate, filtered and evaporated in vacuo. Crude material was purified by reverse phase preparative chromatography to give desired Weinreb amide xiii. LC/MS (M+H)=370.4.
  • Figure US20230030119A1-20230202-C00061
  • A solution of Weinreb amide xiii (4.3 g, 11.7 mmol) in THF (50 mL) was treated with nonylmagnesium bromide (23.4 mmol, 23.4 mL of a 1M solution) at ambient temperature. The reaction was quenched with ammonium chloride solution after 1 hour and partitioned between water and pentane. The organics were dried over sodium sulfate; filtered and evaporated in vacuo. This material was carried into next step crude.
  • Figure US20230030119A1-20230202-C00062
  • Ketone xiv (5.1 g, 11.7 mmol) was treated with dimethylamine (29.3 mmol, 14.7 mL of a 2M solution in THF) and titanium(IV) isopropoxide (6.7 g, 23.5 mmol) and the reaction was stirred at ambient temperature for 16 hours. To the reaction mixture was added ethanol (50 mL) followed by sodium borohydride (0.67 g, 17.6 mmol). The reaction was loaded directly onto a silica column and purified by flash chromatography (0-15% MeOH/DCM). The material required a second purification by preparative reverse phase chromatography to give (11E,20Z,23Z)—N,N-dimethylnonacosa-11,20,23-trien-10-amine. HRMS calc'd 446.4720, found 446.4724, 1H NMR (400 MHz, CDCl3) δ 5.48 (m, 1H), 5.37 (m, 4H), 5.23 (m, 1H), 2.78 (t, 2H), 2.58 (m, 1H), 2.22 (5, 6H), 2.04 (m, 6H), 1.56 (m, 1H), 1.30 (m, 31H), 0.89 (m, 6H).
  • Compound 45 is DLinKC2DMA as described in Nature Biotechnology, 2010, 28, 172-176, WO 2010/042877 A1, WO 2010/048536 A2, WO 2010/088537 A2, and WO 2009/127060 A1.
  • Figure US20230030119A1-20230202-C00063
  • Compound 46 is MC3 as described in WO 2010/054401, and WO 2010/144740 A1.
  • Figure US20230030119A1-20230202-C00064
  • D. Lipid Nonoparticle Compositions
  • The following lipid nanoparticle compositions (LNPs) of the instant invention are useful for the delivery of oligonucleotides, specifically siNA molecules of the invention:
  • Cationic Lipid/Cholesterol/PEG-DMG 56.6/38/5.4; Cationic Lipid/Cholesterol/PEG-DMG 60/38/2; Cationic Lipid/Cholesterol/PEG-DMG 67.3/29/3.7; Cationic Lipid/Cholesterol/PEG-DMG 49.3/47/3.7; Cationic Lipid/Cholesterol/PEG-DMG 50.3/44.3/5.4; Cationic Lipid/Cholesterol/PEG-C-DMA/DSPC 40/48/2/10; Cationic Lipid/Cholesterol/PEG-DMG/DSPC 40/48/2/10; and Cationic Lipid/Cholesterol/PEG-DMG/DSPC 58/30/2/1.0.
  • One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods and compositions described herein, as presently representative of preferred embodiments, are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.
  • TABLE 8
    CTNNB1 Accession Numbers
    NM_001098210
    Homo sapiens catenin
    (cadherin-associated protein),
    beta 1, 88 kDa. (CTNNB1),
    transcript variant 3, mRNA.
    NM_001098210.1 GI:148227671
    NM_007614
    Mus musculus catenin
    (cadherin associated protein),
    beta 1 (Ctnnb1),
    transcript variant 1, mRNA
    NM_007614.2 GI:31560726
    NM_001115474
    Macaca mulatta catenin
    (cadherin-associated protein),
    beta 1, 88 kDa. transcript variant
    (CTNNB1), mRNA.
    NM_001115474.1 GI:109041278
  • TABLE 9
    Non-limiting examples of Stabilization Chemistries for chemically modified siNA constructs
    Chemistry pyrimidine purine caps p = S Strand
    “Stab 00” Ribo Ribo TT at 3'- S/AS
    ends
    “Stab 1” Ribo Ribo 5 at 5'-end S/AS
    1 at 3'-end
    “Stab 2” Ribo Ribo All linkages Usually AS
    “Stab 3” 2'-fluoro Ribo 4 at 5'-end Usually S
    4 at 3'-end
    “Stab 4” 2'-fluoro Ribo 5' and 3'- Usually S
    ends
    “Stab 5” 2'-fluoro Ribo 1 at 3'-end Usually AS
    “Stab 6” 2'-O-Methyl Ribo 5' and 3'- Usually S
    ends
    “Stab 7” 2'-fluoro 2'-deoxy 5' and 3'- Usually S
    ends
    “Stab 8” 2'-fluoro 2'-O- 1 at 3'-end S/AS
    Methyl
    “Stab 9” Ribo Ribo 5' and 3'- Usually S
    ends
    “Stab 10” Ribo Ribo 1 at 3'-end Usually AS
    “Stab 11” 2'-fluoro 2'-deoxy 1 at 3'-end Usually AS
    “Stab 12” 2'-fluoro LNA 5' and 3'- Usually S
    ends
    “Stab 13” 2'-fluoro LNA 1 at 3'-end Usually AS
    “Stab 14” 2'-fluoro 2'-deoxy 2 at 5'-end Usually AS
    1 at 3'-end
    “Stab 15” 2'-deoxy 2'-deoxy 2 at 5'-end Usually AS
    1 at 3'-end
    “Stab 16” Ribo 2'-O-Methyl 5' and 3'- Usually S
    ends
    “Stab 17” 2'-O-Methyl 2'-O-Methyl 5' and 3'- Usually S
    ends
    “Stab 18” 2'-fluoro 2'-O-Methyl 5' and 3'- Usually S
    ends
    “Stab 19” 2'-fluoro 2'-O-Methyl 3'-end S/AS
    “Stab 20” 2'-fluoro 2'-deoxy 3'-end Usually AS
    “Stab 21” 2'-fluoro Ribo 3'-end Usually AS
    “Stab 22” Ribo Ribo 3'-end Usually AS
    “Stab 23” 2'-fluoro* 2'-deoxy* 5' and 3'- Usually S
    ends
    “Stab 24” 2'-fluoro* 2'-O-Methyl* 1 at 3'-end S/AS
    “Stab 25” 2'-fluoro* 2'-O-Methyl* 1 at 3'-end S/AS
    “Stab 26” 2'-fluoro* 2'-O-Methyl* S/AS
    “Stab 27” 2'-fluoro* 2'-O-Methyl* 3'-end S/AS
    “Stab 28” 2'-fluoro* 2'-O-Methyl* 3'-end S/AS
    “Stab 29” 2'-fluoro* 2'-O-Methyl* 1 at 3'-end S/AS
    “Stab 30” 2'-fluoro* 2'-O-Methyl* S/AS
    “Stab 31” 2'-fluoro* 2'-O-Methyl* 3'-end S/AS
    “Stab 32” 2'-fluoro* 2'-O-Methyl* S/AS
    “Stab 33” 2'-fluoro 2'-deoxy* 5' and 3'- Usually S
    ends
    “Stab 34” 2'-fluoro 2'-O-Methyl* 5' and 3'- Usually S
    ends
    “Stab 35” 2'-fluoro*† 2'-O-Methyl*† Usually AS
    “Stab 36” 2'-fluoro*† 2'-O-Methyl*† Usually AS
    “Stab04H” 2'-fluoro‡ Ribo‡ 5' and 3'- 1 at 3'-end Ususally S
    ends
    “Stab06C” 2'-O-Methyl‡ Ribo‡ 5' and 3'- Ususally S
    ends
    “Stab07H” 2'-fluoro‡ 2'-deoxy‡ 5' and 3'- 1 at 3'-end Ususally S
    ends
    “Stab07mU” 2'-fluoro‡ 2'-deoxy‡ 5' and 3'- Ususally S
    ends
    “Stab09H” Ribo‡ Ribo‡ 5' and 3'- 1 at 3'-end Ususally S
    ends
    “Stab16C” Ribo‡ 2'-O-Methyl‡ 5' and 3'- Ususally S
    ends
    “Stab16H” Ribo‡ 2'-O-Methyl‡ 5' and 3'- 1 at 3'-end Ususally S
    ends
    “Stab18C” 2'-fluoro‡ 2'-O-Methyl‡ 5' and 3'- Ususally S
    ends
    “Stab18H” 2'-fluoro‡ 2'-O-Methyl‡ 5' and 3'- 1 at 3'-end Ususally S
    ends
    “Stab52H” 2'-O-Methyl‡ Ribo‡ 5' and 3'- 1 at 3'-end Ususally S
    ends
    “Stab05C” 2'-fluoro‡ Ribo‡ Ususally AS
    “Stab05N” 2'-fluoro‡ Ribo‡ 1 at 3'-end Ususally AS
    “Stab10C” Ribo‡ Ribo‡ Ususally AS
    “Stab10N” Ribo‡ Ribo‡ 1 at 3'-end Ususally AS
    “Stab35G-*” 2-fluoro‡ 2'-O-Methyl‡ Ususally AS
    “Stab35N*” 2'-fluoro‡ 2'-O-Methyl‡ 1 at 3'-end Ususally AS
    “Stab35rev*” 2'-O-Methyl‡ 2'-fluoro‡ Ususally AS
    “Stab50*” Ribo‡ 2'-O-Methyl‡ Ususally AS
    “Stab53” 2'-O-Methyl‡ Ribo‡ Ususally AS
    “Stab53N*” 2'-O-Methyl‡ Ribo‡ 1 at 3'-end Ususally AS
    Stab54 Ribo‡ 2'-fluoro‡ Ususally AS
    CAP = any terminal cap, see for example FIG. 6.
    All Stab chemistries can be used in combination with each other for duplexes of the invention (e.g. as combinations of sense and antisense strand chemistries), or alternately can be used in isolation, e.g., for single stranded nucleic acid molecules of the invention.
    All Stab chemistries can comprise 3'-overhang nucleotides having 2'-O-alkyl, 2'-deoxy-2'- fluoro, 2’-deoxy, LNA or other modified nucleotides or non-nucleotides.
    All Stab chemistries typically comprise about 19-21 nucleotides, but can vary as described herein.
    All Stab chemistries can also include a single ribonucleotide in the sense or passenger strand at the 11th base paired position of the double-stranded nucleic acid duplex as determined from the 5'-end of the antisense or guide strand.
    All Stab chemistries can also have in place of the Stab designation above a 2'-deoxy-2'-fluoro modification at position 14 from the 5'end of the antisense strand regardless of whether it is a purine or pyrimidine at that position.
    All Stab chemistries of the antisense strand presented above can have a thymidine in place of a 2'-deoxy uridine at position 1, 2, and/or 3 from the 5' end of the antisense strand.
    S = sense strand.
    AS = antisense strand.
    *Stab 23 has a single ribonucleotide adjacent to 3'-CAP.
    *Stab 24 and Stab 28 have a single ribonucleotide at 5'-terminus.
    *Stab 25, Stab 26, Stab 27, Stab 35, Stab 35G*, Stab 35N*, Stab 35rev*, Stab 36, Stab 50*, Stab53*, Stab 53N*, and Stab 54 have three ribonucleotides at 5'-terminus.
    *Stab 29, Stab 30, Stab 31, Stab 33, and Stab 34 any purine at first three nucleotide positions from 5’-terminus are ribonucleotides.
    p = phosphorothioate linkage.
    †Stab 35 has 2'-O-methyl U at 3'-overhangs and three ribonucleotides at 5'-terminus.
    †Stab 36 has 2'-O-methyl overhangs that are complementary to the target sequence, (naturally occurring overhangs) and three ribonucleotides at 5'-terminus.
    ‡Stab 04H, Stab 06C, Stabl07H, Stab07mU, Stab09H, Stab16C, Stab 16H, Stab18C, Stab 18H, Stab 52H, Stab05C, Stab05N, Stab10C, Stab10N, Stab35G*, Stab35N*, Stab35N*, Stab35rev*, Stab 50*, Stab 53*, Stab 53N*, Stab 54 have two 2'-O-methyl U 3'-overhangs. Stab35G*, Stab 35N*, Stab35rev*, Stab50*, Stab53*, and Stab53N* do not allow for a 2'-O- methyl modification at position 14 of the guide strand as determined from the 5'-end.
  • TABLE 10
    Exemplary Solid Phase Oligonucleotide Synthsis Conditions
    Wait Wait Wait
    Time* Time* Time*
    Reagent Equivalents Amount DNA 2'-O-methyl RNA
    A. 2.5 μmol Synthesis Cycle ABI 394 Instrument
    Phosphoramidites 6.5 163 μL 45 sec 2.5 min 7.5 min
    S-Ethyl Tetrazole 23.8 238 μL 45 sec 2.5 min 7.5 min
    Acetic 100 233 μL 5 sec 5 sec 5 sec
    Anhydride
    N- 186 233 μL 5 sec 5 sec 5 sec
    CTNNB1hyl
    IMidazole
    ICA 176 2.3 mL 21 sec 21 sec 21 sec
    Iodine 11.2 1.7 mL 45 sec 45 sec 45 sec
    Beaucage 12.9 645 μL 100 sec 300 sec 300 sec
    Acetonitrile NA 6.67 mL NA NA NA
    B. 0.2 μmol Synthesis Cycle ABI 394 Instrument
    Phosphoramidites 15 31 μL 45 sec 233 sec 465 sec
    S-Ethyl Tetrazole 38.7 31 μL 45 sec 233 min 465 sec
    Acetic 655 124 μL 5 sec 5 sec 5 sec
    Anhydride
    N- 1245 124 μL 5 sec 5 sec 5 sec
    CTNNB1hyl
    Imidazole
    TCA 700 732 μL 10 sec 10 sec 10 sec
    Iodine 20.6 244 μL 15 sec 15 sec 15 sec
    Beaucage 7.7 232 μL 100 sec 300 sec 300 sec
    Acetonitrile NA 2.64 mL NA NA NA
    C. 0.2 μmol Synthesis Cycle 96 well Instrument
    Equivalents: Wait Wait Wait
    DNA/2'-O- Amount: Time* Time* Time*
    Reagent methyl/Ribo DNA/2'-O-methyl/Ribo DNA 2'-O-methyl Ribo
    Phospheramidites 22/33/66  40/60/120 μL 60 sec 180 sec 360 sec
    S-Ethyl Tetrazole  70/105/210 40/60/120 μL 60 sec 180 min 360 sec
    Acetic 265/265/265 50/50/50 μL 10 sec 10 sec 10 sec
    Anhydride
    N- 502/502/502 50/50/50 μL 10 sec 10 sec 10 sec
    CTNNB1hyl
    Imidazole
    TCA 238/475/475 250/500/500 μL 15 sec 15 sec 15 sec
    Iodine 6.8/6.8/6.8  80/80/80 μL 30 sec 30 sec 30 see
    Beaucage 34/51/51   80/120/120 100 sec 200 sec 200 sec
    Acctonitrile NA 1150/1150/1150 μL NA NA NA
    *Wait time contact time during does not include delivery,
    *Tandem synthesis utilizes double coupling of linker molecule
  • TABLE 11
    Composition of Select Lipid Nanoparticle Formulations
    LNP siNA
    Identifier Lipid Components and Molar Ratios Duplex N/P
    LNP-1 Compound Cholesterol DSPC PEG-DMG R-008488889- 6
    32 (30%) (10%) (2%) 000M
    (50%)
    LNP-2 Compound Cholesterol DSPC PEG-DMG R-008488882- 6
    32 (30%) (10%) (2%) 000B
    (50%)
    LNP-3 Compound Cholesterol DSPC PEG-DMG R-008380929- 6
    32 (30%) (10%) (2%) 000H
    (50%)
    LNP-4 Compound Cholesterol DSPC PEG-DMG R-008488885- 6
    32 (30%) (10%) (2%) 000C
    (50%)
    N/P ratio = Nitrogen:Phosphorous ratio between cationic lipid and nucleic acid
  • TABLE 12
    Chemical Structures of Lipids in Formulations of Table 11
    Lipid Chemical Structure
    Compound 32
    Figure US20230030119A1-20230202-C00065
    Cholesterol
    Figure US20230030119A1-20230202-C00066
    DSPC
    Figure US20230030119A1-20230202-C00067
    PEG-DMG
    Figure US20230030119A1-20230202-C00068

Claims (21)

1. An isolated double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of cadherin-associated protein, beta 1 (CTNNB1), wherein
(a) the siNA comprises a sense strand and an antisense strand;
(b) each strand is independently 15 to 30 nucleotides in length; and
(c) at least one strand comprises at least a 15 nucleotide sequence of any one of the nucleotide sequences selected from the group consisting of SEQ ID NO:1-6374.
2.-5. (canceled)
6. The double-stranded short interfering nucleic acid (siNA) molecule according to claim 1, wherein at least one nucleotide is a chemically modified nucleotide.
7. The double-stranded short interfering nucleic acid (siNA) molecule according to claim 1 further comprising at least one non-nucleotide.
8. The double-stranded short interfering nucleic acid (siNA) molecule according to claim 1, wherein at least one nucleotide comprises a universal base.
9. The double-stranded short interfering nucleic acid (siNA) molecule according to claim 1, having at least one phosphorothioate internucleotide linkage.
10. The double-stranded short interfering nucleic acid (siNA) molecule according to claim 1, comprising a cap on the 3′-end, 5′-end or both 3′ and 5′ ends of at least one strand.
11. The double-stranded short interfering nucleic acid (siNA) molecule according to claim 1, comprising one or more 3′-overhang nucleotides on one or both strands.
12. (canceled)
13. The double-stranded short interfering nucleic acid (siNA) molecule of claim 11, wherein the 3′-overhang nucleotides on at least one strand are 2′-O-methyl nucleotides.
14. The double-stranded short interfering nucleic acid (siNA) molecule of claim 13, wherein the 2′-O-methyl nucleotides are linked with a phosphorothioate internucleotide linkage
15. The double-stranded short interfering nucleic acid (siNA) molecule of claim 6, wherein the chemically modified nucleotide is a 2′-deoxy-2′-fluoro nucleotide.
16. The double-stranded short interfering nucleic acid (siNA) molecule of claim 6, wherein the chemically modified nucleotide is a 2′-deoxy nucleotide.
17. The double-stranded short interfering nucleic acid (siNA) molecule of claim 6, wherein the chemically modified nucleotide is a 2′-0-alkyl nucleotide.
18.-29. (canceled)
30. A composition comprising the double-stranded short interfering nucleic acid (siNA) according to claim 1 in a pharmaceutically acceptable carrier or diluent.
31.-37. (canceled)
38. A method of treating a human subject suffering from a condition which is mediated by the action, or by loss of action, of CTNNB1, which comprises administering to said subject an effective amount of the double-stranded short interfering nucleic acid (siNA) molecule of claim 1.
39. The method according to claim 38, wherein the condition is cancer.
40. A method of treating a human subject suffering from a condition which is mediated by the action, or by loss of action, of CTNNB1, which comprises administering to the subject an effective amount of the composition of claim 30.
41. The method according to claim 40, wherein the condition is cancer.
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