US20070260051A1 - siRNA targeting pituitary tumor-transforming 1 (PTTG1) - Google Patents

siRNA targeting pituitary tumor-transforming 1 (PTTG1) Download PDF

Info

Publication number
US20070260051A1
US20070260051A1 US11/811,925 US81192507A US2007260051A1 US 20070260051 A1 US20070260051 A1 US 20070260051A1 US 81192507 A US81192507 A US 81192507A US 2007260051 A1 US2007260051 A1 US 2007260051A1
Authority
US
United States
Prior art keywords
sirna
position
base
sense strand
sequence
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/811,925
Inventor
Anastasia Khvorova
Angela Reynolds
Devin Leake
William Marshall
Steven Read
Stephen Scaringe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dharmacon Inc
Original Assignee
Dharmacon Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US42613702P priority Critical
Priority to US50205003P priority
Priority to US10/714,333 priority patent/US8090542B2/en
Priority to PCT/US2004/014885 priority patent/WO2006006948A2/en
Priority to US10/940,892 priority patent/US20120052487A9/en
Application filed by Dharmacon Inc filed Critical Dharmacon Inc
Priority to US11/811,925 priority patent/US20070260051A1/en
Assigned to DHARMACON, INC. reassignment DHARMACON, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: READ, STEVEN, SCARINGE, STEPHEN, LEAKE, DEVIN, MARSHALL, WILLIAM, REYNOLDS, ANGELA, KHVOROVA, ANASTASIA
Publication of US20070260051A1 publication Critical patent/US20070260051A1/en
Application status is Abandoned legal-status Critical

Links

Images

Classifications

    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/11DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/11DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/111General methods applicable to biologically active non-coding nucleic acids
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/11DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1135Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against oncogenes or tumor suppressor genes
    • GPHYSICS
    • G16INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16BBIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B20/00ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/10Type of nucleic acid
    • C12N2310/11Antisense
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/10Type of nucleic acid
    • C12N2310/14Type of nucleic acid interfering N.A.
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2320/00Applications; Uses
    • C12N2320/10Applications; Uses in screening processes
    • C12N2320/11Applications; Uses in screening processes for the determination of target sites, i.e. of active nucleic acids

Abstract

Efficient sequence specific gene silencing is possible through the use of siRNA technology. By selecting particular siRNAs by rational design, one can maximize the generation of an effective gene silencing reagent, as well as methods for silencing genes. Methods, compositions, and kits generated through rational design of siRNAs are disclosed including those directed to PTTG1.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation-in-part of U.S. Ser. No. 10/714,333, filed Nov. 14, 2003, which claims the benefit of U.S. Provisional Application No. 60/426,137, filed Nov. 14, 2002, and also claims the benefit of U.S. Provisional Application No. 60/502,050, filed Sep. 10, 2003; this application is also a continuation-in-part of U.S. Ser. No. 10/940,892, filed Sep. 14, 2004, which is a continuation of PCT Application No. PCT/US 04/14885, international filing date May 12, 2004. The disclosures of the priority applications, including the sequence listings and tables submitted in electronic form in lieu of paper, are incorporated by reference into the instant specification.
  • SEQUENCE LISTING
  • The sequence listing for this application has been submitted in accordance with 37 CFR § 1.52(e) and 37 CFR § 1.821 on CD-ROM in lieu of paper on a disk containing the sequence listing file entitled “DHARMA2100-US45_CRF.txt” created May 30, 2007, 88 kb. Applicants hereby incorporate by reference the sequence listing provided on CD-ROM in lieu of paper into the instant specification.
  • FIELD OF INVENTION
  • The present invention relates to RNA interference (“RNAi”).
  • BACKGROUND OF THE INVENTION
  • Relatively recently, researchers observed that double stranded RNA (“dsRNA”) could be used to inhibit protein expression. This ability to silence a gene has broad potential for treating human diseases, and many researchers and commercial entities are currently investing considerable resources in developing therapies based on this technology.
  • Double stranded RNA induced gene silencing can occur on at least three different levels: (i) transcription inactivation, which refers to RNA guided DNA or histone methylation; (ii) siRNA induced mRNA degradation; and (iii) mRNA induced transcriptional attenuation.
  • It is generally considered that the major mechanism of RNA induced silencing (RNA interference, or RNAi) in mammalian cells is mRNA degradation. Initial attempts to use RNAi in mammalian cells focused on the use of long strands of dsRNA. However, these attempts to induce RNAi met with limited success, due in part to the induction of the interferon response, which results in a general, as opposed to a target-specific, inhibition of protein synthesis. Thus, long dsRNA is not a viable option for RNAi in mammalian systems.
  • More recently it has been shown that when short (18-30 bp) RNA duplexes are introduced into mammalian cells in culture, sequence-specific inhibition of target mRNA can be realized without inducing an interferon response. Certain of these short dsRNAs, referred to as small inhibitory RNAs (“siRNAs”), can act catalytically at sub-molar concentrations to cleave greater than 95% of the target mRNA in the cell. A description of the mechanisms for siRNA activity, as well as some of its applications are described in Provost et al. (2002) Ribonuclease Activity and RNA Binding of Recombinant Human Dicer, EMBO J. 21(21): 5864-5874; Tabara et al. (2002) The dsRNA Binding Protein RDE-4 Interacts with RDE-1, DCR-1 and a DexH-box Helicase to Direct RNAi in C. elegans, Cell 109(7):861-71; Ketting et al. (2002) Dicer Functions in RNA Interference and in Synthesis of Small RNA Involved in Developmental Timing in C. elegans; Martinez et al., Single-Stranded Antisense siRNAs Guide Target RNA Cleavage in RNAi, Cell 110(5):563; Hutvagner & Zamore (2002) A microRNA in a multiple-turnover RNAi enzyme complex, Science 297:2056.
  • From a mechanistic perspective, introduction of long double stranded RNA into plants and invertebrate cells is broken down into siRNA by a Type III endonuclease known as Dicer. Sharp, RNA interference—2001, Genes Dev. 2001, 15:485. Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair short interfering RNAs with characteristic two base 3′ overhangs. Bernstein, Caudy, Hammond, & Hannon (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference, Nature 409:363. The siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition. Nykanen, Haley, & Zamore (2001) ATP requirements and small interfering RNA structure in the RNA interference pathway, Cell 107:309. Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleaves the target to induce silencing. Elbashir, Lendeckel, & Tuschl (2001) RNA interference is mediated by 21- and 22-nucleotide RNAs, Genes Dev. 15:188, FIG. 1.
  • The interference effect can be long lasting and may be detectable after many cell divisions. Moreover, RNAi exhibits sequence specificity. Kisielow, M. et al. (2002) Isoform-specific knockdown and expression of adaptor protein ShcA using small interfering RNA, J. Biochem. 363:1-5. Thus, the RNAi machinery can specifically knock down one type of transcript, while not affecting closely related mRNA. These properties make siRNA a potentially valuable tool for inhibiting gene expression and studying gene function and drug target validation. Moreover, siRNAs are potentially useful as therapeutic agents against: (1) diseases that are caused by over-expression or misexpression of genes; and (2) diseases brought about by expression of genes that contain mutations.
  • Successful siRNA-dependent gene silencing depends on a number of factors. One of the most contentious issues in RNAi is the question of the necessity of siRNA design, i.e., considering the sequence of the siRNA used. Early work in C. elegans and plants circumvented the issue of design by introducing long dsRNA (see, for instance, Fire, A. et al. (1998) Nature 391:806-811). In this primitive organism, long dsRNA molecules are cleaved into siRNA by Dicer, thus generating a diverse population of duplexes that can potentially cover the entire transcript. While some fraction of these molecules are non-functional (i.e., induce little or no silencing) one or more have the potential to be highly functional, thereby silencing the gene of interest and alleviating the need for siRNA design. Unfortunately, due to the interferon response, this same approach is unavailable for mammalian systems. While this effect can be circumvented by bypassing the Dicer cleavage step and directly introducing siRNA, this tactic carries with it the risk that the chosen siRNA sequence may be non-functional or semi-functional.
  • A number of researches have expressed the view that siRNA design is not a crucial element of RNAi. On the other hand, others in the field have begun to explore the possibility that RNAi can be made more efficient by paying attention to the design of the siRNA. Unfortunately, none of the reported methods have provided a satisfactory scheme for reliably selecting siRNA with acceptable levels of functionality. Accordingly, there is a need to develop rational criteria by which to select siRNA with an acceptable level of functionality, and to identify siRNA that have this improved level of functionality, as well as to identify siRNAs that are hyperfunctional.
  • SUMMARY OF THE INVENTION
  • The present invention is directed to increasing the efficiency of RNAi, particularly in mammalian systems. Accordingly, the present invention provides kits, siRNAs and methods for increasing siRNA efficacy.
  • According to a first embodiment, the present invention provides a kit for gene silencing, wherein said kit is comprised of a pool of at least two siRNA duplexes, each of which is comprised of a sequence that is complementary to a portion of the sequence of one or more target messenger RNA, and each of which is selected using non-target specific criteria.
  • According to a second embodiment, the present invention provides a method for selecting an siRNA, said method comprising applying selection criteria to a set of potential siRNA that comprise 18-30 base pairs, wherein said selection criteria are non-target specific criteria, and said set comprises at least two siRNAs and each of said at least two siRNAs contains a sequence that is at least substantially complementary to a target gene; and determining the relative functionality of the at least two siRNAs.
  • According to a third embodiment, the present invention also provides a method for selecting an siRNA wherein said selection criteria are embodied in a formula comprising:
    (−14)*G13−13*A1−12*U7−11*U2−10*A11−10*U4−10*C3−10*C5−10*C6−9*A10−9*U9−9*C18−8*G10−7*U1−7*U16−7*C17−7*C19+7*U17+8*A2+8*A4+8*A5+8*C4+9*G8+10*A7+10*U18+11*A19+11*C9+15*G1+18*A3+19*U10−Tm−3*(GCtotal)−6*(GC15-19)−30*X; or  Formula VIII:
    (−8)*A1+(−1)*A2+(12)*A3+(7)*A4+(18)*A5+(12)*A6+(19)*A7+(6)*A8+(−4)*A9+(−5)*A10+(−2)*A11+(−5)*A12+(17)*A13+(−3)*A14+(4)*A15+(2)*A16+(8)*A17+(11)*A18+(30)*A19+(−13)*U1+(−10)*U2+(2)*U3+(−2)*U4+(−5)*U5+(5)*U6+(−2)*U7+(−10)*U8+(−5)*U9+(15)*U10+(−1)*U11+(0)*U12+(10)*U13+(−9)*U14+(−13)*U15+(−10)*U16+(3)*U17+(9)*U18+(9)*U19+(7)*C1+(3)*C2+(−21)*C3+(5)*C4+(−9)*C5+(−20)*C6+(−18)*C7+(−5)*C8+(5)*C9+(1)*C10+(2)*C11+(−5)*C12+(−3)*C13+(−6)*C14+(−2)*C15+(−5)*C16+(−3)*C17+(−12)*C18+(−18)*C19+(14)*G1+(8)*G2+(7)*G3+(−10)*G4+(−4)*G5+(2)*G6+(1)*G7+(9)*G8+(5)*G9+(−11)*G10+(1)*G11+(9)*G12+(−24)*G13+(18)*G14+(11)*G15+(13)*G16+(−7)*G17+(−9)*G18+(−22)*G19+6*(number of A+U in position 15-19)−3*(number of G+C in whole siRNA),  Formula X
    wherein position numbering begins at the 5′-most position of a sense strand, and
    • A1=1 if A is the base at position 1 of the sense strand, otherwise its value is 0;
    • A2=1 if A is the base at position 2 of the sense strand, otherwise its value is 0;
    • A3=1 if A is the base at position 3 of the sense strand, otherwise its value is 0;
    • A4=1 if A is the base at position 4 of the sense strand, otherwise its value is 0;
    • A5=1 if A is the base at position 5 of the sense strand, otherwise its value is 0;
    • A6=1 if A is the base at position 6 of the sense strand, otherwise its value is 0;
    • A7=1 if A is the base at position 7 of the sense strand, otherwise its value is 0;
    • A10=1 if A is the base at position 10 of the sense strand, otherwise its value is 0;
    • A11=1 if A is the base at position 11 of the sense strand, otherwise its value is 0;
    • A13=1 if A is the base at position 13 of the sense strand, otherwise its value is 0;
    • A19=1 if A is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
    • C3=1 if C is the base at position 3 of the sense strand, otherwise its value is 0;
    • C4=1 if C is the base at position 4 of the sense strand, otherwise its value is 0;
    • C5=1 if C is the base at position 5 of the sense strand, otherwise its value is 0;
    • C6=1 if C is the base at position 6 of the sense strand, otherwise its value is 0;
    • C7=1 if C is the base at position 7 of the sense strand, otherwise its value is 0;
    • C9=1 if C is the base at position 9 of the sense strand, otherwise its value is 0;
    • C17=1 if C is the base at position 17 of the sense strand, otherwise its value is 0;
    • C18=1 if C is the base at position 18 of the sense strand, otherwise its value is 0;
    • C19=1 if C is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
    • G1=1 if G is the base at position 1 on the sense strand, otherwise its value is 0;
    • G2=1 if G is the base at position 2 of the sense strand, otherwise its value is 0;
    • G8=1 if G is the base at position 8 on the sense strand, otherwise its value is 0;
    • G10=1 if G is the base at position 10 on the sense strand, otherwise its value is 0;
    • G13=1 if G is the base at position 13 on the sense strand, otherwise its value is 0;
    • G19=1 if G is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
    • U1=1 if U is the base at position 1 on the sense strand, otherwise its value is 0;
    • U2=1 if U is the base at position 2 on the sense strand, otherwise its value is 0;
    • U3=1 if U is the base at position 3 on the sense strand, otherwise its value is 0;
    • U4=1 if U is the base at position 4 on the sense strand, otherwise its value is 0;
    • U7=1 if U is the base at position 7 on the sense strand, otherwise its value is 0;
    • U9=1 if U is the base at position 9 on the sense strand, otherwise its value is 0;
    • U10=1 if U is the base at position 10 on the sense strand, otherwise its value is 0;
    • U15=1 if U is the base at position 15 on the sense strand, otherwise its value is 0;
    • U16=1 if U is the base at position 16 on the sense strand, otherwise its value is 0;
    • U17=1 if U is the base at position 17 on the sense strand, otherwise its value is 0;
    • U18=1 if U is the base at position 18 on the sense strand, otherwise its value is 0.
    • GC15-19=the number of G and C bases within positions 15-19 of the sense strand, or within positions 15-18 if the sense strand is only 18 base pairs in length;
    • GCtotal=the number of G and C bases in the sense strand;
    • Tm=100 if the siRNA oligo has the internal repeat longer then 4 base pairs, otherwise its value is 0; and
    • X=the number of times that the same nucleotide repeats four or more times in a row.
  • According to a fourth embodiment, the invention provides a method for developing an algorithm for selecting siRNA, said method comprising: (a) selecting a set of siRNA; (b) measuring gene silencing ability of each siRNA from said set; (c) determining relative functionality of each siRNA; (d) determining improved functionality by the presence or absence of at least one variable selected from the group consisting of the presence or absence of a particular nucleotide at a particular position, the total number of As and Us in positions 15-19, the number of times that the same nucleotide repeats within a given sequence, and the total number of Gs and Cs; and (e) developing an algorithm using the information of step (d).
  • According to a fifth embodiment, the present invention provides a kit, wherein said kit is comprised of at least two siRNAs, wherein said at least two siRNAs comprise a first optimized siRNA and a second optimized siRNA, wherein said first optimized siRNA and said second optimized siRNA are optimized according a formula comprising Formula X.
  • The present invention also provides a method for identifying a hyperfunctional siRNA, comprising applying selection criteria to a set of potential siRNA that comprise 18-30 base pairs, wherein said selection criteria are non-target specific criteria, and said set comprises at least two siRNAs and each of said at least two siRNAs contains a sequence that is at least substantially complementary to a target gene; determining the relative functionality of the at least two siRNAs and assigning each of the at least two siRNAs a functionality score; and selecting siRNAs from the at least two siRNAs that have a functionality score that reflects greater than 80 percent silencing at a concentration in the picomolar range, wherein said greater than 80 percent silencing endures for greater than 120 hours.
  • According to a sixth embodiment, the present invention provides a hyperfunctional siRNA that is capable of silencing Bcl2.
  • According to a seventh embodiment, the present invention provides a method for developing an siRNA algorithm for selecting functional and hyperfunctional siRNAs for a given sequence. The method comprises:
  • (a) selecting a set of siRNAs;
  • (b) measuring the gene silencing ability of each siRNA from said set;
  • (c) determining the relative functionality of each siRNA;
  • (d) determining the amount of improved functionality by the presence or absence of at least one variable selected from the group consisting of the total GC content, melting temperature of the siRNA, GC content at positions 15-19, the presence or absence of a particular nucleotide at a particular position, relative thermodynamic stability at particular positions in a duplex, and the number of times that the same nucleotide repeats within a given sequence; and
  • (e) developing an algorithm using the information of step (d).
  • According to this embodiment, preferably the set of siRNAs comprises at least 90 siRNAs from at least one gene, more preferably at least 180 siRNAs from at least two different genes, and most preferably at least 270 and 360 siRNAs from at least three and four different genes, respectively. Additionally, in step (d) the determination is made with preferably at least two, more preferably at least three, even more preferably at least four, and most preferably all of the variables. The resulting algorithm is not target sequence specific.
  • In another embodiment, the present invention provides rationally designed siRNAs identified using the formulas above.
  • In yet another embodiment, the present invention is directed to hyperfunctional siRNA.
  • The ability to use the above algorithms, which are not sequence or species specific, allows for the cost-effective selection of optimized siRNAs for specific target sequences. Accordingly, there will be both greater efficiency and reliability in the use of siRNA technologies.
  • In various embodiments, siRNAs that target pituitary tumor-transforming 1 (PTTG1) are provided. In various embodiments, the siRNAs are rationally designed. In various embodiments, the siRNAs are functional or hyperfunctional.
  • In various embodiments, an siRNA that targets PTTG1 is provided, wherein the siRNA is selected from the group consisting of various siRNA sequences targeting PTTG1 that are disclosed herein. In various embodiments, the siRNA sequence is selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 498.
  • In various embodiments, siRNA comprising a sense region and an antisense region are provided, wherein said sense region and said antisense region are at least 90% complementary, said sense region and said antisense region together form a duplex region comprising 18-30 base pairs, and said sense region comprises a sequence that is at least 90% similar to a sequence selected from the group consisting of siRNA sequences targeting PTTG1 that are disclosed herein. In various embodiments, the siRNA sequence is selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 498.
  • In various embodiments, an siRNA comprising a sense region and an antisense region is provided, wherein said sense region and said antisense region are at least 90% complementary, said sense region and said antisense region together form a duplex region comprising 18-30 base pairs, and said sense region comprises a sequence that is identical to a contiguous stretch of at least 18 bases of a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 498. In various embodiments, the duplex region is 19-30 base pairs, and the sense region comprises a sequence that is identical to a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 498.
  • In various embodiments, a pool of at least two siRNAs is provided, wherein said pool comprises a first siRNA and a second siRNA, said first siRNA comprising a duplex region of length 18-30 base pairs that has a first sense region that is at least 90% similar to 18 bases of a first sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 498, and said second siRNA comprises a duplex region of length 18-30 base pairs that has a second sense region that is at least 90% similar to 18 bases of a second sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 498, wherein said first sense region and said second sense region are not identical.
  • In various embodiments, the first sense region comprises a sequence that is identical to at least 18 bases of a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 498, and said second sense region comprises a sequence that is identical to at least 18 bases of a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 498. In various embodiments, the duplex of said first siRNA is 19-30 base pairs, and said first sense region comprises a sequence that is at least 90% similar to a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 498, and said duplex of said second siRNA is 19-30 base pairs and comprises a sequence that is at least 90% similar to a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 498.
  • In various embodiments, the duplex of said first siRNA is 19-30 base pairs and said first sense region comprises a sequence that is identical to at least 18 bases of a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 498, and said duplex of said second siRNA is 19-30 base pairs and said second region comprises a sequence that is identical to a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 498.
  • For a better understanding of the present invention together with other and further advantages and embodiments, reference is made to the following description taken in conjunction with the examples, the scope of which is set forth in the appended claims.
  • BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 shows a model for siRNA-RISC interactions. RISC has the ability to interact with either end of the siRNA or miRNA molecule. Following binding, the duplex is unwound, and the relevant target is identified, cleaved, and released.
  • FIG. 2 is a representation of the functionality of two hundred and seventy siRNA duplexes that were generated to target human cyclophilin, human diazepam-binding inhibitor (DB), and firefly luciferase.
  • FIG. 3 a is a representation of the silencing effect of 30 siRNAs in three different cells lines, HEK293, DU145, and Hela. FIG. 3 b shows the frequency of different functional groups (>95% silencing (black), >80% silencing (gray), >50% silencing (dark gray), and <50% silencing (white)) based on GC content. In cases where a given bar is absent from a particular GC percentage, no siRNA were identified for that particular group. FIG. 3 c shows the frequency of different functional groups based on melting temperature (Tm).
  • FIGS. 4A-4E are representations of a statistical analysis that revealed correlations between silencing and five sequence-related properties of siRNA: (A) an A at position 19 of the sense strand, (B) an A at position 3 of the sense strand, (C) a U at position 10 of the sense strand, (D) a base other than G at position 13 of the sense strand, and (E) a base other than C at position 19 of the sense strand. All variables were correlated with siRNA silencing of firefly luciferase and human cyclophilin. siRNAs satisfying the criterion are grouped on the left (Selected) while those that do not, are grouped on the right (Eliminated). Y-axis is “% Silencing of Control.” Each position on the X-axis represents a unique siRNA.
  • FIGS. 5A and 5B are representations of firefly luciferase and cyclophilin siRNA panels sorted according to functionality and predicted values using Formula VIII. The siRNA found within the circle represent those that have Formula VIII values (SMARTSCORES™, or siRNA rank) above zero. siRNA outside the indicated area have calculated Formula VIII values that are below zero. Y-axis is “Expression (% Control).” Each position on the X-axis represents a unique siRNA.
  • FIG. 6A is a representation of the average internal stability profile (AISP) derived from 270 siRNAs taken from three separate genes (cyclophilin B, DBI and firefly luciferase). Graphs represent AISP values of highly functional, functional, and non-functional siRNA. FIG. 6B is a comparison between the AISP of naturally derived GFP siRNA (filled squares) and the AISP of siRNA from cyclophilin B, DBI, and luciferase having >90% silencing properties (no fill) for the antisense strand. “DG” is the symbol for ΔG, free energy.
  • FIG. 7 is a histogram showing the differences in duplex functionality upon introduction of base pair mismatches. The X-axis shows the mismatch introduced in the siRNA and the position it is introduced (e.g., 8C>A reveals that position 8 (which normally has a C) has been changed to an A). The Y-axis is “% Silencing (Normalized to Control).” The samples on the X-axis represent siRNAs at 100 nM and are, reading from left to right: 1A to C, 1A to G, 1A to U; 2A to C, 2A to G, 2A to U; 3A to C, 3A to G, 3A to U; 4G to A, 4G to C; 4G to U; 5U to A, 5U to C, 5U to G; 6U to A, 6U to C, 6U to G; 7G to A, 7G to C, 7G to U; 8C to A, 8C to G, 8C to U; 9G to A, 9G to C, 9G to U; 10C to A, 10C to G, 10C to U; 11G to A, 11G to C, 11G to U; 12G to A, 12G to C, 12G to U; 13A to C, 13A to G, 13A to U; 14G to A, 14G to C, 14G to U; 15G to A, 15G to C, 15G to U; 16A to C, 16A to G, 16A to U; 17G to A, 17G to C, 17G to U; 18U to A, 18U to C, 18U to G; 19U to A, 19U to C, 19U to G; 20 wt; Control.
  • FIG. 8A is histogram that shows the effects of 5′sense and antisense strand modification with 2′-O-methylation on functionality. FIG. 8B is an expression profile showing a comparison of sense strand off-target effects for IGF1R-3 and 2′-O-methyl IGF1R-3. Sense strand off-targets (lower box) are not induced when the 5′ end of the sense strand is modified with 2′-O-methyl groups (top box).
  • FIG. 9 shows a graph of SMARTSCORES™, or siRNA rank, versus RNAi silencing values for more than 360 siRNA directed against 30 different genes. SiRNA to the right of the vertical bar represent those siRNA that have desirable SMARTSCORES™, or siRNA rank.
  • FIGS. 10A-E compare the RNAi of five different genes (SEAP, DBI, PLK, Firefly Luciferase, and Renilla Luciferase) by varying numbers of randomly selected siRNA and four rationally designed (SMART-selected) siRNA chosen using the algorithm described in Formula VIII. In addition, RNAi induced by a pool of the four SMART-selected siRNA is reported at two different concentrations (100 and 400 nM). 10F is a comparison between a pool of randomly selected EGFR siRNA (Pool 1) and a pool of SMART-selected EGFR siRNA (Pool 2). Pool 1, S1-S4 and Pool 2 S1-S4 represent the individual members that made up each respective pool. Note that numbers for random siRNAs represent the position of the 5′ end of the sense strand of the duplex. The Y-axis represents the % expression of the control(s). The X-axis is the percent expression of the control.
  • FIG. 11 shows the Western blot results from cells treated with siRNA directed against twelve different genes involved in the clathrin-dependent endocytosis pathway (CHC, DynII, CALM, CLCa, CLCb, Eps15, Eps15R, Rab5a, Rab5b, Rab5c, β2 subunit of AP-2 and EEA.1). siRNA were selected using Formula VIII. “Pool” represents a mixture of duplexes 1-4. Total concentration of each siRNA in the pool is 25 nM. Total concentration=4×25=100 nM.
  • FIG. 12 is a representation of the gene silencing capabilities of rationally-selected siRNA directed against ten different genes (human and mouse cyclophilin, C-myc, human lamin A/C, QB (ubiquinol-cytochrome c reductase core protein I), MEK1 and MEK2, ATE1 (arginyl-tRNA protein transferase), GAPDH, and Eg5). The Y-axis is the percent expression of the control. Numbers 1, 2, 3 and 4 represent individual rationally selected siRNA. “Pool” represents a mixture of the four individual siRNA.
  • FIG. 13 is the sequence of the top ten Bcl2 siRNAs as determined by Formula VIII. Sequences are listed 5′ to 3′.
  • FIG. 14 is the knockdown by the top ten Bcl2 siRNAs at 100 nM concentrations. The Y-axis represents the amount of expression relative to the non-specific (ns) and transfection mixture control.
  • FIG. 15 represents a functional walk where siRNA beginning on every other base pair of a region of the luciferase gene are tested for the ability to silence the luciferase gene. The Y-axis represents the percent expression relative to a control. The X-axis represents the position of each individual siRNA. Reading from left to right across the X-axis, the position designations are 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, and Plasmid.
  • FIGS. 16A and 16B are histograms demonstrating the inhibition of target gene expression by pools of 2 (16A) and 3 (16B) siRNA duplexes taken from the walk described in FIG. 15. The Y-axis in each represents the percent expression relative to control. The X-axis in each represents the position of the first siRNA in paired pools, or trios of siRNAs. For instance, the first paired pool contains siRNAs 1 and 3. The second paired pool contains siRNAs 3 and 5. Pool 3 (of paired pools) contains siRNAs 5 and 7, and so on. For each of 16A and 16B, the X-axis from left to right reads 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, and Plasmid.
  • FIGS. 17A and 17B are histograms demonstrating the inhibition of target gene expression by pools of 4 (17A) and 5 (17B) siRNA duplexes. The Y-axis in each represents the percent expression relative to control. The X-axis in each represents the position of the first siRNA in each pool. For each of 17A and 17B, the X-axis from left to right reads 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, and Plasmid.
  • FIGS. 18A and 18B are histograms demonstrating the inhibition of target gene expression by siRNAs that are ten (18A) and twenty (18B) base pairs base pairs apart. The Y-axis represents the percent expression relative to a control. The X-axis represents the position of the first siRNA in each pool. For each of 18A and 18B, the X-axis from left to right reads 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, and Plasmid.
  • FIG. 19 shows that pools of siRNAs (dark gray bar) work as well (or better) than the best siRNA in the pool (light gray bar). The Y-axis represents the percent expression relative to a control. The X-axis represents the position of the first siRNA in each pool. The X-axis from left to right reads 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, and Plasmid.
  • FIG. 20 shows that the combination of several semifunctional siRNAs (dark gray) result in a significant improvement of gene expression inhibition over individual (semi-functional; light gray) siRNA. The Y-axis represents the percent expression relative to a control.
  • FIGS. 21A, 21B and 21C show both pools (Library, Lib) and individual siRNAs in inhibition of gene expression of Beta-Galactosidase, Renilla Luciferase and SEAP (alkaline phosphatase). Numbers on the X-axis indicate the position of the 5′-most nucleotide of the sense strand of the duplex. The Y-axis represents the percent expression of each gene relative to a control. Libraries contain 19 nucleotide long siRNAs (not including overhangs) that begin at the following nucleotides: SEAP: Lib 1: 206, 766, 812, 923, Lib 2: 1117, 1280, 1300, 1487, Lib 3: 206, 766, 812, 923, 1117, 1280, 1300, 1487, Lib 4: 206, 812, 1117, 1300, Lib 5: 766, 923, 1280, 1487, Lib 6: 206, 1487; Bgal: Lib 1: 979, 1339, 2029, 2590, Lib 2: 1087, 1783, 2399, 3257, Lib 3: 979, 1783, 2590, 3257, Lib 4: 979, 1087, 1339, 1783, 2029, 2399, 2590, 3257, Lib 5: 979, 1087, 1339, 1783, Lib 6: 2029, 2399, 2590, 3257; Renilla: Lib 1: 174, 300, 432, 568, Lib 2: 592, 633, 729, 867, Lib 3: 174, 300, 432, 568, 592, 633, 729, 867, Lib 4: 174, 432, 592, 729, Lib 5: 300, 568, 633, 867, Lib 6: 592, 568.
  • FIG. 22 shows the results of an EGFR and TfnR internalization assay when single gene knockdowns are performed. The Y-axis represents percent internalization relative to control.
  • FIG. 23 shows the results of an EGFR and TfnR internalization assay when multiple genes are knocked down (e.g., Rab5a, b, c). The Y-axis represents the percent internalization relative to control.
  • FIG. 24 shows the simultaneous knockdown of four different genes. siRNAs directed against G6PD, GAPDH, PLK, and UQC were simultaneously introduced into cells. Twenty-four hours later, cultures were harvested and assayed for mRNA target levels for each of the four genes. A comparison is made between cells transfected with individual siRNAs vs. a pool of siRNAs directed against all four genes.
  • FIG. 25 shows the functionality of ten siRNAs at 0.3 nM concentrations.
  • DETAILED DESCRIPTION
  • Definitions
  • Unless stated otherwise, the following terms and phrases have the meanings provided below:
  • Complementary
  • The term “complementary” refers to the ability of polynucleotides to form base pairs with one another. Base pairs are typically formed by hydrogen bonds between nucleotide units in antiparallel polynucleotide strands. Complementary polynucleotide strands can base pair in the Watson-Crick manner (e.g., A to T, A to U, C to G), or in any other manner that allows for the formation of duplexes. As persons skilled in the art are aware, when using RNA as opposed to DNA, uracil rather than thymine is the base that is considered to be complementary to adenosine. However, when a U is denoted in the context of the present invention, the ability to substitute a T is implied, unless otherwise stated.
  • Perfect complementarity or 100% complementarity refers to the situation in which each nucleotide unit of one polynucleotide strand can hydrogen bond with a nucleotide unit of a second polynucleotide strand. Less than perfect complementarity refers to the situation in which some, but not all, nucleotide units of two strands can hydrogen bond with each other. For example, for two 20-mers, if only two base pairs on each strand can hydrogen bond with each other, the polynucleotide strands exhibit 10% complementarity. In the same example, if 18 base pairs on each strand can hydrogen bond with each other, the polynucleotide strands exhibit 90% complementarity.
  • Deoxynucleotide
  • The term “deoxynucleotide” refers to a nucleotide or polynucleotide lacking a hydroxyl group (OH group) at the 2′ and/or 3′ position of a sugar moiety. Instead, it has a hydrogen bonded to the 2′ and/or 3′ carbon. Within an RNA molecule that comprises one or more deoxynucleotides, “deoxynucleotide” refers to the lack of an OH group at the 2′ position of the sugar moiety, having instead a hydrogen bonded directly to the 2′ carbon.
  • Deoxyribonucleotide
  • The terms “deoxyribonucleotide” and “DNA” refer to a nucleotide or polynucleotide comprising at least one sugar moiety that has an H, rather than an OH, at its 2′ and/or 3′position.
  • Duplex Region
  • The phrase “duplex region” refers to the region in two complementary or substantially complementary polynucleotides that form base pairs with one another, either by Watson-Crick base pairing or any other manner that allows for a stabilized duplex between polynucleotide strands that are complementary or substantially complementary. For example, a polynucleotide strand having 21 nucleotide units can base pair with another polynucleotide of 21 nucleotide units, yet only 19 bases on each strand are complementary or substantially complementary, such that the “duplex region” has 19 base pairs. The remaining bases may, for example, exist as 5′ and 3′ overhangs. Further, within the duplex region, 100% complementarity is not required; substantial complementarity is allowable within a duplex region. Substantial complementarity refers to 79% or greater complementarity. For example, a mismatch in a duplex region consisting of 19 base pairs results in 94.7% complementarity, rendering the duplex region substantially complementary.
  • Filters
  • The term “filter” refers to one or more procedures that are performed on sequences that are identified by the algorithm. In some instances, filtering includes in silico procedures where sequences identified by the algorithm can be screened to identify duplexes carrying desirable or undesirable motifs. Sequences carrying such motifs can be selected for, or selected against, to obtain a final set with the preferred properties. In other instances, filtering includes wet lab experiments. For instance, sequences identified by one or more versions of the algorithm can be screened using any one of a number of procedures to identify duplexes that have hyperfunctional traits (e.g., they exhibit a high degree of silencing at subnanomolar concentrations and/or exhibit high degrees of silencing longevity).
  • Gene Silencing
  • The phrase “gene silencing” refers to a process by which the expression of a specific gene product is lessened or attenuated. Gene silencing can take place by a variety of pathways. Unless specified otherwise, as used herein, gene silencing refers to decreases in gene product expression that results from RNA interference (RNAi), a defined, though partially characterized pathway whereby small inhibitory RNA (siRNA) act in concert with host proteins (e.g., the RNA induced silencing complex, RISC) to degrade messenger RNA (mRNA) in a sequence-dependent fashion. The level of gene silencing can be measured by a variety of means, including, but not limited to, measurement of transcript levels by Northern Blot Analysis, B-DNA techniques, transcription-sensitive reporter constructs, expression profiling (e.g., DNA chips), and related technologies. Alternatively, the level of silencing can be measured by assessing the level of the protein encoded by a specific gene. This can be accomplished by performing a number of studies including Western Analysis, measuring the levels of expression of a reporter protein that has e.g., fluorescent properties (e.g., GFP) or enzymatic activity (e.g., alkaline phosphatases), or several other procedures.
  • miRNA
  • The term “miRNA” refers to microRNA.
  • Nucleotide
  • The term “nucleotide” refers to a ribonucleotide or a deoxyribonucleotide or modified form thereof, as well as an analog thereof. Nucleotides include species that comprise purines, e.g., adenine, hypoxanthine, guanine, and their derivatives and analogs, as well as pyrimidines, e.g., cytosine, uracil, thymine, and their derivatives and analogs.
  • Nucleotide analogs include nucleotides having modifications in the chemical structure of the base, sugar and/or phosphate, including, but not limited to, 5-position pyrimidine modifications, 8-position purine modifications, modifications at cytosine exocyclic amines, and substitution of 5-bromo-uracil; and 2′-position sugar modifications, including but not limited to, sugar-modified ribonucleotides in which the 2′-OH is replaced by a group such as an H, OR, R, halo, SH, SR, NH2, NHR, NR2, or CN, wherein R is an alkyl moiety. Nucleotide analogs are also meant to include nucleotides with bases such as inosine, queuosine, xanthine, sugars such as 2′-methyl ribose, non-natural phosphodiester linkages such as methylphosphonates, phosphorothioates and peptides.
  • Modified bases refer to nucleotide bases such as, for example, adenine, guanine, cytosine, thymine, uracil, xanthine, inosine, and queuosine that have been modified by the replacement or addition of one or more atoms or groups. Some examples of types of modifications that can comprise nucleotides that are modified with respect to the base moieties include but are not limited to, alkylated, halogenated, thiolated, aminated, amidated, or acetylated bases, individually or in combination. More specific examples include, for example, 5-propynyluridine, 5-propynylcytidine, 6-methyladenine, 6-methylguanine, N,N,-dimethyladenine, 2-propyladenine, 2-propylguanine, 2-aminoadenine, 1-methylinosine, 3-methyluridine, 5-methylcytidine, 5-methyluridine and other nucleotides having a modification at the 5 position, 5-(2-amino)propyl uridine, 5-halocytidine, 5-halouridine, 4-acetylcytidine, 1-methyladenosine, 2-methyladenosine, 3-methylcytidine, 6-methyluridine, 2-methylguanosine, 7-methylguanosine, 2,2-dimethylguanosine, 5-methylaminoethyluridine, 5-methyloxyuridine, deazanucleotides such as 7-deaza-adenosine, 6-azouridine, 6-azocytidine, 6-azothymidine, 5-methyl-2-thiouridine, other thio bases such as 2-thiouridine and 4-thiouridine and 2-thiocytidine, dihydrouridine, pseudouridine, queuosine, archaeosine, naphthyl and substituted naphthyl groups, any O- and N-alkylated purines and pyrimidines such as N6-methyladenosine, 5-methylcarbonylmethyluridine, uridine 5-oxyacetic acid, pyridine-4-one, pyridine-2-one, phenyl and modified phenyl groups such as aminophenol or 2,4,6-trimethoxy benzene, modified cytosines that act as G-clamp nucleotides, 8-substituted adenines and guanines, 5-substituted uracils and thymines, azapyrimidines, carboxyhydroxyalkyl nucleotides, carboxyalkylaminoalkyl nucleotides, and alkylcarbonylalkylated nucleotides. Modified nucleotides also include those nucleotides that are modified with respect to the sugar moiety, as well as nucleotides having sugars or analogs thereof that are not ribosyl. For example, the sugar moieties may be, or be based on, mannoses, arabinoses, glucopyranoses, galactopyranoses, 4′-thioribose, and other sugars, heterocycles, or carbocycles.
  • The term nucleotide is also meant to include what are known in the art as universal bases. By way of example, universal bases include but are not limited to 3-nitropyrrole, 5-nitroindole, or nebularine. The term “nucleotide” is also meant to include the N3′ to P5′ phosphoramidate, resulting from the substitution of a ribosyl 3′ oxygen with an amine group.
  • Further, the term nucleotide also includes those species that have a detectable label, such as for example a radioactive or fluorescent moiety, or mass label attached to the nucleotide.
  • Off-Target Silencing and Off-Target Interference
  • The phrases “off-target silencing” and “off-target interference” are defined as degradation of mRNA other than the intended target mRNA due to overlapping and/or partial homology with secondary mRNA messages.
  • Polynucleotide
  • The term “polynucleotide” refers to polymers of nucleotides, and includes but is not limited to DNA, RNA, DNA/RNA hybrids including polynucleotide chains of regularly and/or irregularly alternating deoxyribosyl moieties and ribosyl moieties (i.e., wherein alternate nucleotide units have an —OH, then and —H, then an —OH, then an —H, and so on at the 2′ position of a sugar moiety), and modifications of these kinds of polynucleotides, wherein the attachment of various entities or moieties to the nucleotide units at any position are included.
  • Polyribonucleotide
  • The term “polyribonucleotide” refers to a polynucleotide comprising two or more modified or unmodified ribonucleotides and/or their analogs. The term “polyribonucleotide” is used interchangeably with the term “oligoribonucleotide.”
  • Ribonucleotide and Ribonucleic Acid
  • The term “ribonucleotide” and the phrase “ribonucleic acid” (RNA), refer to a modified or unmodified nucleotide or polynucleotide comprising at least one ribonucleotide unit. A ribonucleotide unit comprises an hydroxyl group attached to the 2′ position of a ribosyl moiety that has a nitrogenous base attached in N-glycosidic linkage at the 1′ position of a ribosyl moiety, and a moiety that either allows for linkage to another nucleotide or precludes linkage.
  • siRNA
  • The term “siRNA” refers to small inhibitory RNA duplexes that induce the RNA interference (RNAi) pathway. These molecules can vary in length (generally 18-30 base pairs) and contain varying degrees of complementarity to their target mRNA in the antisense strand. Some, but not all, siRNA have unpaired overhanging bases on the 5′ or 3′ end of the sense strand and/or the antisense strand. The term “siRNA” includes duplexes of two separate strands, as well as single strands that can form hairpin structures comprising a duplex region.
  • siRNA may be divided into five (5) groups (non-functional, semi-functional, functional, highly functional, and hyper-functional) based on the level or degree of silencing that they induce in cultured cell lines. As used herein, these definitions are based on a set of conditions where the siRNA is transfected into said cell line at a concentration of 100 nM and the level of silencing is tested at a time of roughly 24 hours after transfection, and not exceeding 72 hours after transfection. In this context, “non-functional siRNA” are defined as those siRNA that induce less than 50% (<50%) target silencing. “Semi-functional siRNA” induce 50-79% target silencing. “Functional siRNA” are molecules that induce 80-95% gene silencing. “Highly-functional siRNA” are molecules that induce greater than 95% gene silencing. “Hyperfunctional siRNA” are a special class of molecules. For purposes of this document, hyperfunctional siRNA are defined as those molecules that: (1) induce greater than 95% silencing of a specific target when they are transfected at subnanomolar concentrations (i.e., less than one nanomolar); and/or (2) induce functional (or better) levels of silencing for greater than 96 hours. These relative functionalities (though not intended to be absolutes) may be used to compare siRNAs to a particular target for applications such as functional genomics, target identification and therapeutics.
  • SMARTSCORE™, or siRNA Rank
  • The term “SMARTSCORE™”, or “siRNA rank” refers to a number determined by applying any of the formulas to a given siRNA sequence. The term “SMART-selected” or “rationally selected” or “rational selection” refers to siRNA that have been selected on the basis of their SMARTSCORES™, or siRNA ranking.
  • Substantially Similar
  • The phrase “substantially similar” refers to a similarity of at least 90% with respect to the identity of the bases of the sequence.
  • Target
  • The term “target” is used in a variety of different forms throughout this document and is defined by the context in which it is used. “Target mRNA” refers to a messenger RNA to which a given siRNA can be directed against. “Target sequence” and “target site” refer to a sequence within the mRNA to which the sense strand of an siRNA shows varying degrees of homology and the antisense strand exhibits varying degrees of complementarity. The phrase “siRNA target” can refer to the gene, mRNA, or protein against which an siRNA is directed. Similarly, “target silencing” can refer to the state of a gene, or the corresponding mRNA or protein.
  • Transfection
  • The term “transfection” refers to a process by which agents are introduced into a cell. The list of agents that can be transfected is large and includes, but is not limited to, siRNA, sense and/or anti-sense sequences, DNA encoding one or more genes and organized into an expression plasmid, proteins, protein fragments, and more. There are multiple methods for transfecting agents into a cell including, but not limited to, electroporation, calcium phosphate-based transfections, DEAE-dextran-based transfections, lipid-based transfections, molecular conjugate-based transfections (e.g., polylysine-DNA conjugates), microinjection and others.
  • The present invention is directed to improving the efficiency of gene silencing by siRNA. Through the inclusion of multiple siRNA sequences that are targeted to a particular gene and/or selecting an siRNA sequence based on certain defined criteria, improved efficiency may be achieved.
  • The present invention will now be described in connection with preferred embodiments. These embodiments are presented in order to aid in an understanding of the present invention and are not intended, and should not be construed, to limit the invention in any way. All alternatives, modifications and equivalents that may become apparent to those of ordinary skill upon reading this disclosure are included within the spirit and scope of the present invention.
  • Furthermore, this disclosure is not a primer on RNA interference. Basic concepts known to persons skilled in the art have not been set forth in detail.
  • The present invention is directed to increasing the efficiency of RNAi, particularly in mammalian systems. Accordingly, the present invention provides kits, siRNAs and methods for increasing siRNA efficacy.
  • According to a first embodiment, the present invention provides a kit for gene silencing, wherein said kit is comprised of a pool of at least two siRNA duplexes, each of which is comprised of a sequence that is complementary to a portion of the sequence of one or more target messenger RNA, and each of which is selected using non-target specific criteria. Each of the at least two siRNA duplexes of the kit complementary to a portion of the sequence of one or more target mRNAs is preferably selected using Formula X.
  • According to a second embodiment, the present invention provides a method for selecting an siRNA, said method comprising applying selection criteria to a set of potential siRNA that comprise 18-30 base pairs, wherein said selection criteria are non-target specific criteria, and said set comprises at least two siRNAs and each of said at least two siRNAs contains a sequence that is at least substantially complementary to a target gene; and determining the relative functionality of the at least two siRNAs.
  • In one embodiment, the present invention also provides a method wherein said selection criteria are embodied in a formula comprising:
    (−14)*G13−13*A1−12*U7−11*U2−10*A11−10*U4−10*C3−10*C5−10*C6−9*A10−9*U9−9*C18−8*G10−7*U1−7*U16−7*C17−7*C19+7*U17+8*A2+8*A4+8*A5+8*C4+9*G8+10*A7+10*U18+11*A19+11*C9+15*G1+18*A3+19*U10−Tm−3*(GCtotal)−6*(GC15-19)−30*X; or  Formula VIII:
    (−8)*A1+(−1)*A2+(12)*A3+(7)*A4+(18)*A5+(12)*A6+(19)*A7+(6)*A8+(−4)*A9+(−5)*A10+(−2)*A11+(−5)*A12+(17)*A13+(−3)*A14+(4)*A15+(2)*A16+(8)*A17+(11)*A18+(30)*A19+(−13)*U1+(−10)*U2+(2)*U3+(−2)*U4+(−5)*U5+(5)*U6+(−2)*U7+(−10)*U8+(−5)*U9+(15)*U10+(−1)*U11+(0)*U12+(10)*U13+(−9)*U14+(−13)*U15+(−10)*U16+(3)*U17+(9)*U18+(9)*U19+(7)*C1+(3)*C2+(−21)*C3+(5)*C4+(−9)*C5+(−20)*C6+(−18)*C7+(−5)*C8+(5)*C9+(1)*C10+(2)*C11+(−5)*C12+(−3)*C13+(−6)*C14+(−2)*C15+(−5)*C16+(−3)*C17+(−12)*C18+(−18)*C19+(14)*G1+(8)*G2+(7)*G3+(−10)*G4+(−4)*G5+(2)*G6+(1)*G7+(9)*G8+(5)*G9+(−1)*G10+(1)*G11+(9)*G12+(−24)*G13+(18)*G14+(11)*G15+(13)*G16+(−7)*G17+(−9)*G18+(−22)*G19+6*(number of A+U in position 15-19)−3*(number of G+C in whole siRNA),  Formula X
    wherein position numbering begins at the 5′-most position of a sense strand, and
  • A1=1 if A is the base at position 1 of the sense strand, otherwise its value is 0;
    • A2=1 if A is the base at position 2 of the sense strand, otherwise its value is 0;
    • A3=1 if A is the base at position 3 of the sense strand, otherwise its value is 0;
    • A4=1 if A is the base at position 4 of the sense strand, otherwise its value is 0;
    • A5=1 if A is the base at position 5 of the sense strand, otherwise its value is 0;
    • A6=1 if A is the base at position 6 of the sense strand, otherwise its value is 0;
    • A7=1 if A is the base at position 7 of the sense strand, otherwise its value is 0;
    • A10=1 if A is the base at position 10 of the sense strand, otherwise its value is 0;
    • A11=1 if A is the base at position 11 of the sense strand, otherwise its value is 0;
    • A13=1 if A is the base at position 13 of the sense strand, otherwise its value is 0;
    • A19=1 if A is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
  • C3=1 if C is the base at position 3 of the sense strand, otherwise its value is 0;
    • C4=1 if C is the base at position 4 of the sense strand, otherwise its value is 0;
    • C5=1 if C is the base at position 5 of the sense strand, otherwise its value is 0;
    • C6=1 if C is the base at position 6 of the sense strand, otherwise its value is 0;
    • C7=1 if C is the base at position 7 of the sense strand, otherwise its value is 0;
    • C9=1 if C is the base at position 9 of the sense strand, otherwise its value is 0;
    • C17=1 if C is the base at position 17 of the sense strand, otherwise its value is 0;
    • C18=1 if C is the base at position 18 of the sense strand, otherwise its value is 0;
    • C19=1 if C is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
  • G1=1 if G is the base at position 1 on the sense strand, otherwise its value is 0;
    • G2=1 if G is the base at position 2 of the sense strand, otherwise its value is 0;
    • G8=1 if G is the base at position 8 on the sense strand, otherwise its value is 0;
    • G10=1 if G is the base at position 10 on the sense strand, otherwise its value is 0;
    • G13=1 if G is the base at position 13 on the sense strand, otherwise its value is 0;
    • G19=1 if G is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
  • U1=1 if U is the base at position 1 on the sense strand, otherwise its value is 0;
    • U2=1 if U is the base at position 2 on the sense strand, otherwise its value is 0;
    • U3=1 if U is the base at position 3 on the sense strand, otherwise its value is 0;
    • U4=1 if U is the base at position 4 on the sense strand, otherwise its value is 0;
    • U7=1 if U is the base at position 7 on the sense strand, otherwise its value is 0;
    • U9=1 if U is the base at position 9 on the sense strand, otherwise its value is 0;
    • U10=1 if U is the base at position 10 on the sense strand, otherwise its value is 0;
    • U15=1 if U is the base at position 15 on the sense strand, otherwise its value is 0;
    • U16=1 if U is the base at position 16 on the sense strand, otherwise its value is 0;
    • U17=1 if U is the base at position 17 on the sense strand, otherwise its value is 0;
    • U18=1 if U is the base at position 18 on the sense strand, otherwise its value is 0.
  • GC15-19=the number of G and C bases within positions 15-19 of the sense strand, or within positions 15-18 if the sense strand is only 18 base pairs in length;
  • GCtotal=the number of G and C bases in the sense strand;
  • Tm=100 if the siRNA oligo has the internal repeat longer then 4 base pairs, otherwise its value is 0; and
  • X=the number of times that the same nucleotide repeats four or more times in a row.
  • Any of the methods of selecting siRNA in accordance with the invention can further comprise comparing the internal stability profiles of the siRNAs to be selected, and selecting those siRNAs with the most favorable internal stability profiles. Any of the methods of selecting siRNA can further comprise selecting either for or against sequences that contain motifs that induce cellular stress. Such motifs include, for example, toxicity motifs. Any of the methods of selecting siRNA can further comprise either selecting for or selecting against sequences that comprise stability motifs.
  • In another embodiment, the present invention provides a method of gene silencing, comprising introducing into a cell at least one siRNA selected according to any of the methods of the present invention. The siRNA can be introduced by allowing passive uptake of siRNA, or through the use of a vector.
  • According to a third embodiment, the invention provides a method for developing an algorithm for selecting siRNA, said method comprising: (a) selecting a set of siRNA; (b) measuring gene silencing ability of each siRNA from said set; (c) determining relative functionality of each siRNA; (d) determining improved functionality by the presence or absence of at least one variable selected from the group consisting of the presence or absence of a particular nucleotide at a particular position, the total number of As and Us in positions 15-19, the number of times that the same nucleotide repeats within a given sequence, and the total number of Gs and Cs; and (e) developing an algorithm using the information of step (d).
  • In another embodiment, the invention provides a method for selecting an siRNA with improved functionality, comprising using the above-mentioned algorithm to identify an siRNA of improved functionality.
  • According to a fourth embodiment, the present invention provides a kit, wherein said kit is comprised of at least two siRNAs, wherein said at least two siRNAs comprise a first optimized siRNA and a second optimized siRNA, wherein said first optimized siRNA and said second optimized siRNA are optimized according a formula comprising Formula X.
  • According to a fifth embodiment, the present invention provides a method for identifying a hyperfunctional siRNA, comprising applying selection criteria to a set of potential siRNA that comprise 18-30 base pairs, wherein said selection criteria are non-target specific criteria, and said set comprises at least two siRNAs and each of said at least two siRNAs contains a sequence that is at least substantially complementary to a target gene; determining the relative functionality of the at least two siRNAs and assigning each of the at least two siRNAs a functionality score; and selecting siRNAs from the at least two siRNAs that have a functionality score that reflects greater than 80 percent silencing at a concentration in the picomolar range, wherein said greater than 80 percent silencing endures for greater than 120 hours.
  • In other embodiments, the invention provides kits and/or methods wherein the siRNA are comprised of two separate polynucleotide strands; wherein the siRNA are comprised of a single contiguous molecule such as, for example, a unimolecular siRNA (comprising, for example, either a nucleotide or non-nucleotide loop); wherein the siRNA are expressed from one or more vectors; and wherein two or more genes are silenced by a single administration of siRNA.
  • According to a sixth embodiment, the present invention provides a hyperfunctional siRNA that is capable of silencing Bcl2.
  • According to a seventh embodiment, the present invention provides a method for developing an siRNA algorithm for selecting functional and hyperfunctional siRNAs for a given sequence. The method comprises:
  • (a) selecting a set of siRNAs;
  • (b) measuring the gene silencing ability of each siRNA from said set;
  • (c) determining the relative functionality of each siRNA;
  • (d) determining the amount of improved functionality by the presence or absence of at least one variable selected from the group consisting of the total GC content, melting temperature of the siRNA, GC content at positions 15-19, the presence or absence of a particular nucleotide at a particular position, relative thermodynamic stability at particular positions in a duplex, and the number of times that the same nucleotide repeats within a given sequence; and
  • (e) developing an algorithm using the information of step (d).
  • According to this embodiment, preferably the set of siRNAs comprises at least 90 siRNAs from at least one gene, more preferably at least 180 siRNAs from at least two different genes, and most preferably at least 270 and 360 siRNAs from at least three and four different genes, respectively. Additionally, in step (d) the determination is made with preferably at least two, more preferably at least three, even more preferably at least four, and most preferably all of the variables. The resulting algorithm is not target sequence specific.
  • In another embodiment, the present invention provides rationally designed siRNAs identified using the formulas above.
  • In yet another embodiment, the present invention is directed to hyperfunctional siRNA.
  • The ability to use the above algorithms, which are not sequence or species specific, allows for the cost-effective selection of optimized siRNAs for specific target sequences. Accordingly, there will be both greater efficiency and reliability in the use of siRNA technologies.
  • The methods disclosed herein can be used in conjunction with comparing internal stability profiles of selected siRNAs, and designing an siRNA with a desirable internal stability profile; and/or in conjunction with a selection either for or against sequences that contain motifs that induce cellular stress, for example, cellular toxicity.
  • Any of the methods disclosed herein can be used to silence one or more genes by introducing an siRNA selected, or designed, in accordance with any of the methods disclosed herein. The siRNA(s) can be introduced into the cell by any method known in the art, including passive uptake or through the use of one or more vectors.
  • Any of the methods and kits disclosed herein can employ either unimolecular siRNAs, siRNAs comprised of two separate polynucleotide strands, or combinations thereof. Any of the methods disclosed herein can be used in gene silencing, where two or more genes are silenced by a single administration of siRNA(s). The siRNA(s) can be directed against two or more target genes, and administered in a single dose or single transfection, as the case may be.
  • Optimizing siRNA
  • According to one embodiment, the present invention provides a method for improving the effectiveness of gene silencing for use to silence a particular gene through the selection of an optimal siRNA. An siRNA selected according to this method may be used individually, or in conjunction with the first embodiment, i.e., with one or more other siRNAs, each of which may or may not be selected by this criteria in order to maximize their efficiency.
  • The degree to which it is possible to select an siRNA for a given mRNA that maximizes these criteria will depend on the sequence of the mRNA itself. However, the selection criteria will be independent of the target sequence. According to this method, an siRNA is selected for a given gene by using a rational design. That said, rational design can be described in a variety of ways. Rational design is, in simplest terms, the application of a proven set of criteria that enhance the probability of identifying a functional or hyperfunctional siRNA. In one method, rationally designed siRNA can be identified by maximizing one or more of the following criteria:
  • (1) A low GC content, preferably between about 30-52%.
  • (2) At least 2, preferably at least 3 A or U bases at positions 15-19 of the siRNA on the sense strand.
    • (3) An A base at position 19 of the sense strand.
    • (4) An A base at position 3 of the sense strand.
    • (5) A U base at position 10 of the sense strand.
    • (6) An A base at position 14 of the sense strand.
    • (7) A base other than C at position 19 of the sense strand.
    • (8) A base other than G at position 13 of the sense strand.
  • (9) A Tm, which refers to the character of the internal repeat that results in inter- or intramolecular structures for one strand of the duplex, that is preferably not stable at greater than 50° C., more preferably not stable at greater than 37° C., even more preferably not stable at greater than 30° C. and most preferably not stable at greater than 20° C.
    • (10) A base other than U at position 5 of the sense strand.
    • (11) A base other than A at position 11 of the sense strand.
    • (12) A base other than an A at position 1 of the sense strand.
    • (13) A base other than an A at position 2 of the sense strand.
    • (14) An A base at position 4 of the sense strand.
    • (15) An A base at position 5 of the sense strand.
    • (16) An A base at position 6 of the sense strand.
    • (17) An A base at position 7 of the sense strand.
    • (18) An A base at position 8 of the sense strand.
    • (19) A base other than an A at position 9 of the sense strand.
    • (20) A base other than an A at position 10 of the sense strand.
    • (21) A base other than an A at position 11 of the sense strand.
    • (22) A base other than an A at position 12 of the sense strand.
    • (23) An A base at position 13 of the sense strand.
    • (24) A base other than an A at position 14 of the sense strand.
    • (25) An A base at position 15 of the sense strand
    • (26) An A base at position 16 of the sense strand.
    • (27) An A base at position 17 of the sense strand.
    • (28) An A base at position 18 of the sense strand.
    • (29) A base other than a U at position 1 of the sense strand.
    • (30) A base other than a U at position 2 of the sense strand.
    • (31) A U base at position 3 of the sense strand.
    • (32) A base other than a U at position 4 of the sense strand.
    • (33) A base other than a U at position 5 of the sense strand.
    • (34) A U base at position 6 of the sense strand.
    • (35) A base other than a U at position 7 of the sense strand.
    • (36) A base other than a U at position 8 of the sense strand.
    • (37) A base other than a U at position 9 of the sense strand.
    • (38) A base other than a U at position 11 of the sense strand.
    • (39) A U base at position 13 of the sense strand.
    • (40) A base other than a U at position 14 of the sense strand.
    • (41) A base other than a U at position 15 of the sense strand.
    • (42) A base other than a U at position 16 of the sense strand.
    • (43) A U base at position 17 of the sense strand.
    • (44) A U base at position 18 of the sense strand.
    • (45) A U base at position 19 of the sense strand.
    • (46) A C base at position 1 of the sense strand.
    • (47) A C base at position 2 of the sense strand.
    • (48) A base other than a C at position 3 of the sense strand.
    • (49) A C base at position 4 of the sense strand.
    • (50) A base other than a C at position 5 of the sense strand.
    • (51) A base other than a C at position 6 of the sense strand.
    • (52) A base other than a C at position 7 of the sense strand.
    • (53) A base other than a C at position 8 of the sense strand.
    • (54) A C base at position 9 of the sense strand.
    • (55) A C base at position 10 of the sense strand.
    • (56) A C base at position 11 of the sense strand.
    • (57) A base other than a C at position 12 of the sense strand.
    • (58) A base other than a C at position 13 of the sense strand.
    • (59) A base other than a C at position 14 of the sense strand.
    • (60) A base other than a C at position 15 of the sense strand.
    • (61) A base other than a C at position 16 of the sense strand.
    • (62) A base other than a C at position 17 of the sense strand.
    • (63) A base other than a C at position 18 of the sense strand.
    • (64) A G base at position 1 of the sense strand.
    • (65) A G base at position 2 of the sense strand.
    • (66) A G base at position 3 of the sense strand.
    • (67) A base other than a G at position 4 of the sense strand.
    • (68) A base other than a G at position 5 of the sense strand.
    • (69) A G base at position 6 of the sense strand.
    • (70) A G base at position 7 of the sense strand.
    • (71) A G base at position 8 of the sense strand.
    • (72) A G base at position 9 of the sense strand.
    • (73) A base other than a G at position 10 of the sense strand.
    • (74) A G base at position 11 of the sense strand.
    • (75) A G base at position 12 of the sense strand.
    • (76) A G base at position 14 of the sense strand.
    • (77) A G base at position 15 of the sense strand.
    • (78) A G base at position 16 of the sense strand.
    • (79) A base other than a G at position 17 of the sense strand.
    • (80) A base other than a G at position 18 of the sense strand.
    • (81) A base other than a G at position 19 of the sense strand.
  • The importance of various criteria can vary greatly. For instance, a C base at position 10 of the sense strand makes a minor contribution to duplex functionality. In contrast, the absence of a C at position 3 of the sense strand is very important. Accordingly, preferably an siRNA will satisfy as many of the aforementioned criteria as possible.
  • With respect to the criteria, GC content, as well as a high number of AU in positions 15-19 of the sense strand, may be important for easement of the unwinding of double stranded siRNA duplex. Duplex unwinding has been shown to be crucial for siRNA functionality in vivo.
  • With respect to criterion 9, the internal structure is measured in terms of the melting temperature of the single strand of siRNA, which is the temperature at which 50% of the molecules will become denatured. With respect to criteria 2-8 and 10-11, the positions refer to sequence positions on the sense strand, which is the strand that is identical to the mRNA.
  • In one preferred embodiment, at least criteria 1 and 8 are satisfied. In another preferred embodiment, at least criteria 7 and 8 are satisfied. In still another preferred embodiment, at least criteria 1, 8 and 9 are satisfied.
  • It should be noted that all of the aforementioned criteria regarding sequence position specifics are with respect to the 5′ end of the sense strand. Reference is made to the sense strand, because most databases contain information that describes the information of the mRNA. Because according to the present invention a chain can be from 18 to 30 bases in length, and the aforementioned criteria assumes a chain 19 base pairs in length, it is important to keep the aforementioned criteria applicable to the correct bases.
  • When there are only 18 bases, the base pair that is not present is the base pair that is located at the 3′ of the sense strand. When there are twenty to thirty bases present, then additional bases are added at the 5′ end of the sense chain and occupy positions 1 to 11. Accordingly, with respect to SEQ. ID NO. 0001 NNANANNNNUCNAANNNNA and SEQ. ID NO. 0028 GUCNNANANNNNUCNAANNNNA, both would have A at position 3, A at position 5, U at position 10, C at position 11, A and position 13, A and position 14 and A at position 19. However, SEQ. ID NO. 0028 would also have C at position −1, U at position −2 and G at position −3.
  • For a 19 base pair siRNA, an optimal sequence of one of the strands may be represented below, where N is any base, A, C, G, or U:

Claims (9)

1. An siRNA comprising a sense region and an antisense region, wherein said sense region and said antisense region together form a duplex region, said antisense region and said sense region are each 18-30 nucleotides in length and said antisense region comprises a sequence that is at least 90% complementary to a sequence selected from the group consisting of SEQ. ID NOs. 438-498.
2. An siRNA comprising a sense region and an antisense region, wherein said sense region and said antisense region together form a duplex region and said sense region and said antisense region are each 18-30 nucleotides in length, and said antisense region comprises a sequence that is 100% complementary to a contiguous stretch of at least 18 bases of a sequence selected from the group consisting of SEQ. ID NOs. 438-498.
3. The siRNA of claim 2, wherein each of said antisense region and said sense region are 19-30 nucleotides in length, and said antisense region comprises a sequence that is 100% complementary to said sequence selected from the group consisting of: SEQ. ID NOs. 438-498.
4. A pool of at least two siRNAs, wherein said pool comprises a first siRNA and a second siRNA, said first siRNA comprises a first antisense region and a first sense region that together form a first duplex region and each of said first antisense region and said first sense region are 18-30 nucleotides in length and said first antisense region is at least 90% complementary to 18 bases of a first sequence selected from the group consisting of: SEQ. ID NOs. 438-498 and said second siRNA comprises a second antisense region and a second sense region that together form a second duplex region and each of said second antisense region and said second sense region are 18-30 nucleotides in length and said second antisense region is at least 90% complementary to 18 bases of a second sequence selected from the group consisting of: SEQ. ID NOs. 438-498, wherein said first antisense region and said second antisense region are not identical.
5. The pool of claim 4, wherein said first antisense region comprises a sequence that is 100% complementary to at least 18 bases of said first sequence, and said second antisense region comprises a sequence that is 100% complementary to at least 18 bases of said second sequence.
6. The pool of claim 4, wherein said first siRNA is 19-30 nucleotides in length and said first antisense region comprises a sequence that is at least 90% complementary to said first sequence, and second siRNA is 19-30 nucleotides in length and said second antisense region comprises a sequence that is at least 90% complementary to said second sequence.
7. The pool of claim 4, wherein said first antisense region is 19-30 nucleotides in length and said first antisense region comprises a sequence that is 100% complementary to at least 18 bases of said first sequence, and said second antisense region is 19-30 nucleotides in length and said second antisense region comprises a sequence that is 100% complementary to said second sequence.
8. The siRNA of claim 1, wherein said antisense region and said sense region are each 19-25 nucleotides in length.
9. The siRNA of claim 4, wherein said first antisense region, said first sense region, said second sense region and said second antisense region are each 19-25 nucleotides in length.
US11/811,925 2002-11-14 2007-06-12 siRNA targeting pituitary tumor-transforming 1 (PTTG1) Abandoned US20070260051A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US42613702P true 2002-11-14 2002-11-14
US50205003P true 2003-09-10 2003-09-10
US10/714,333 US8090542B2 (en) 2002-11-14 2003-11-14 Functional and hyperfunctional siRNA
PCT/US2004/014885 WO2006006948A2 (en) 2002-11-14 2004-05-12 METHODS AND COMPOSITIONS FOR SELECTING siRNA OF IMPROVED FUNCTIONALITY
US10/940,892 US20120052487A9 (en) 2002-11-14 2004-09-14 Methods and compositions for selecting sirna of improved functionality
US11/811,925 US20070260051A1 (en) 2002-11-14 2007-06-12 siRNA targeting pituitary tumor-transforming 1 (PTTG1)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US11/811,925 US20070260051A1 (en) 2002-11-14 2007-06-12 siRNA targeting pituitary tumor-transforming 1 (PTTG1)

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US10/714,333 Continuation-In-Part US8090542B2 (en) 2002-11-14 2003-11-14 Functional and hyperfunctional siRNA
US10/940,892 Continuation-In-Part US20120052487A9 (en) 2002-11-14 2004-09-14 Methods and compositions for selecting sirna of improved functionality

Publications (1)

Publication Number Publication Date
US20070260051A1 true US20070260051A1 (en) 2007-11-08

Family

ID=38119221

Family Applications (118)

Application Number Title Priority Date Filing Date
US11/593,100 Active 2025-02-11 US7615541B2 (en) 2002-11-14 2006-11-03 siRNA targeting TIE-2
US11/594,530 Active 2024-06-11 US7608706B2 (en) 2002-11-14 2006-11-08 siRNA targeting ras-related nuclear protein
US11/594,666 Abandoned US20070128641A1 (en) 2002-11-14 2006-11-08 siRNA targeting hypoxia-inducible factor 1
US11/598,179 Active 2024-08-19 US7541453B2 (en) 2002-11-14 2006-11-09 siRNA targeting aquaporin 4
US11/595,698 Active 2024-08-01 US7598369B2 (en) 2002-11-14 2006-11-09 siRNA targeting histamine receptor H1
US11/729,388 Abandoned US20070185317A1 (en) 2002-11-14 2007-03-28 siRNA targeting HtrA serine peptidase 1
US11/729,924 Abandoned US20080015114A1 (en) 2002-11-14 2007-03-29 siRNA targeting connective tissue growth factor (CTGF)
US11/731,843 Active US7569684B2 (en) 2002-11-14 2007-03-30 siRNA targeting gremlin
US11/731,890 Abandoned US20080045703A1 (en) 2002-11-14 2007-03-30 siRNA targeting platelet-derived growth factor receptor beta polypeptide (PDGFR)
US11/731,875 Abandoned US20070299253A1 (en) 2002-11-14 2007-03-30 siRNA targeting vacuolar ATPase
US11/731,894 Active 2024-03-22 US7521191B2 (en) 2002-11-14 2007-03-30 siRNA targeting connexin 43
US11/732,457 Active US7638621B2 (en) 2002-11-14 2007-04-03 siRNA targeting insulin-like growth factor 1 receptor (IGF-1R)
US11/732,413 Abandoned US20070238868A1 (en) 2002-11-14 2007-04-03 siRNA targeting chemokine (C-X-C motif) receptor 4 (CXCR4)
US11/732,809 Abandoned US20070255046A1 (en) 2002-11-14 2007-04-04 siRNA targeting spectrin SH3 domain binding protein 1 (SSH3BP1)
US11/732,810 Abandoned US20070219362A1 (en) 2002-11-14 2007-04-04 siRNA targeting azurocidin 1 (Cartionic Antimicrobial protein 37)
US11/784,559 Abandoned US20070213520A1 (en) 2002-11-14 2007-04-06 siRNA targeting calcium/calmodulin dependent protein kinase IV (CAMK4)
US11/784,536 Abandoned US20070179286A1 (en) 2002-11-14 2007-04-06 siRNA targeting testis-specific serine kinase 4
US11/784,752 Abandoned US20070213521A1 (en) 2002-11-14 2007-04-09 siRNA targeting cell division cycle 25 (CDC25C)
US11/784,756 Abandoned US20070232797A1 (en) 2002-11-14 2007-04-09 siRNA targeting cell division cycle 2-like 5(CDC2L5)
US11/784,755 Active 2024-03-21 US7550572B2 (en) 2002-11-14 2007-04-09 siRNA targeting cell division cycle 20 homolog (CDC20)
US11/807,577 Abandoned US20070260048A1 (en) 2002-11-14 2007-05-29 siRNA targeting centromere protein E, 312kDa (CENPE)
US11/807,486 Active 2024-07-25 US7745610B2 (en) 2002-11-14 2007-05-29 siRNA targeting cyclin dependent kinase 11 (CDK11)
US11/807,530 Abandoned US20070255047A1 (en) 2002-11-14 2007-05-29 siRNA targeting cell division cycle 6 homolog (CDC6)
US11/809,909 Abandoned US20070255048A1 (en) 2002-11-14 2007-06-01 siRNA targeting discoidin domain receptor family, member 1 (DDR1)
US11/810,074 Abandoned US20070276135A1 (en) 2002-11-14 2007-06-04 siRNA targeting dual specificity phosphate 5 (DUSP5)
US11/810,384 Abandoned US20070260049A1 (en) 2002-11-14 2007-06-05 siRNA targeting MAD2 mitotic arrest deficient-like (MAD2L2)
US11/810,382 Abandoned US20070260047A1 (en) 2002-11-14 2007-06-05 siRNA targeting EPH receptor A4 (EPHA4)
US11/810,383 Active US7595388B2 (en) 2002-11-14 2007-06-05 siRNA targeting EPH receptor A3 (EPHA3)
US11/810,672 Abandoned US20070255050A1 (en) 2002-11-14 2007-06-06 siRNA targeting minichromosome maintenance deficient 2, mitotin (MCM2)
US11/810,673 Abandoned US20070293664A1 (en) 2002-11-14 2007-06-06 siRNA targeting minichromosome maintenance deficient 5 (MCM5)
US11/811,005 Abandoned US20070265437A1 (en) 2002-11-14 2007-06-07 siRNA targeting testes development-related NYD-SP21 (NYD-SP21)
US11/811,012 Abandoned US20070260050A1 (en) 2002-11-14 2007-06-07 siRNA targeting minichromosome maintenance deficient 7 (MCM7)
US11/811,003 Abandoned US20070287833A1 (en) 2002-11-14 2007-06-07 siRNA targeting minichromosome maintenance deficient 6 (MCM6)
US11/811,209 Abandoned US20080085997A1 (en) 2002-11-14 2007-06-08 siRNA targeting phosphoinositide-3-kinase, class 2, beta polypeptide (PIK3C2B)
US11/811,423 Active US7645870B2 (en) 2002-11-14 2007-06-08 siRNA targeting proteasome 26S subunit, non-ATPase, 10 (Gankyrin or PSMD10)
US11/811,424 Abandoned US20070244312A1 (en) 2002-11-14 2007-06-08 siRNA targeting phosphoinositide-3-kinase, class 2, alpha polypeptide (PIK3C2A)
US11/811,925 Abandoned US20070260051A1 (en) 2002-11-14 2007-06-12 siRNA targeting pituitary tumor-transforming 1 (PTTG1)
US11/811,954 Abandoned US20070249819A1 (en) 2002-11-14 2007-06-12 siRNA targeting WEE1 homolog (WEE1)
US11/811,929 Abandoned US20070255051A1 (en) 2002-11-14 2007-06-12 siRNA targeting serine/threonine kinase 22B (STK22B)
US11/811,950 Abandoned US20070260052A1 (en) 2002-11-14 2007-06-12 siRNA targeting RAD1 homolog (RAD1)
US11/818,547 Abandoned US20070255052A1 (en) 2002-11-14 2007-06-14 siRNA targeting v-myc myelocytomatosis viral oncogene homolog (MYC)
US11/818,938 Active US7678896B2 (en) 2002-11-14 2007-06-15 siRNA targeting serine/threonine kinase 12 (STK12 or aurora B kinase)
US11/818,936 Active 2024-01-05 US7598370B2 (en) 2002-11-14 2007-06-15 siRNA targeting polo-like kinase-1 (PLK-1)
US11/880,624 Abandoned US20080027215A1 (en) 2002-11-14 2007-07-23 siRNA targeting vascular endothelial growth factor (VEGF)
US11/880,965 Active US7579458B2 (en) 2002-11-14 2007-07-25 siRNA targeting synuclein, alpha (SNCA-1)
US11/881,767 Abandoned US20080039617A1 (en) 2002-11-14 2007-07-27 siRNA targeting neuropeptide Y (NPY)
US11/881,772 Abandoned US20080027216A1 (en) 2002-11-14 2007-07-27 siRNA targeting sodium channel, voltage-gated, type X, alpha (SCN10A)
US11/975,902 Abandoned US20080097091A1 (en) 2002-11-14 2007-10-22 siRNA targeting TNFalpha
US11/977,128 Abandoned US20080097092A1 (en) 2002-11-14 2007-10-23 siRNA targeting kinases
US11/977,347 Abandoned US20080076908A1 (en) 2002-11-14 2007-10-24 siRNA targeting nuclear receptors
US11/977,558 Abandoned US20080097089A1 (en) 2002-11-14 2007-10-25 siRNA targeting deubiqutination enzymes
US11/977,675 Abandoned US20080071073A1 (en) 2002-11-14 2007-10-25 siRNA targeting ubiquitin ligases
US11/978,070 Active 2024-01-18 US7582746B2 (en) 2002-11-14 2007-10-26 siRNA targeting complement component 3 (C3)
US11/978,125 Abandoned US20080086002A1 (en) 2002-11-14 2007-10-26 siRNA targeting secreted frizzled-related protein 1 (sFRP1)
US11/978,120 Abandoned US20080081904A1 (en) 2002-11-14 2007-10-26 siRNA targeting carbonic anhydrase 4(CA4)
US11/978,107 Active US7605252B2 (en) 2002-11-14 2007-10-26 siRNA targeting kinase insert domain receptor (KDR)
US11/978,106 Active US7655789B2 (en) 2002-11-14 2007-10-26 siRNA targeting transient receptor potential cation channel, subfamily V, member 1 (TRPV1)
US11/978,097 Active US7638622B2 (en) 2002-11-14 2007-10-26 SiRNA targeting intercellular adhesion molecule 1 (ICAM1)
US11/978,487 Abandoned US20080113374A1 (en) 2002-11-14 2007-10-29 siRNA targeting fructose-1,6-bisphosphatase 1 (FBP1)
US11/978,457 Abandoned US20080113371A1 (en) 2002-11-14 2007-10-29 siRNA targeting beta secretase (BACE)
US11/978,476 Active 2024-01-06 US7635771B2 (en) 2002-11-14 2007-10-29 siRNA targeting amyloid beta (A4) precursor protein (APP)
US11/978,475 Abandoned US20080113372A1 (en) 2002-11-14 2007-10-29 siRNA targeting glucagon receptor (GCGR)
US11/978,518 Active US7632938B2 (en) 2002-11-14 2007-10-29 siRNA targeting superoxide dismutase 1 (SOD1)
US11/978,398 Active 2024-01-11 US7709629B2 (en) 2002-11-14 2007-10-29 siRNA targeting diacylglycerol O-acyltransferase homolog 2 (DGAT2)
US11/978,455 Active 2024-05-18 US7795421B2 (en) 2002-11-14 2007-10-29 siRNA targeting apolipoprotein B (APOB)
US11/980,263 Active 2024-03-29 US7632939B2 (en) 2002-11-14 2007-10-30 siRNA targeting proto-oncogene MET
US11/980,102 Active US7662950B2 (en) 2002-11-14 2007-10-30 siRNA targeting myeloid differentiation primary response gene (88) (MYD88)
US11/980,300 Active 2024-01-15 US7592443B2 (en) 2002-11-14 2007-10-30 siRNA targeting interleukin-1 receptor-associated kinase 4 (IRAK4)
US12/321,749 Active US7666853B2 (en) 2002-11-14 2009-01-23 siRNA targeting connective tissue growth factor (CTGF)
US12/322,387 Active US7589191B2 (en) 2002-11-14 2009-02-02 siRNA targeting hypoxia-inducible factor 1
US12/455,098 Active US7741470B2 (en) 2002-11-14 2009-05-28 siRNA targeting gremlin
US12/460,876 Abandoned US20100004141A1 (en) 2002-11-14 2009-07-24 siRNA targeting polo-like Kinase-1 (PLK-1)
US12/462,029 Active US7745612B2 (en) 2002-11-14 2009-07-28 siRNA targeting interleukin-1 receptor-associated kinase 4 (IRAK4)
US12/462,420 Active US7737267B2 (en) 2002-11-14 2009-08-04 siRNA targeting hypoxia-inducible factor 1
US12/462,820 Active 2024-04-12 US8022198B2 (en) 2002-11-14 2009-08-10 siRNA targeting histamine receptor H1
US12/584,352 Active 2024-08-05 US8222395B2 (en) 2002-11-14 2009-09-03 siRNA targeting kinase insert domain receptor (KDR)
US12/584,850 Expired - Fee Related US7897754B2 (en) 2002-11-14 2009-09-11 SiRNA targeting ras-related nuclear protein RAN
US12/586,167 Expired - Fee Related US7855186B2 (en) 2002-11-14 2009-09-17 siRNA targeting TIE-2
US12/589,879 Active 2023-12-22 US8039610B2 (en) 2002-11-14 2009-10-29 siRNA targeting superoxide dismutase 1 (SOD1)
US12/590,097 Expired - Fee Related US7816512B2 (en) 2002-11-14 2009-11-02 siRNA targeting proto-oncogene MET
US12/590,252 Active US7829696B2 (en) 2002-11-14 2009-11-04 siRNA targeting amyloid beta (A4) precursor protein (APP)
US12/592,872 Active 2024-09-09 US8304528B2 (en) 2002-11-14 2009-12-03 SiRNA targeting fructose-1, 6-bisphosphatase 1 (FBP1)
US12/653,120 Active US8022199B2 (en) 2002-11-14 2009-12-08 SiRNA targeting myeloid differentiation primary response gene (88) (MYD88)
US12/653,402 Active US7807820B2 (en) 2002-11-14 2009-12-11 siRNA targeting beta secretase (BACE)
US12/655,107 Active US7833989B2 (en) 2002-11-14 2009-12-23 siRNA targeting connective tissue growth factor (CTGF)
US12/657,448 Active US8067576B2 (en) 2002-11-14 2010-01-21 siRNA targeting serine/threonine kinase 12 (STK12 or aurora B kinase)
US12/660,582 Active 2023-08-04 US8247169B2 (en) 2002-11-14 2010-03-01 SiRNA targeting diacylglycerol O-acyltransferase homolog 2 (DGAT2)
US12/798,603 Active US8030476B2 (en) 2002-11-14 2010-04-07 siRNA targeting gremlin
US12/798,802 Active US7935813B2 (en) 2002-11-14 2010-04-12 siRNA target hypoxia-inducible factor 1
US12/798,906 Active 2024-06-21 US8236942B2 (en) 2002-11-14 2010-04-13 SiRNA targeting glucagon receptor (GCGR)
US12/799,758 Active 2023-12-06 US8217162B2 (en) 2002-11-14 2010-04-30 siRNA targeting interleukin-1 receptor-associated kinase 4(IRAK4)
US12/799,975 Abandoned US20100267587A1 (en) 2002-11-14 2010-05-05 siRNA targeting cyclin dependent kinase 11 (CDK11)
US12/804,014 Active US8071754B2 (en) 2002-11-14 2010-07-12 siRNA targeting apolipoprotein B (APOB)
US12/806,570 Active US7999097B2 (en) 2002-11-14 2010-08-17 siRNA targeting beta secretase (BACE)
US12/807,526 Active 2024-01-12 US8222396B2 (en) 2002-11-14 2010-09-08 SiRNA targeting proto-oncogene MET
US12/924,078 Active US8268985B2 (en) 2002-11-14 2010-09-20 siRNA targeting amyloid beta (A4) precursor protein (APP)
US12/924,653 Active US8138329B2 (en) 2002-11-14 2010-10-01 siRNA targeting connective tissue growth factor (CTGF)
US12/927,144 Active 2024-01-06 US8314229B2 (en) 2002-11-14 2010-11-08 siRNA targeting tie-2
US13/135,336 Active US8293887B2 (en) 2002-11-14 2011-07-01 SiRNA targeting beta secretase (BACE)
US13/136,780 Active 2024-10-28 US8633306B2 (en) 2002-11-14 2011-08-10 SiRNA targeting histamine receptor H1
US13/136,812 Active US8426579B2 (en) 2002-11-14 2011-08-11 SiRNA targeting myeloid differentiation primary response gene (88) (MYD88)
US13/199,240 Abandoned US20110319297A1 (en) 2002-11-14 2011-08-23 siRNA targeting gremlin
US13/199,946 Abandoned US20120015850A1 (en) 2002-11-14 2011-09-13 siRNA targeting Superoxide
US13/317,752 Active US8232386B2 (en) 2002-11-14 2011-10-27 SiRNA targeting apolipoprotein B (APOB)
US13/385,320 Active US8461326B2 (en) 2002-11-14 2012-02-14 SiRNA targeting connective tissue growth factor (CTGF)
US13/489,725 Abandoned US20120252873A1 (en) 2002-11-14 2012-06-06 siRNA Targeting Interleukin-1 Receptor-associated Kinase 4 (IRAK4)
US13/494,360 Abandoned US20120258888A1 (en) 2002-11-14 2012-06-12 siRNA Targeting Proto-oncogene MET
US13/524,015 Active US8575329B2 (en) 2002-11-14 2012-06-15 siRNA targeting kinase insert domain receptor (KDR)
US13/536,005 Active US8445668B2 (en) 2002-11-14 2012-06-28 SiRNA targeting apolipoprotein (APOB)
US13/539,630 Abandoned US20120270751A1 (en) 2002-11-14 2012-07-02 siRNA Targeting Diacylglycerol O-Acyltransferase Homolog 2 (DGAT2)
US13/542,332 Abandoned US20120283311A1 (en) 2002-11-14 2012-07-05 siRNA Targeting Glucagon Receptor (GCCR)
US13/551,794 Active US8658784B2 (en) 2002-11-14 2012-07-18 siRNA targeting amyloid beta (A4) precursor protein (APP)
US13/613,910 Abandoned US20130023446A1 (en) 2002-11-14 2012-09-13 siRNA Targeting Beta Secretase (BACE)
US13/632,519 Abandoned US20130059760A1 (en) 2002-11-14 2012-10-01 siRNA Targeting Fructose-1, 6-bisphosphatase 1 (FBP1)
US13/647,869 Active US8658785B1 (en) 2002-11-14 2012-10-09 siRNA targeting tie-2
US13/847,544 Active US8883998B2 (en) 2002-11-14 2013-03-20 siRNA targeting myeloid differentiation primary response gene (88) (MYD88)
US13/867,175 Abandoned US20130225447A1 (en) 2002-11-14 2013-04-22 siRNA Targeting Apolipoprotein B (APOB)
US14/099,339 Expired - Fee Related US8907077B2 (en) 2002-11-14 2013-12-06 siRNA targeting TIE-2

Family Applications Before (36)

Application Number Title Priority Date Filing Date
US11/593,100 Active 2025-02-11 US7615541B2 (en) 2002-11-14 2006-11-03 siRNA targeting TIE-2
US11/594,530 Active 2024-06-11 US7608706B2 (en) 2002-11-14 2006-11-08 siRNA targeting ras-related nuclear protein
US11/594,666 Abandoned US20070128641A1 (en) 2002-11-14 2006-11-08 siRNA targeting hypoxia-inducible factor 1
US11/598,179 Active 2024-08-19 US7541453B2 (en) 2002-11-14 2006-11-09 siRNA targeting aquaporin 4
US11/595,698 Active 2024-08-01 US7598369B2 (en) 2002-11-14 2006-11-09 siRNA targeting histamine receptor H1
US11/729,388 Abandoned US20070185317A1 (en) 2002-11-14 2007-03-28 siRNA targeting HtrA serine peptidase 1
US11/729,924 Abandoned US20080015114A1 (en) 2002-11-14 2007-03-29 siRNA targeting connective tissue growth factor (CTGF)
US11/731,843 Active US7569684B2 (en) 2002-11-14 2007-03-30 siRNA targeting gremlin
US11/731,890 Abandoned US20080045703A1 (en) 2002-11-14 2007-03-30 siRNA targeting platelet-derived growth factor receptor beta polypeptide (PDGFR)
US11/731,875 Abandoned US20070299253A1 (en) 2002-11-14 2007-03-30 siRNA targeting vacuolar ATPase
US11/731,894 Active 2024-03-22 US7521191B2 (en) 2002-11-14 2007-03-30 siRNA targeting connexin 43
US11/732,457 Active US7638621B2 (en) 2002-11-14 2007-04-03 siRNA targeting insulin-like growth factor 1 receptor (IGF-1R)
US11/732,413 Abandoned US20070238868A1 (en) 2002-11-14 2007-04-03 siRNA targeting chemokine (C-X-C motif) receptor 4 (CXCR4)
US11/732,809 Abandoned US20070255046A1 (en) 2002-11-14 2007-04-04 siRNA targeting spectrin SH3 domain binding protein 1 (SSH3BP1)
US11/732,810 Abandoned US20070219362A1 (en) 2002-11-14 2007-04-04 siRNA targeting azurocidin 1 (Cartionic Antimicrobial protein 37)
US11/784,559 Abandoned US20070213520A1 (en) 2002-11-14 2007-04-06 siRNA targeting calcium/calmodulin dependent protein kinase IV (CAMK4)
US11/784,536 Abandoned US20070179286A1 (en) 2002-11-14 2007-04-06 siRNA targeting testis-specific serine kinase 4
US11/784,752 Abandoned US20070213521A1 (en) 2002-11-14 2007-04-09 siRNA targeting cell division cycle 25 (CDC25C)
US11/784,756 Abandoned US20070232797A1 (en) 2002-11-14 2007-04-09 siRNA targeting cell division cycle 2-like 5(CDC2L5)
US11/784,755 Active 2024-03-21 US7550572B2 (en) 2002-11-14 2007-04-09 siRNA targeting cell division cycle 20 homolog (CDC20)
US11/807,577 Abandoned US20070260048A1 (en) 2002-11-14 2007-05-29 siRNA targeting centromere protein E, 312kDa (CENPE)
US11/807,486 Active 2024-07-25 US7745610B2 (en) 2002-11-14 2007-05-29 siRNA targeting cyclin dependent kinase 11 (CDK11)
US11/807,530 Abandoned US20070255047A1 (en) 2002-11-14 2007-05-29 siRNA targeting cell division cycle 6 homolog (CDC6)
US11/809,909 Abandoned US20070255048A1 (en) 2002-11-14 2007-06-01 siRNA targeting discoidin domain receptor family, member 1 (DDR1)
US11/810,074 Abandoned US20070276135A1 (en) 2002-11-14 2007-06-04 siRNA targeting dual specificity phosphate 5 (DUSP5)
US11/810,384 Abandoned US20070260049A1 (en) 2002-11-14 2007-06-05 siRNA targeting MAD2 mitotic arrest deficient-like (MAD2L2)
US11/810,382 Abandoned US20070260047A1 (en) 2002-11-14 2007-06-05 siRNA targeting EPH receptor A4 (EPHA4)
US11/810,383 Active US7595388B2 (en) 2002-11-14 2007-06-05 siRNA targeting EPH receptor A3 (EPHA3)
US11/810,672 Abandoned US20070255050A1 (en) 2002-11-14 2007-06-06 siRNA targeting minichromosome maintenance deficient 2, mitotin (MCM2)
US11/810,673 Abandoned US20070293664A1 (en) 2002-11-14 2007-06-06 siRNA targeting minichromosome maintenance deficient 5 (MCM5)
US11/811,005 Abandoned US20070265437A1 (en) 2002-11-14 2007-06-07 siRNA targeting testes development-related NYD-SP21 (NYD-SP21)
US11/811,012 Abandoned US20070260050A1 (en) 2002-11-14 2007-06-07 siRNA targeting minichromosome maintenance deficient 7 (MCM7)
US11/811,003 Abandoned US20070287833A1 (en) 2002-11-14 2007-06-07 siRNA targeting minichromosome maintenance deficient 6 (MCM6)
US11/811,209 Abandoned US20080085997A1 (en) 2002-11-14 2007-06-08 siRNA targeting phosphoinositide-3-kinase, class 2, beta polypeptide (PIK3C2B)
US11/811,423 Active US7645870B2 (en) 2002-11-14 2007-06-08 siRNA targeting proteasome 26S subunit, non-ATPase, 10 (Gankyrin or PSMD10)
US11/811,424 Abandoned US20070244312A1 (en) 2002-11-14 2007-06-08 siRNA targeting phosphoinositide-3-kinase, class 2, alpha polypeptide (PIK3C2A)

Family Applications After (81)

Application Number Title Priority Date Filing Date
US11/811,954 Abandoned US20070249819A1 (en) 2002-11-14 2007-06-12 siRNA targeting WEE1 homolog (WEE1)
US11/811,929 Abandoned US20070255051A1 (en) 2002-11-14 2007-06-12 siRNA targeting serine/threonine kinase 22B (STK22B)
US11/811,950 Abandoned US20070260052A1 (en) 2002-11-14 2007-06-12 siRNA targeting RAD1 homolog (RAD1)
US11/818,547 Abandoned US20070255052A1 (en) 2002-11-14 2007-06-14 siRNA targeting v-myc myelocytomatosis viral oncogene homolog (MYC)
US11/818,938 Active US7678896B2 (en) 2002-11-14 2007-06-15 siRNA targeting serine/threonine kinase 12 (STK12 or aurora B kinase)
US11/818,936 Active 2024-01-05 US7598370B2 (en) 2002-11-14 2007-06-15 siRNA targeting polo-like kinase-1 (PLK-1)
US11/880,624 Abandoned US20080027215A1 (en) 2002-11-14 2007-07-23 siRNA targeting vascular endothelial growth factor (VEGF)
US11/880,965 Active US7579458B2 (en) 2002-11-14 2007-07-25 siRNA targeting synuclein, alpha (SNCA-1)
US11/881,767 Abandoned US20080039617A1 (en) 2002-11-14 2007-07-27 siRNA targeting neuropeptide Y (NPY)
US11/881,772 Abandoned US20080027216A1 (en) 2002-11-14 2007-07-27 siRNA targeting sodium channel, voltage-gated, type X, alpha (SCN10A)
US11/975,902 Abandoned US20080097091A1 (en) 2002-11-14 2007-10-22 siRNA targeting TNFalpha
US11/977,128 Abandoned US20080097092A1 (en) 2002-11-14 2007-10-23 siRNA targeting kinases
US11/977,347 Abandoned US20080076908A1 (en) 2002-11-14 2007-10-24 siRNA targeting nuclear receptors
US11/977,558 Abandoned US20080097089A1 (en) 2002-11-14 2007-10-25 siRNA targeting deubiqutination enzymes
US11/977,675 Abandoned US20080071073A1 (en) 2002-11-14 2007-10-25 siRNA targeting ubiquitin ligases
US11/978,070 Active 2024-01-18 US7582746B2 (en) 2002-11-14 2007-10-26 siRNA targeting complement component 3 (C3)
US11/978,125 Abandoned US20080086002A1 (en) 2002-11-14 2007-10-26 siRNA targeting secreted frizzled-related protein 1 (sFRP1)
US11/978,120 Abandoned US20080081904A1 (en) 2002-11-14 2007-10-26 siRNA targeting carbonic anhydrase 4(CA4)
US11/978,107 Active US7605252B2 (en) 2002-11-14 2007-10-26 siRNA targeting kinase insert domain receptor (KDR)
US11/978,106 Active US7655789B2 (en) 2002-11-14 2007-10-26 siRNA targeting transient receptor potential cation channel, subfamily V, member 1 (TRPV1)
US11/978,097 Active US7638622B2 (en) 2002-11-14 2007-10-26 SiRNA targeting intercellular adhesion molecule 1 (ICAM1)
US11/978,487 Abandoned US20080113374A1 (en) 2002-11-14 2007-10-29 siRNA targeting fructose-1,6-bisphosphatase 1 (FBP1)
US11/978,457 Abandoned US20080113371A1 (en) 2002-11-14 2007-10-29 siRNA targeting beta secretase (BACE)
US11/978,476 Active 2024-01-06 US7635771B2 (en) 2002-11-14 2007-10-29 siRNA targeting amyloid beta (A4) precursor protein (APP)
US11/978,475 Abandoned US20080113372A1 (en) 2002-11-14 2007-10-29 siRNA targeting glucagon receptor (GCGR)
US11/978,518 Active US7632938B2 (en) 2002-11-14 2007-10-29 siRNA targeting superoxide dismutase 1 (SOD1)
US11/978,398 Active 2024-01-11 US7709629B2 (en) 2002-11-14 2007-10-29 siRNA targeting diacylglycerol O-acyltransferase homolog 2 (DGAT2)
US11/978,455 Active 2024-05-18 US7795421B2 (en) 2002-11-14 2007-10-29 siRNA targeting apolipoprotein B (APOB)
US11/980,263 Active 2024-03-29 US7632939B2 (en) 2002-11-14 2007-10-30 siRNA targeting proto-oncogene MET
US11/980,102 Active US7662950B2 (en) 2002-11-14 2007-10-30 siRNA targeting myeloid differentiation primary response gene (88) (MYD88)
US11/980,300 Active 2024-01-15 US7592443B2 (en) 2002-11-14 2007-10-30 siRNA targeting interleukin-1 receptor-associated kinase 4 (IRAK4)
US12/321,749 Active US7666853B2 (en) 2002-11-14 2009-01-23 siRNA targeting connective tissue growth factor (CTGF)
US12/322,387 Active US7589191B2 (en) 2002-11-14 2009-02-02 siRNA targeting hypoxia-inducible factor 1
US12/455,098 Active US7741470B2 (en) 2002-11-14 2009-05-28 siRNA targeting gremlin
US12/460,876 Abandoned US20100004141A1 (en) 2002-11-14 2009-07-24 siRNA targeting polo-like Kinase-1 (PLK-1)
US12/462,029 Active US7745612B2 (en) 2002-11-14 2009-07-28 siRNA targeting interleukin-1 receptor-associated kinase 4 (IRAK4)
US12/462,420 Active US7737267B2 (en) 2002-11-14 2009-08-04 siRNA targeting hypoxia-inducible factor 1
US12/462,820 Active 2024-04-12 US8022198B2 (en) 2002-11-14 2009-08-10 siRNA targeting histamine receptor H1
US12/584,352 Active 2024-08-05 US8222395B2 (en) 2002-11-14 2009-09-03 siRNA targeting kinase insert domain receptor (KDR)
US12/584,850 Expired - Fee Related US7897754B2 (en) 2002-11-14 2009-09-11 SiRNA targeting ras-related nuclear protein RAN
US12/586,167 Expired - Fee Related US7855186B2 (en) 2002-11-14 2009-09-17 siRNA targeting TIE-2
US12/589,879 Active 2023-12-22 US8039610B2 (en) 2002-11-14 2009-10-29 siRNA targeting superoxide dismutase 1 (SOD1)
US12/590,097 Expired - Fee Related US7816512B2 (en) 2002-11-14 2009-11-02 siRNA targeting proto-oncogene MET
US12/590,252 Active US7829696B2 (en) 2002-11-14 2009-11-04 siRNA targeting amyloid beta (A4) precursor protein (APP)
US12/592,872 Active 2024-09-09 US8304528B2 (en) 2002-11-14 2009-12-03 SiRNA targeting fructose-1, 6-bisphosphatase 1 (FBP1)
US12/653,120 Active US8022199B2 (en) 2002-11-14 2009-12-08 SiRNA targeting myeloid differentiation primary response gene (88) (MYD88)
US12/653,402 Active US7807820B2 (en) 2002-11-14 2009-12-11 siRNA targeting beta secretase (BACE)
US12/655,107 Active US7833989B2 (en) 2002-11-14 2009-12-23 siRNA targeting connective tissue growth factor (CTGF)
US12/657,448 Active US8067576B2 (en) 2002-11-14 2010-01-21 siRNA targeting serine/threonine kinase 12 (STK12 or aurora B kinase)
US12/660,582 Active 2023-08-04 US8247169B2 (en) 2002-11-14 2010-03-01 SiRNA targeting diacylglycerol O-acyltransferase homolog 2 (DGAT2)
US12/798,603 Active US8030476B2 (en) 2002-11-14 2010-04-07 siRNA targeting gremlin
US12/798,802 Active US7935813B2 (en) 2002-11-14 2010-04-12 siRNA target hypoxia-inducible factor 1
US12/798,906 Active 2024-06-21 US8236942B2 (en) 2002-11-14 2010-04-13 SiRNA targeting glucagon receptor (GCGR)
US12/799,758 Active 2023-12-06 US8217162B2 (en) 2002-11-14 2010-04-30 siRNA targeting interleukin-1 receptor-associated kinase 4(IRAK4)
US12/799,975 Abandoned US20100267587A1 (en) 2002-11-14 2010-05-05 siRNA targeting cyclin dependent kinase 11 (CDK11)
US12/804,014 Active US8071754B2 (en) 2002-11-14 2010-07-12 siRNA targeting apolipoprotein B (APOB)
US12/806,570 Active US7999097B2 (en) 2002-11-14 2010-08-17 siRNA targeting beta secretase (BACE)
US12/807,526 Active 2024-01-12 US8222396B2 (en) 2002-11-14 2010-09-08 SiRNA targeting proto-oncogene MET
US12/924,078 Active US8268985B2 (en) 2002-11-14 2010-09-20 siRNA targeting amyloid beta (A4) precursor protein (APP)
US12/924,653 Active US8138329B2 (en) 2002-11-14 2010-10-01 siRNA targeting connective tissue growth factor (CTGF)
US12/927,144 Active 2024-01-06 US8314229B2 (en) 2002-11-14 2010-11-08 siRNA targeting tie-2
US13/135,336 Active US8293887B2 (en) 2002-11-14 2011-07-01 SiRNA targeting beta secretase (BACE)
US13/136,780 Active 2024-10-28 US8633306B2 (en) 2002-11-14 2011-08-10 SiRNA targeting histamine receptor H1
US13/136,812 Active US8426579B2 (en) 2002-11-14 2011-08-11 SiRNA targeting myeloid differentiation primary response gene (88) (MYD88)
US13/199,240 Abandoned US20110319297A1 (en) 2002-11-14 2011-08-23 siRNA targeting gremlin
US13/199,946 Abandoned US20120015850A1 (en) 2002-11-14 2011-09-13 siRNA targeting Superoxide
US13/317,752 Active US8232386B2 (en) 2002-11-14 2011-10-27 SiRNA targeting apolipoprotein B (APOB)
US13/385,320 Active US8461326B2 (en) 2002-11-14 2012-02-14 SiRNA targeting connective tissue growth factor (CTGF)
US13/489,725 Abandoned US20120252873A1 (en) 2002-11-14 2012-06-06 siRNA Targeting Interleukin-1 Receptor-associated Kinase 4 (IRAK4)
US13/494,360 Abandoned US20120258888A1 (en) 2002-11-14 2012-06-12 siRNA Targeting Proto-oncogene MET
US13/524,015 Active US8575329B2 (en) 2002-11-14 2012-06-15 siRNA targeting kinase insert domain receptor (KDR)
US13/536,005 Active US8445668B2 (en) 2002-11-14 2012-06-28 SiRNA targeting apolipoprotein (APOB)
US13/539,630 Abandoned US20120270751A1 (en) 2002-11-14 2012-07-02 siRNA Targeting Diacylglycerol O-Acyltransferase Homolog 2 (DGAT2)
US13/542,332 Abandoned US20120283311A1 (en) 2002-11-14 2012-07-05 siRNA Targeting Glucagon Receptor (GCCR)
US13/551,794 Active US8658784B2 (en) 2002-11-14 2012-07-18 siRNA targeting amyloid beta (A4) precursor protein (APP)
US13/613,910 Abandoned US20130023446A1 (en) 2002-11-14 2012-09-13 siRNA Targeting Beta Secretase (BACE)
US13/632,519 Abandoned US20130059760A1 (en) 2002-11-14 2012-10-01 siRNA Targeting Fructose-1, 6-bisphosphatase 1 (FBP1)
US13/647,869 Active US8658785B1 (en) 2002-11-14 2012-10-09 siRNA targeting tie-2
US13/847,544 Active US8883998B2 (en) 2002-11-14 2013-03-20 siRNA targeting myeloid differentiation primary response gene (88) (MYD88)
US13/867,175 Abandoned US20130225447A1 (en) 2002-11-14 2013-04-22 siRNA Targeting Apolipoprotein B (APOB)
US14/099,339 Expired - Fee Related US8907077B2 (en) 2002-11-14 2013-12-06 siRNA targeting TIE-2

Country Status (2)

Country Link
US (118) US7615541B2 (en)
WO (1) WO2006006948A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10125369B2 (en) 2012-12-05 2018-11-13 Alnylam Pharmaceuticals, Inc. PCSK9 iRNA compositions and methods of use thereof

Families Citing this family (160)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2950073A (en) * 1957-02-18 1960-08-23 Lockheed Aircraft Corp Hoist mechanism
US20060009409A1 (en) 2002-02-01 2006-01-12 Woolf Tod M Double-stranded oligonucleotides
CA2475003A1 (en) 2002-02-01 2003-08-07 Sequitur, Inc. Double-stranded oligonucleotides
EP1572902B1 (en) * 2002-02-01 2014-06-11 Life Technologies Corporation HIGH POTENCY siRNAS FOR REDUCING THE EXPRESSION OF TARGET GENES
EP1532271A4 (en) * 2002-06-12 2006-10-18 Ambion Inc Methods and compositions relating to polypeptides with rnase iii domains that mediate rna interference
US20040248094A1 (en) * 2002-06-12 2004-12-09 Ford Lance P. Methods and compositions relating to labeled RNA molecules that reduce gene expression
US20100075423A1 (en) * 2002-06-12 2010-03-25 Life Technologies Corporation Methods and compositions relating to polypeptides with rnase iii domains that mediate rna interference
US20090227780A1 (en) * 2002-11-14 2009-09-10 Dharmacon, Inc. siRNA targeting connexin 43
US9771586B2 (en) 2002-11-14 2017-09-26 Thermo Fisher Scientific Inc. RNAi targeting ZNF205
US9228186B2 (en) 2002-11-14 2016-01-05 Thermo Fisher Scientific Inc. Methods and compositions for selecting siRNA of improved functionality
US9879266B2 (en) 2002-11-14 2018-01-30 Thermo Fisher Scientific Inc. Methods and compositions for selecting siRNA of improved functionality
WO2006006948A2 (en) 2002-11-14 2006-01-19 Dharmacon, Inc. METHODS AND COMPOSITIONS FOR SELECTING siRNA OF IMPROVED FUNCTIONALITY
US10011836B2 (en) 2002-11-14 2018-07-03 Thermo Fisher Scientific Inc. Methods and compositions for selecting siRNA of improved functionality
EP2314691A3 (en) 2002-11-14 2012-01-18 Dharmacon, Inc. Fuctional and hyperfunctional siRNA
US7691998B2 (en) * 2002-11-14 2010-04-06 Dharmacon, Inc. siRNA targeting nucleoporin 62kDa (Nup62)
US20100113307A1 (en) * 2002-11-14 2010-05-06 Dharmacon, Inc. siRNA targeting vascular endothelial growth factor (VEGF)
US7781575B2 (en) 2002-11-14 2010-08-24 Dharmacon, Inc. siRNA targeting tumor protein 53 (p53)
US7951935B2 (en) 2002-11-14 2011-05-31 Dharmacon, Inc. siRNA targeting v-myc myelocytomatosis viral oncogene homolog (MYC)
US9839649B2 (en) 2002-11-14 2017-12-12 Thermo Fisher Scientific Inc. Methods and compositions for selecting siRNA of improved functionality
US9719092B2 (en) 2002-11-14 2017-08-01 Thermo Fisher Scientific Inc. RNAi targeting CNTD2
US8198427B1 (en) 2002-11-14 2012-06-12 Dharmacon, Inc. SiRNA targeting catenin, beta-1 (CTNNB1)
US7612196B2 (en) 2002-11-14 2009-11-03 Dharmacon, Inc. siRNA targeting cyclin-dependent kinase inhibitor 1B (p27, Kip1) (CDKN1B)
US9719094B2 (en) 2002-11-14 2017-08-01 Thermo Fisher Scientific Inc. RNAi targeting SEC61G
US7592442B2 (en) * 2002-11-14 2009-09-22 Dharmacon, Inc. siRNA targeting ribonucleotide reductase M2 polypeptide (RRM2 or RNR-R2)
US7618948B2 (en) 2002-11-26 2009-11-17 Medtronic, Inc. Devices, systems and methods for improving and/or cognitive function through brain delivery of siRNA
US7829694B2 (en) * 2002-11-26 2010-11-09 Medtronic, Inc. Treatment of neurodegenerative disease through intracranial delivery of siRNA
US7595306B2 (en) * 2003-06-09 2009-09-29 Alnylam Pharmaceuticals Inc Method of treating neurodegenerative disease
CA2542608A1 (en) * 2003-10-14 2005-04-21 University College Cork-National University Of Ireland, Cork Igf-i responsive gene and use thereof
US8088902B2 (en) 2004-04-05 2012-01-03 The Rockefeller University DNA virus microRNA and methods for inhibiting same
EP2292757A3 (en) * 2004-08-23 2011-11-16 Sylentis S.A.U. Treatment of eye disorders characterized by an elevated intraocular pressure by siRNAs
MX2007003795A (en) 2004-09-28 2007-07-11 Quark Biotech Inc Oligoribonucleotides and methods of use thereof for treatment of alopecia, acute renal failure and other diseases.
US20060142228A1 (en) 2004-12-23 2006-06-29 Ambion, Inc. Methods and compositions concerning siRNA's as mediators of RNA interference
DE102005003788A1 (en) * 2005-01-19 2006-07-20 Eberhard-Karls-Universität Tübingen Universitätsklinikum siRNA molecules for the treatment of blood vessels
EP2510939A1 (en) 2005-02-03 2012-10-17 Coda Therapeutics Limited Anti-connexin peptide mimetics and therapeutic uses thereof
JP4131271B2 (en) * 2005-03-30 2008-08-13 ソニー株式会社 An information processing apparatus and method, and program
BRPI0616091A2 (en) * 2005-09-20 2013-02-13 Simplot Co J R Product processed by heat and their methods of edible plant product produÇço and transgenic plant of the acrylamide reduÇço conteédo in plant gene product and sobreexpressço in potato tuber and isolated polynucleotide sequence plant
GB0521351D0 (en) * 2005-10-20 2005-11-30 Genomica Sau Modulation of TRPV expression levels
US8258109B2 (en) * 2005-10-20 2012-09-04 Isis Pharmaceuticals, Inc. Compositions and methods for modulation of LMNA expression
US20070135518A1 (en) * 2005-12-09 2007-06-14 Marta Weinstock-Rosin Use of low-dose ladostigil for neuroprotection
MX2008008302A (en) * 2005-12-22 2009-01-21 Exegenics Inc Compositions and methods for regulating complement system.
TW200808360A (en) 2006-04-13 2008-02-16 Alcon Mfg Ltd RNAi-mediated inhibition of spleen tyrosine kinase-related inflammatory conditions
US8017592B2 (en) 2006-04-13 2011-09-13 Alcon Research, Ltd. RNAi-mediated inhibition of histamine receptor H1-related conditions
WO2007147067A2 (en) 2006-06-14 2007-12-21 Rosetta Inpharmatics Llc Methods and compositions for regulating cell cycle progression
CA2659464A1 (en) * 2006-08-24 2008-02-28 Alcon Research, Ltd. Rnai-mediated inhibition of gremlin for treatment of iop-related conditions
WO2008067382A2 (en) * 2006-11-28 2008-06-05 Alcon Research, Ltd. Rnai-mediated inhibition of aquaporin 4 for treatment of iop-related conditions
DK2094863T3 (en) * 2006-12-18 2014-08-18 Panagene Inc Peptide nucleic acid oligomers comprising universal bases, manufacturing methods thereof, and kits, devices and methods for the analysis, detection or modulation of nucleic acids using these
JP2010519908A (en) * 2007-03-02 2010-06-10 エムディーアールエヌエー,インコーポレイテッド Nucleic acid compounds and their use for inhibiting the expression of Hif1a gene
JP5832721B2 (en) 2007-03-14 2015-12-16 バイオンシル・エス.アール.エル.Bionsil S.R.L. Modulator compound of drug resistance in epithelial tumor cells
US8112570B2 (en) * 2007-03-15 2012-02-07 Broadcom Corporation Pipelined buffer interconnect with trigger core controller
US8906632B2 (en) * 2007-03-23 2014-12-09 Korea University Research & Business Foundation Use of inhibitors of leukotriene B4 receptor BLT2 for treating asthma
ES2474176T3 (en) 2007-06-27 2014-07-08 Quark Pharmaceuticals, Inc. Compositions and methods for inhibiting gene expression pro-apoptticos
TW200911290A (en) * 2007-07-02 2009-03-16 Alcon Res Ltd RNAI-mediated inhibition of HTRA1 for treatment of macular degeneration
US7910722B2 (en) 2007-07-05 2011-03-22 Florida State University Research Foundation RNAi therapeutic for treatment of hepatitis C infection
EP2316943B1 (en) 2007-07-05 2013-06-19 Novartis AG DSRNA for treating viral infection
EP2170351A4 (en) * 2007-07-06 2011-07-06 Intradigm Corp Methods and compositions for treatment of cancer and other angiogenesis - related diseases
US20110160279A1 (en) * 2007-08-13 2011-06-30 Board Of Trustees Of Southern Illinois University METHODS FOR TREATMENT AND PREVENTION OF OTOTOXICITY BY siRNA
US20090176729A1 (en) * 2007-12-14 2009-07-09 Alnylam Pharmaceuticals, Inc. Method of treating neurodegenerative disease
EP2237796A2 (en) * 2007-12-21 2010-10-13 Coda Therapeutics, Inc. Use of anti-connexin peptides, alone or in combination with anti-connexin polynucleotides, for the treatment of surgical adhesions
AU2008343756A1 (en) * 2007-12-21 2009-07-09 Coda Therapeutics, Inc. Use of anti-connexin polypeptide agent in combination with anti-connexin polynucleotide agent for the treatment of fibrotic conditions
CA2710380A1 (en) * 2007-12-21 2009-07-09 Coda Therapeutics, Inc. Use of anti-connexin 43 poly nucleotide for the treatment of fibrotic conditions
AU2008343754A1 (en) * 2007-12-21 2009-07-09 Coda Therapeutics, Inc. Use of anti-connexin polynucleotides for the treatment of surgical adhesions
EP2077335A1 (en) * 2007-12-22 2009-07-08 Universitätsklinikum Schleswig-Holstein EXO1 promoter polymorphism associated with exceptional life expectancy in humans
EP2238251B1 (en) * 2007-12-27 2015-02-11 Protiva Biotherapeutics Inc. Silencing of polo-like kinase expression using interfering rna
EP2075333A1 (en) * 2007-12-28 2009-07-01 Qiagen GmbH Positive controls for expression modulating experiments
CA2711635A1 (en) * 2008-01-07 2009-08-06 Coda Therapeutics, Inc. Wound healing compositions and treatments
US9173896B2 (en) * 2008-02-15 2015-11-03 Arrowhead Research Corporation RNAi-mediated inhibition of connexin 43 for treatment of IOP-related conditions
WO2009113579A1 (en) * 2008-03-11 2009-09-17 学校法人埼玉医科大学 Double-stranded nucleic acid molecule suitable for prevention or treatment of cancer, cancer cell proliferation inhibitor, and pharmaceutical preparation
CA2721333A1 (en) 2008-04-15 2009-10-22 Protiva Biotherapeutics, Inc. Novel lipid formulations for nucleic acid delivery
JP5479453B2 (en) * 2008-04-17 2014-04-23 ザ・ジョンズ・ホプキンス・ユニバーシティ ON01910. Na enhances chemotherapeutic agents active in drug resistant tumors
US8217161B2 (en) * 2008-04-22 2012-07-10 Clemson University Research Foundation Methods of inhibiting multiple cytochrome P450 genes with siRNA
DE102008029669A1 (en) * 2008-05-16 2009-11-19 Schlaak, Jörg Friedrich, Prof. Dr. med. New therapeutics for hepatitis therapy
EP2307456B1 (en) 2008-06-27 2014-10-15 Amgen Inc. Ang-2 inhibition to treat multiple sclerosis
US20150247148A1 (en) * 2011-01-31 2015-09-03 Kyowa Hakko Kirin Co., Ltd. Composition for suppressing expression of target gene
EP2331141B1 (en) 2008-08-25 2016-01-06 Excaliard Pharmaceuticals, Inc. Antisense oligonucleotides directed against connective tissue growth factor and uses thereof
US8946172B2 (en) * 2008-08-25 2015-02-03 Excaliard Pharmaceuticals, Inc. Method for reducing scarring during wound healing using antisense compounds directed to CTGF
WO2010027279A2 (en) * 2008-09-04 2010-03-11 Genesis Research And Development Corporation Limited Compositions and methods for the treatment and prevention of neoplastic disorders
US8664189B2 (en) 2008-09-22 2014-03-04 Rxi Pharmaceuticals Corporation RNA interference in skin indications
EP2341924A4 (en) 2008-10-02 2013-01-23 David Gladstone Inst Methods of treating hepatitis c virus infection
US9095592B2 (en) * 2008-11-07 2015-08-04 The Research Foundation For The State University Of New York Bruton's tyrosine kinase as anti-cancer drug target
US20120016011A1 (en) * 2009-03-19 2012-01-19 Merck Sharp & Dohme Corp. RNA Interference Mediated Inhibition of Connective Tissue Growth Factor (CTGF) Gene Expression Using Short Interfering Nucleic Acid (siNA)
US20110045080A1 (en) * 2009-03-24 2011-02-24 William Marsh Rice University Single-Walled Carbon Nanotube/Bioactive Substance Complexes and Methods Related Thereto
EP2411517A2 (en) * 2009-03-27 2012-02-01 Merck Sharp&Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF THE INTERCELLULAR ADHESION MOLECULE 1 (ICAM-1)GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
WO2010113037A1 (en) * 2009-04-03 2010-10-07 Centre National De La Recherche Scientifique Gene transfer vectors comprising genetic insulator elements and methods to identify genetic insulator elements
WO2010144611A2 (en) * 2009-06-10 2010-12-16 3-V Biosciences, Inc. Antivirals that target transporters, carriers, and ion channels
CN101851625B (en) 2009-06-25 2012-07-18 上海交通大学 RNA interference sequences of glucagon receptor gene
CN101586103B (en) 2009-06-25 2010-12-08 上海交通大学 RNA interference sequence of glucagon receptor gene
CN101851624B (en) 2009-06-25 2012-04-18 上海交通大学 RNA interference sequences of glucagon receptor gene
EP2449114B9 (en) 2009-07-01 2017-04-19 Protiva Biotherapeutics Inc. Novel lipid formulations for delivery of therapeutic agents to solid tumors
CA2775092A1 (en) * 2009-09-23 2011-03-31 Protiva Biotherapeutics, Inc. Compositions and methods for silencing genes expressed in cancer
US9799416B2 (en) * 2009-11-06 2017-10-24 Terrapower, Llc Methods and systems for migrating fuel assemblies in a nuclear fission reactor
US20110152343A1 (en) * 2009-12-22 2011-06-23 Functional Genetics, Inc. Protease inhibitors and broad-spectrum antiviral
US20130023578A1 (en) * 2009-12-31 2013-01-24 Samyang Biopharmaceuticals Corporation siRNA for inhibition of c-Met expression and anticancer composition containing the same
CN102102101A (en) * 2010-03-05 2011-06-22 重庆医科大学 SiRNA for inhibiting expression of Plk1 and use thereof
FR2957426B1 (en) * 2010-03-12 2012-03-02 Thales Sa Autonomous positioning system by pseudolites stress zone and method of operation
CN103108642B (en) * 2010-03-24 2015-09-23 雷克西制药公司 rna interference with skin fibrosis symptoms in
CN103200945B (en) 2010-03-24 2016-07-06 雷克西制药公司 rna interference in ocular symptoms
EP2380595A1 (en) 2010-04-19 2011-10-26 Nlife Therapeutics S.L. Compositions and methods for selective delivery of oligonucleotide molecules to specific neuron types
WO2011133658A1 (en) 2010-04-22 2011-10-27 Boston Medical Center Corporation Compositions and methods for targeting and delivering therapeutics into cells
WO2011146732A1 (en) * 2010-05-19 2011-11-24 Beth Israel Deaconess Medical Center Methods for treating inflammatory autoimmune disorders
EP2390327A1 (en) * 2010-05-27 2011-11-30 Sylentis S.A. siRNA and their use in methods and compositions for the treatment and/or prevention of eye conditions
US9074721B2 (en) 2010-06-09 2015-07-07 Alex Lau Support system
US9316346B2 (en) 2010-06-09 2016-04-19 Colebrook Bosson Saunders (Products) Limited Support system
JP6023705B2 (en) * 2010-06-23 2016-11-09 カッパーアールエヌエー,インコーポレイテッド Treatment of sodium channel, voltage-dependent, SCNA related diseases by inhibition of the natural antisense transcripts for α-subunit (SCNA)
CN103068981A (en) 2010-07-28 2013-04-24 爱尔康研究有限公司 Sirna targeting VEGFA and methods for treatment in VIVO
USD684982S1 (en) 2010-08-11 2013-06-25 Colebrook Bosson Saunders (Products) Limited Display support with indicator window
WO2012027713A2 (en) * 2010-08-26 2012-03-01 Alnylam Pharmaceuticals, Inc. Compositions and methods for inhibition of snca
WO2012034942A1 (en) 2010-09-13 2012-03-22 Santaris Pharma A/S Compounds for the modulation of aurora kinase b expression
CN103328633B (en) 2010-10-22 2018-07-10 成均馆大学校产学协力团 Nucleic acid molecules that induce rna interference and uses thereof
WO2012068073A2 (en) 2010-11-15 2012-05-24 University Of Florida Research Foundation, Inc. Therapeutic and diagnostic applications targeting tnk-1
CA2817960A1 (en) 2010-11-17 2012-05-24 Isis Pharmaceuticals, Inc. Modulation of alpha synuclein expression
SI2670411T1 (en) 2011-02-02 2019-06-28 Excaliard Pharmaceuticals, Inc. Antisense compounds targeting connective tissue growth factor (ctgf) for use in a method of treating keloids or hypertrophic scars
KR101839177B1 (en) 2011-04-13 2018-03-15 아이오니스 파마수티컬즈, 인코포레이티드 Antisense modulation of ptpib expression
US8802839B2 (en) 2011-07-15 2014-08-12 Fibrogen, Inc. Connective tissue growth factor antisense oligonucleotides
CA2842034A1 (en) 2011-07-18 2013-01-24 University Of Kentucky Research Foundation Protection of cells from alu-rna-induced degenereation and inhibitors for protecting cells
CN104024413B (en) * 2011-10-19 2016-08-17 苏州瑞博生物技术有限公司 Small interfering RNA and its application and the method of inhibition of gene expression plk1
WO2013068836A1 (en) 2011-11-07 2013-05-16 INSERM (Institut National de la Santé et de la Recherche Médicale) A ddr1 antagonist or an inhibitor of ddr1 gene expression for use in the prevention or treatment of crescentic glomerulonephritis
EP2592146A3 (en) * 2011-11-14 2013-07-24 Silenseed Ltd Methods and compositions for treating prostate cancer
US20130132183A1 (en) * 2011-11-17 2013-05-23 At&T Intellectual Property I, L.P. Providing, storing, redeeming, and managing promotions
US9617331B2 (en) 2011-11-27 2017-04-11 Yeda Research And Development Co. Ltd. Methods of regulating angiogenesis by administering agents which increase apoB-100 polypeptide
WO2013123996A1 (en) * 2012-02-24 2013-08-29 Astrazeneca Uk Limited Novel sirna inhibitors of human icam-1
NZ700075A (en) 2012-02-24 2016-05-27 Protiva Biotherapeutics Inc Trialkyl cationic lipids and methods of use thereof
US9518260B2 (en) 2012-02-29 2016-12-13 Benitec Biopharma Limited Pain treatment
CN104321342B (en) * 2012-03-15 2017-12-22 首尔大学校产学协力团 Gremlin-1 antibody
DE202012003753U1 (en) * 2012-04-13 2013-07-17 Joseph Vögele AG Querverteilanordnung for a road finisher
CN102690826B (en) * 2012-04-19 2014-03-05 山西医科大学 shRNA for specifically reducing human Aurora-A gene expression and application thereof
ES2716818T3 (en) * 2012-05-22 2019-06-17 Olix Pharmaceuticals Inc Nuclear interference-inducing nucleic acid molecule capable of penetrating cells and using it
US9353422B2 (en) * 2012-06-04 2016-05-31 Academia Sinica USP37 inactivation as a treatment for PLZF/RARA-associated acute promyelocytic leukemia
MX2015002800A (en) 2012-09-05 2015-07-17 Sylentis Sau Sirna and their use in methods and compositions for the treatment and/or prevention of eye conditions.
GB201215857D0 (en) 2012-09-05 2012-10-24 Sylentis Sau siRNA and their use in methods and compositions for the treatment and/or prevention of eye conditions
JP6386461B2 (en) * 2012-10-26 2018-09-05 エヌライフ、セラピューティックス、ソシエダッド、リミターダNlife Therapeutics, S.L. Compositions and methods for the treatment of Parkinson's disease by selective delivery of oligonucleotides molecule into specific neuronal types
EP2914260A1 (en) 2012-10-31 2015-09-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for preventing antiphospholipid syndrome (aps)
US20140129345A1 (en) * 2012-11-08 2014-05-08 Michael Grishaver Presenting varied product or service content, based on member targeting criteria
EP2943579B1 (en) 2013-01-10 2018-09-12 Dharmacon, Inc. Libraries and methods for generating molecules
WO2014115158A1 (en) * 2013-01-28 2014-07-31 Council Of Scientific & Industrial Research METHOD FOR INHIBITING TUMOR GROWTH THROUGH RNA-INTERFERENCE USING LIPOSOMALLY ASSOCIATED CDC20 siRNA
KR20160021076A (en) 2013-03-15 2016-02-24 테출론 인코포레이티드 Antisense molecules for treatment of staphylococcus aureus infection
JP2016515518A (en) 2013-03-15 2016-05-30 テチュロン インコーポレイテッド Antisense molecules for the treatment of Staphylococcus aureus infection
KR101867414B1 (en) * 2013-07-05 2018-06-14 (주)바이오니아 Respiratory disease-related gene specific sirna, double-helical oligo rna structure containing sirna, composition containing same for preventing or treating respiratory disease
KR20150006742A (en) * 2013-07-09 2015-01-19 (주)바이오니아 Liver cancer related genes-specific siRNA, double-stranded oligo RNA molecules comprising the siRNA, and composition for the prevention or treatment of cancer comprising the same
WO2015116696A1 (en) 2014-01-28 2015-08-06 Massachusetts Institute Of Technology Combination therapies and methods of use thereof for treating cancer
US10011837B2 (en) 2014-03-04 2018-07-03 Sylentis Sau SiRNAs and their use in methods and compositions for the treatment and/or prevention of eye conditions
KR20150137473A (en) * 2014-05-29 2015-12-09 한국과학기술연구원 siRNA for Inhibition of USP15 Expression and Pharmaceutical Composition Containing the same
AU2015286663A1 (en) * 2014-07-10 2017-01-12 Stichting Katholieke Universiteit Antisense oligonucleotides for the treatment of usher syndrome type 2
CN104258377B (en) * 2014-09-10 2017-06-30 中南大学湘雅医院 Application Pik3c2a protein in liver cancer therapy
EP3204497A1 (en) 2014-10-10 2017-08-16 Dicerna Pharmaceuticals, Inc. Therapeutic inhibition of lactate dehydrogenase and agents therefor
EP3212794A2 (en) 2014-10-30 2017-09-06 Alnylam Pharmaceuticals, Inc. Polynucleotide agents targeting serpinc1 (at3) and methods of use thereof
CN104450710B (en) * 2014-11-28 2018-06-05 广州市锐博生物科技有限公司 Suppressing gene the nucleic acid oligomer and its application myd88
CN104673799B (en) * 2015-03-09 2019-02-05 浙江大学 It targets the siRNA of people RAN and its is preparing the purposes in anti-viral hepatitis type C drug
US20190002547A1 (en) * 2015-12-10 2019-01-03 Fibrogen, Inc. Methods for treatment of motor neuron diseases
CN105462978B (en) * 2015-12-18 2018-05-15 中国科学院北京基因组研究所 Small interfering rna one specific inhibition of gene expression and its application magea1
CN105462977B (en) * 2015-12-18 2018-05-11 中国科学院北京基因组研究所 Small interfering rna one specific inhibition of gene expression and its application magea1
WO2018112240A1 (en) 2016-12-14 2018-06-21 Progenity Inc. Treatment of a disease of the gastrointestinal tract with a tnf inhibitor
WO2018204786A1 (en) * 2017-05-05 2018-11-08 Voyager Therapeutics, Inc. Compositions and methods of treating amyotrophic lateral sclerosis (als)
US20190004823A1 (en) * 2017-06-30 2019-01-03 Microsoft Technology Licensing, Llc Capturing user interactions
WO2019070645A1 (en) * 2017-10-02 2019-04-11 Cedars-Sinai Medical Center Methods and compositions for efficient delivery through multiple bio barriers
WO2019079242A1 (en) 2017-10-16 2019-04-25 Voyager Therapeutics, Inc. Treatment of amyotrophic lateral sclerosis (als)
WO2019079240A1 (en) 2017-10-16 2019-04-25 Voyager Therapeutics, Inc. Treatment of amyotrophic lateral sclerosis (als)
WO2019121838A1 (en) 2017-12-21 2019-06-27 F. Hoffmann-La Roche Ag Companion diagnostic for htra1 rna antagonists
WO2019136456A1 (en) 2018-01-08 2019-07-11 Iovance Biotherapeutics, Inc. Processes for generating til products enriched for tumor antigen-specific t-cells
WO2019136459A1 (en) 2018-01-08 2019-07-11 Iovance Biotherapeutics, Inc. Processes for generating til products enriched for tumor antigen-specific t-cells
WO2019138057A1 (en) 2018-01-12 2019-07-18 Roche Innovation Center Copenhagen A/S Alpha-synuclein antisense oligonucleotides and uses thereof

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020150945A1 (en) * 2000-12-28 2002-10-17 Cell Therapeutics, Inc. Methods for making polynucleotide libraries, polynucleotide arrays, and cell libraries for high-throughput genomics analysis
US20030105051A1 (en) * 2001-05-29 2003-06-05 Mcswiggen James Nucleic acid treatment of diseases or conditions related to levels of HER2
US20040054155A1 (en) * 2002-02-01 2004-03-18 Sequitur, Inc. Oligonucleotide compositions with enhanced efficiency
US20040180357A1 (en) * 2002-11-01 2004-09-16 The Trustees Of The University Of Pennsylvania Compositions and methods for siRNA inhibition of HIF-1 alpha
US20040248299A1 (en) * 2002-12-27 2004-12-09 Sumedha Jayasena RNA interference
US20050130181A1 (en) * 2001-05-18 2005-06-16 Sirna Therapeutics, Inc. RNA interference mediated inhibition of wingless gene expression using short interfering nucleic acid (siNA)
US20050176025A1 (en) * 2001-05-18 2005-08-11 Sirna Therapeutics, Inc. RNA interference mediated inhibition of B-cell CLL/Lymphoma-2 (BCL-2) gene expression using short interfering nucleic acid (siNA)
US20050181382A1 (en) * 2003-06-02 2005-08-18 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of RNAi
US20050186586A1 (en) * 2003-06-02 2005-08-25 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of RNAi
US20050239731A1 (en) * 2001-05-18 2005-10-27 Sirna Therapeutics, Inc. RNA interference mediated inhibition of MAP kinase gene expression using short interfering nucleic acid (siNA)
US20070031844A1 (en) * 2002-11-14 2007-02-08 Anastasia Khvorova Functional and hyperfunctional siRNA

Family Cites Families (164)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US702831A (en) * 1901-08-20 1902-06-17 Samuel Thompson Combined double escutcheon and paint protector.
US760807A (en) * 1903-11-11 1904-05-24 Lee Roberts Cutting-nippers.
US5831066A (en) 1988-12-22 1998-11-03 The Trustees Of The University Of Pennsylvania Regulation of bcl-2 gene expression
US5741671A (en) * 1991-12-12 1998-04-21 The Johns Hopkins University Isolation cloning and expression of transmembrane water channel aquaporin 1(AQP1)
US5981175A (en) * 1993-01-07 1999-11-09 Genpharm Internation, Inc. Methods for producing recombinant mammalian cells harboring a yeast artificial chromosome
US20020086321A1 (en) 1993-02-02 2002-07-04 Craig Ruth W. Myeloid cell leukemia associated gene MCL-1
WO1997021808A1 (en) 1995-12-08 1997-06-19 Hybridon, Inc. Modified vegf antisense oligonucleotides
US5641756A (en) 1993-07-27 1997-06-24 Hybridon, Inc. Modified VEGF oligonucleotides
WO1997020925A1 (en) 1995-12-08 1997-06-12 Hybridon, Inc. Modified vegf antisense oligonucleotides for treatment of skin disorders
US6410322B1 (en) 1993-07-27 2002-06-25 Hybridon Inc Antisense oligonucleotide inhibition of vascular endothelial growth factor expression
US5731294A (en) 1993-07-27 1998-03-24 Hybridon, Inc. Inhibition of neovasularization using VEGF-specific oligonucleotides
DE69503038D1 (en) 1994-02-14 1998-07-23 Univ California Cell cycle protein in mammals
US6150092A (en) 1994-06-27 2000-11-21 Taogosei Company, Ltd. Antisense nucleic acid compound targeted to VEGF
US5830879A (en) 1995-10-02 1998-11-03 St. Elizabeth's Medical Center Of Boston, Inc. Treatment of vascular injury using vascular endothelial growth factor
WO2003070910A2 (en) 2002-02-20 2003-08-28 Ribozyme Pharmaceuticals, Incorporated INHIBITION OF VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) AND VEGF RECEPTOR GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
EP1390385A4 (en) 2001-05-29 2004-11-24 Sirna Therapeutics Inc Nucleic acid based modulation of female reproductive diseases and conditions
US20050148530A1 (en) 2002-02-20 2005-07-07 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US6346398B1 (en) * 1995-10-26 2002-02-12 Ribozyme Pharmaceuticals, Inc. Method and reagent for the treatment of diseases or conditions related to levels of vascular endothelial growth factor receptor
US6716575B2 (en) 1995-12-18 2004-04-06 Sugen, Inc. Diagnosis and treatment of AUR1 and/or AUR2 related disorders
KR20000005561A (en) 1996-04-17 2000-01-25 아로넥스 파마슈티칼즈, 인코포레이티드 Antisense inhibitor of vegf/vpf expression
US20050261485A1 (en) 1996-05-23 2005-11-24 Toagosei Co., Ltd., A Japan Corporation Method of producing antisense oligonucleotide
JP2000513230A (en) 1996-07-01 2000-10-10 エイチ. ヤング,エイピング Their use for modulating oligonucleotides and cell proliferation derived from untranslated regions of the housekeeping gene
AU6237198A (en) 1996-12-19 1998-07-15 Isis Pharmaceuticals, Inc. Large-scale purification of full length oligonucleotides by solid-liquid affinity extraction
US6800744B1 (en) * 1997-07-02 2004-10-05 Genome Therapeutics Corporation Nucleic acid and amino acid sequences relating to Streptococcus pneumoniae for diagnostics and therapeutics
JPH1142091A (en) 1997-07-25 1999-02-16 Toagosei Co Ltd Anti-sense nucleic acid compound
CA2248762A1 (en) * 1997-10-22 1999-04-22 University Technologies International, Inc. Antisense oligodeoxynucleotides regulating expression of tnf-.alpha.
US6506559B1 (en) 1997-12-23 2003-01-14 Carnegie Institute Of Washington Genetic inhibition by double-stranded RNA
WO1999038965A1 (en) 1998-01-29 1999-08-05 The Trustees Of Columbia University In The City Of New York Human hairless gene, protein and uses thereof
US6111086A (en) 1998-02-27 2000-08-29 Scaringe; Stephen A. Orthoester protecting groups
US20030228597A1 (en) 1998-04-13 2003-12-11 Cowsert Lex M. Identification of genetic targets for modulation by oligonucleotides and generation of oligonucleotides for gene modulation
AU3751299A (en) 1998-04-20 1999-11-08 Ribozyme Pharmaceuticals, Inc. Nucleic acid molecules with novel chemical compositions capable of modulating gene expression
WO1999055910A1 (en) 1998-04-24 1999-11-04 Arizona Board Of Regents Method of inducing apoptosis in a target cell
WO1999063975A2 (en) 1998-06-10 1999-12-16 Biognostik Gesellschaft für Biomolekulare Diagnostik mbH A method for stimulating the immune system
WO2000001393A2 (en) 1998-07-02 2000-01-13 The Trustees Of Columbia University In The City Of New York OLIGONUCLEOTIDE INHIBITORS OF bcl-xL
US6228642B1 (en) 1998-10-05 2001-05-08 Isis Pharmaceuticals, Inc. Antisense oligonucleotide modulation of tumor necrosis factor-(α) (TNF-α) expression
US6172216B1 (en) 1998-10-07 2001-01-09 Isis Pharmaceuticals Inc. Antisense modulation of BCL-X expression
WO2000021559A2 (en) 1998-10-09 2000-04-20 Musc Foundation For Research Development Blocking factor b to treat complement-mediated immune disease
SK5052001A3 (en) 1998-11-06 2002-10-08 Knoll Gmbh Inhibition of the formation of vascular hyperpermeability
US20040235041A1 (en) * 1998-11-17 2004-11-25 Shimkets Richard A. Nucleic acids containing single nucleotide polymorphisms and methods of use thereof
EP1147189A2 (en) 1998-12-04 2001-10-24 Immusol,Inc. Ribozyme therapy for the treatment and/or prevention of restenosis
US5958773A (en) 1998-12-17 1999-09-28 Isis Pharmaceuticals Inc. Antisense modulation of AKT-1 expression
US20040204380A1 (en) 1999-01-07 2004-10-14 Ackermann Elizabeth J Antisense modulation of novel anti-apoptotic bcl-2-related proteins
US6001992A (en) 1999-01-07 1999-12-14 Isis Pharmaceuticals Inc. Antisense modulation of novel anti-apoptotic bcl-2-related proteins
CN1166249C (en) 1999-01-19 2004-09-08 西门子公司 Method for the time synchronisation of a computer network and computer network with time synchronisation
DE19956568A1 (en) 1999-01-30 2000-08-17 Roland Kreutzer Method and medicament for the inhibition of expression of a given gene
DE60027719T2 (en) 1999-06-14 2007-04-26 Cancer Research Technology Ltd. cancer therapy
DE19928367A1 (en) * 1999-06-21 2000-12-28 Will E C H Gmbh & Co Handling of stacked sheet materials has a facility for stacking and separating into selected stack size
US6770633B1 (en) 1999-10-26 2004-08-03 Immusol, Inc. Ribozyme therapy for the treatment of proliferative skin and eye diseases
GB9927444D0 (en) 1999-11-19 2000-01-19 Cancer Res Campaign Tech Inhibiting gene expression
US7179796B2 (en) 2000-01-18 2007-02-20 Isis Pharmaceuticals, Inc. Antisense modulation of PTP1B expression
WO2002081628A2 (en) 2001-04-05 2002-10-17 Ribozyme Pharmaceuticals, Incorporated Modulation of gene expression associated with inflammation proliferation and neurite outgrowth, using nucleic acid based technologies
US20030084471A1 (en) 2000-03-16 2003-05-01 David Beach Methods and compositions for RNA interference
CA2403397A1 (en) 2000-03-16 2001-09-20 Genetica, Inc. Methods and compositions for rna interference
KR20080023768A (en) 2000-03-30 2008-03-14 막스-플랑크-게젤샤프트 츄어 푀르더룽 데어 비쎈샤프텐 에.파우. Rna sequence-specific mediators of rna interference
US6509559B1 (en) * 2000-06-20 2003-01-21 Ppt Vision, Inc. Binary optical grating and method for generating a moire pattern for 3D imaging
US6521258B1 (en) 2000-09-08 2003-02-18 Ferro Corporation Polymer matrices prepared by supercritical fluid processing techniques
AU1029502A (en) 2000-10-13 2002-04-22 Inst Cardiologie Montreal Antisense oligonucleotide directed toward mammalian vegf receptor genes and usesthereof
MXPA03003856A (en) 2000-11-01 2004-04-20 Bki Holding Corp Cellulose ethers and method of preparing the same.
EP2348133B1 (en) 2000-12-01 2014-07-16 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. RNA interference mediating small RNA molecules
JP2004532616A (en) 2000-12-28 2004-10-28 ジョンソン・アンド・ジョンソン・リサーチ・ピー・ティー・ワイ・リミテッドJohnson & Johnson, Research, Pty. Limited. Double-stranded rna mediated gene suppression
US20030143597A1 (en) 2000-12-28 2003-07-31 Finney Robert E. Methods for making polynucleotide libraries, polynucleotide arrays, and cell libraries for high-throughput genomics analysis
EP1353676A4 (en) 2000-12-29 2006-05-31 Alteon Inc Method for treating fibrotic diseases or other indications
WO2003035869A1 (en) 2001-10-26 2003-05-01 Ribopharma Ag Use of a double-stranded ribonucleic acid for specifically inhibiting the expression of a given target gene
WO2003035870A1 (en) 2001-10-26 2003-05-01 Ribopharma Ag Drug for treating a carcinoma of the pancreas
DE10160151A1 (en) 2001-01-09 2003-06-26 Ribopharma Ag Inhibiting expression of target gene, useful e.g. for inhibiting oncogenes, by administering double-stranded RNA complementary to the target and having an overhang
WO2002078105A1 (en) * 2001-03-22 2002-10-03 Matsushita Electric Industrial Co., Ltd. Positive-electrode active material and nonaqueous-electrolyte secondary battery containing the same
US20030087259A1 (en) 2001-04-18 2003-05-08 Clancy Brian M. Methods and compositions for regulating bone and cartilage formation
AU2002305236A1 (en) 2001-04-24 2002-11-05 Epigenesis Pharmaceuticals, Inc. Composition, formulations and kits for treatment of respiratory and lung disease with anti-sense oligonucleotides and a bronchodilating agent
WO2002085308A2 (en) 2001-04-24 2002-10-31 Epigenesis Pharmaceuticals, Inc. Antisense and anti-inflammatory based compositions to treat respiratory disorders
US20050227935A1 (en) 2001-05-18 2005-10-13 Sirna Therapeutics, Inc. RNA interference mediated inhibition of TNF and TNF receptor gene expression using short interfering nucleic acid (siNA)
US20050048529A1 (en) 2002-02-20 2005-03-03 Sirna Therapeutics, Inc. RNA interference mediated inhibition of intercellular adhesion molecule (ICAM) gene expression using short interfering nucleic acid (siNA)
US8202979B2 (en) 2002-02-20 2012-06-19 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid
CN100463967C (en) * 2001-05-29 2009-02-25 人体细胞组织有限公司 Testicular carnitine transfer protein and its gene
MXPA04000224A (en) 2001-07-10 2005-07-25 4Sc Ag Novel compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents.
US6734017B2 (en) * 2001-09-28 2004-05-11 Isis Pharmaceuticals, Inc. Antisense modulation of vascular endothelial growth factor receptor-2 expression
WO2003038077A1 (en) * 2001-10-30 2003-05-08 Daiichi Pharmaceutical Co., Ltd. Method of amplyfying hematopoietic stem cells
US20040063654A1 (en) 2001-11-02 2004-04-01 Davis Mark E. Methods and compositions for therapeutic use of RNA interference
IL161733D0 (en) 2001-11-02 2005-11-20 Insert Therapeutics Inc Methods and compositions for therapeutic use of rna interference
FR2832154B1 (en) 2001-11-09 2007-03-16 Centre Nat Rech Scient Oligonucleotide inhibitors and their use for specifically repress a gene
US20030186903A1 (en) 2001-11-23 2003-10-02 Isis Pharmaceuticals Inc. Antisense modulation of MyD88 expression
EP2014674B1 (en) 2001-11-26 2014-02-12 Laboratoire Biodim Protein-protein interactions in human immunodeficiency virus
US6965025B2 (en) 2001-12-10 2005-11-15 Isis Pharmaceuticals, Inc. Antisense modulation of connective tissue growth factor expression
KR100441894B1 (en) * 2002-01-26 2004-07-27 한국전자통신연구원 Micro-integrated near-field optical recording head and optical recording system using the same
AU2003207708A1 (en) 2002-02-20 2003-09-09 Sirna Therapeutics, Inc. Rna interference mediated inhibition of map kinase genes
AU2003213119A1 (en) 2002-02-20 2003-09-09 Sirna Therapeutics, Inc. RNA INTERFERENCE MEDIATED INHIBITION OF BCL2 GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
AU2003217550A1 (en) 2002-02-20 2003-09-09 Ribozyme Pharmaceuticals, Incorporated RNA INTERFERENCE MEDIATED INHIBITION OF TNF AND TNF RECEPTOR SUPERFAMILY GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
WO2003070918A2 (en) 2002-02-20 2003-08-28 Ribozyme Pharmaceuticals, Incorporated Rna interference by modified short interfering nucleic acid
US20040219671A1 (en) 2002-02-20 2004-11-04 Sirna Therapeutics, Inc. RNA interference mediated treatment of parkinson disease using short interfering nucleic acid (siNA)
CA2479530A1 (en) 2002-03-20 2003-10-02 Massachusetts Institute Of Technology Hiv therapeutic
CN1642968A (en) 2002-03-29 2005-07-20 阎云 A human ribonucleotide reductase M2 subunit
AU2003231886A1 (en) 2002-05-13 2003-11-11 Salviac Limited Retrieval catheter for an embolic filter
US20040009946A1 (en) 2002-05-23 2004-01-15 Ceptyr, Inc. Modulation of PTP1B expression and signal transduction by RNA interference
US20030224512A1 (en) 2002-05-31 2003-12-04 Isis Pharmaceuticals Inc. Antisense modulation of beta-site APP-cleaving enzyme expression
CA2489726A1 (en) 2002-06-18 2003-12-24 Irm Llc Diagnosis and treatment of chemoresistant tumors
US7148342B2 (en) 2002-07-24 2006-12-12 The Trustees Of The University Of Pennyslvania Compositions and methods for sirna inhibition of angiogenesis
US6906186B1 (en) 2002-07-30 2005-06-14 Isis Pharmaceuticals, Inc. Antisense modulation of polo-like kinase expression
GB0218010D0 (en) * 2002-08-05 2002-09-11 Ciba Spec Chem Water Treat Ltd Production of a fermentation product
US20040029275A1 (en) 2002-08-10 2004-02-12 David Brown Methods and compositions for reducing target gene expression using cocktails of siRNAs or constructs expressing siRNAs
WO2004027030A2 (en) 2002-09-18 2004-04-01 Isis Pharmaceuticals, Inc. Efficient reduction of target rna’s by single- and double-stranded oligomeric compounds
WO2004031237A1 (en) 2002-09-30 2004-04-15 Oncotherapy Science, Inc. Genes and polypeptides relating to human myeloid leukemia
WO2005013886A2 (en) 2002-10-30 2005-02-17 The Center For Blood Research, Inc. Methods for treating and preventing apoptosis-related diseases using rna interfering agents
JP2006505288A (en) 2002-11-04 2006-02-16 ユニバーシティー オブ マサチューセッツ Allele-specific rna interference
US7592442B2 (en) 2002-11-14 2009-09-22 Dharmacon, Inc. siRNA targeting ribonucleotide reductase M2 polypeptide (RRM2 or RNR-R2)
WO2006006948A2 (en) 2002-11-14 2006-01-19 Dharmacon, Inc. METHODS AND COMPOSITIONS FOR SELECTING siRNA OF IMPROVED FUNCTIONALITY
US7250496B2 (en) 2002-11-14 2007-07-31 Rosetta Genomics Ltd. Bioinformatically detectable group of novel regulatory genes and uses thereof
US7619081B2 (en) 2002-11-14 2009-11-17 Dharmacon, Inc. siRNA targeting coatomer protein complex, subunit beta 2 (COPB2)
US7582747B2 (en) 2002-11-14 2009-09-01 Dharmacon, Inc. siRNA targeting inner centromere protein antigens (INCENP)
US7605250B2 (en) 2004-05-12 2009-10-20 Dharmacon, Inc. siRNA targeting cAMP-specific phosphodiesterase 4D
US7691998B2 (en) 2002-11-14 2010-04-06 Dharmacon, Inc. siRNA targeting nucleoporin 62kDa (Nup62)
US7781575B2 (en) * 2002-11-14 2010-08-24 Dharmacon, Inc. siRNA targeting tumor protein 53 (p53)
US7612196B2 (en) 2002-11-14 2009-11-03 Dharmacon, Inc. siRNA targeting cyclin-dependent kinase inhibitor 1B (p27, Kip1) (CDKN1B)
US7977471B2 (en) 2002-11-14 2011-07-12 Dharmacon, Inc. siRNA targeting TNFα
US7217807B2 (en) 2002-11-26 2007-05-15 Rosetta Genomics Ltd Bioinformatically detectable group of novel HIV regulatory genes and uses thereof
US7951935B2 (en) 2002-11-14 2011-05-31 Dharmacon, Inc. siRNA targeting v-myc myelocytomatosis viral oncogene homolog (MYC)
US7635770B2 (en) 2002-11-14 2009-12-22 Dharmacon, Inc. siRNA targeting protein kinase N-3 (PKN-3)
AU2003295539A1 (en) 2002-11-15 2004-06-15 University Of Massachusetts Allele-targeted rna interference
US20040102391A1 (en) 2002-11-21 2004-05-27 Isis Pharmaceuticals Inc. Modulation of Gankyrin expression
US20040101857A1 (en) 2002-11-23 2004-05-27 Isis Pharmaceuticals Inc. Modulation of cytokine-inducible kinase expression
AU2003302167A1 (en) 2002-12-12 2004-06-30 The Burnham Institute Conversion of apoptotic proteins
US20040265230A1 (en) * 2003-01-06 2004-12-30 Martinez Robert Vincent Compositions and methods for diagnosing and treating colon cancers
FR2835837B1 (en) 2003-02-06 2007-03-16 Centre Nat Rech Scient Oligonucleotides inhibitors and their use to suppress specifically a gene encoding a growth factor
FR2835838B1 (en) 2003-02-06 2007-11-16 Centre Nat Rech Scient Oligonucleotides inhibitors and their use to suppress specifically a gene encoding a transcription factor
CA2515677A1 (en) * 2003-02-11 2004-08-26 Wyeth Methods for monitoring drug activities in vivo
WO2004076639A2 (en) * 2003-02-26 2004-09-10 Wyeth Use of gene expression profiling in the diagnosis and treatment of lupus nephritis and systemic lupus erythematosus
EP2239329A1 (en) * 2003-03-07 2010-10-13 Alnylam Pharmaceuticals, Inc. Therapeutic compositions
US20070167384A1 (en) 2003-04-02 2007-07-19 Dharmacon, Inc. Modified polynucleotides for use in rna interference
JP4605799B2 (en) 2003-04-02 2011-01-05 ダーマコン, インコーポレイテッド Modified polynucleotide for use in Rna interference
WO2004094636A1 (en) 2003-04-24 2004-11-04 Galapagos Genomics N.V. Effective sirna knock-down constructs
US7399853B2 (en) 2003-04-28 2008-07-15 Isis Pharmaceuticals Modulation of glucagon receptor expression
CA2527301A1 (en) 2003-05-30 2004-12-09 Nippon Shinyaku Co., Ltd. Oligonucleic acid-bearing composite and pharmaceutical composition containing the composite
DK1633767T3 (en) 2003-06-02 2019-03-25 Univ Massachusetts Methods and compositions for controlling the action of RNA silencing
EP1633770B1 (en) 2003-06-13 2015-04-29 Alnylam Europe AG Double-stranded ribonucleic acid with increased effectiveness in an organism
US7825235B2 (en) 2003-08-18 2010-11-02 Isis Pharmaceuticals, Inc. Modulation of diacylglycerol acyltransferase 2 expression
DE10341333B4 (en) 2003-09-08 2006-06-08 Siemens Ag Piezoelectric actuator and method of manufacturing of a piezoactuator
CN1886793A (en) 2003-11-27 2006-12-27 皇家飞利浦电子股份有限公司 Method and system for chapter marker and title boundary insertion in dv video
KR100586654B1 (en) * 2003-12-19 2006-06-07 이처닷컴 주식회사 Wireless banking system and wireless banking method using mobile phone
WO2005062937A2 (en) 2003-12-22 2005-07-14 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of single and double blunt-ended sirna
JP2005233933A (en) * 2004-01-19 2005-09-02 Nec Electronics Corp Combination test method and testing device
KR101054402B1 (en) * 2004-02-06 2011-08-04 엘지전자 주식회사 Pulley assembly of the washing machine
US20050176045A1 (en) 2004-02-06 2005-08-11 Dharmacon, Inc. SNP discriminatory siRNA
JP4937899B2 (en) 2004-03-12 2012-05-23 アルナイラム ファーマシューティカルズ, インコーポレイテッドAlnylam Pharmaceuticals, Inc. iRNA agents targeting VEGF
AU2005238034A1 (en) 2004-04-23 2005-11-10 The Trustees Of Columbia University In The City Of New York Inhibition of hairless protein mRNA
EP1750775A2 (en) 2004-05-04 2007-02-14 Nastech Pharmaceutical Company, Inc. Compositions and methods for enhancing delivery of nucleic acids into cells and for modifying expression of target genes in cells
JPWO2005116204A1 (en) 2004-05-11 2008-06-19 株式会社アルファジェン Polynucleotide causing Rna interference, and the gene silencing method using the same
MX2007003795A (en) 2004-09-28 2007-07-11 Quark Biotech Inc Oligoribonucleotides and methods of use thereof for treatment of alopecia, acute renal failure and other diseases.
EP2199298A1 (en) * 2004-11-17 2010-06-23 Protiva Biotherapeutics Inc. Sirna silencing of Apolipoprotein B
US7879992B2 (en) * 2005-01-31 2011-02-01 Isis Pharmaceuticals, Inc. Modification of MyD88 splicing using modified oligonucleotides
US7150451B2 (en) * 2005-02-18 2006-12-19 Gm Global Technology Operations, Inc. Air spring and jounce shock assembly
MX2007012766A (en) 2005-04-12 2008-10-01 Intradigm Corp Composition and methods of rnai therapeutics for treatment of cancer and other neovascularization diseases.
US20060286575A1 (en) 2005-04-16 2006-12-21 Cylene Pharmaceuticals, Inc. MCL-1 quadruplex nucleic acids and uses thereof
US8268629B2 (en) * 2005-06-21 2012-09-18 dTEC Systems L.L.C. Method for the measurement of water and water-soluble components in non-aqueous liquids
EP1772274B2 (en) 2005-09-29 2011-05-25 Brother Kogyo Kabushiki Kaisha Ink cartridge, set of ink cartridges and ink jet recording system
US7825099B2 (en) 2006-01-20 2010-11-02 Quark Pharmaceuticals, Inc. Treatment or prevention of oto-pathologies by inhibition of pro-apoptotic genes
US7910566B2 (en) 2006-03-09 2011-03-22 Quark Pharmaceuticals Inc. Prevention and treatment of acute renal failure and other kidney diseases by inhibition of p53 by siRNA
US20070259827A1 (en) 2006-01-25 2007-11-08 University Of Massachusetts Compositions and methods for enhancing discriminatory RNA interference
JP2009537566A (en) 2006-05-19 2009-10-29 アルコン リサーチ, リミテッド RNAi-mediated inhibition of tumor necrosis factor alpha related status
US8523707B2 (en) * 2006-05-31 2013-09-03 Bridgestone Sports Co., Ltd. Multi-piece solid golf ball
US8138160B2 (en) 2006-08-03 2012-03-20 Warsaw Orthopedic, Inc. Reagents, methods and systems to suppress pro-inflammatory cytokines
CA2659464A1 (en) * 2006-08-24 2008-02-28 Alcon Research, Ltd. Rnai-mediated inhibition of gremlin for treatment of iop-related conditions
JP2010507387A (en) * 2006-10-25 2010-03-11 クアーク・ファーマスーティカルス、インコーポレイテッドQuark Pharmaceuticals,Inc. New siRNA and methods of use thereof
ES2474176T3 (en) 2007-06-27 2014-07-08 Quark Pharmaceuticals, Inc. Compositions and methods for inhibiting gene expression pro-apoptticos
US7572747B2 (en) * 2007-09-27 2009-08-11 Alfred University Optical glass
WO2009044392A2 (en) 2007-10-03 2009-04-09 Quark Pharmaceuticals, Inc. Novel sirna structures
CN101640467B (en) 2008-07-28 2012-05-30 鸿富锦精密工业(深圳)有限公司 Shrapnel and voice coil motor

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020150945A1 (en) * 2000-12-28 2002-10-17 Cell Therapeutics, Inc. Methods for making polynucleotide libraries, polynucleotide arrays, and cell libraries for high-throughput genomics analysis
US20050239731A1 (en) * 2001-05-18 2005-10-27 Sirna Therapeutics, Inc. RNA interference mediated inhibition of MAP kinase gene expression using short interfering nucleic acid (siNA)
US20050130181A1 (en) * 2001-05-18 2005-06-16 Sirna Therapeutics, Inc. RNA interference mediated inhibition of wingless gene expression using short interfering nucleic acid (siNA)
US20050176025A1 (en) * 2001-05-18 2005-08-11 Sirna Therapeutics, Inc. RNA interference mediated inhibition of B-cell CLL/Lymphoma-2 (BCL-2) gene expression using short interfering nucleic acid (siNA)
US20030105051A1 (en) * 2001-05-29 2003-06-05 Mcswiggen James Nucleic acid treatment of diseases or conditions related to levels of HER2
US20040054155A1 (en) * 2002-02-01 2004-03-18 Sequitur, Inc. Oligonucleotide compositions with enhanced efficiency
US20040180357A1 (en) * 2002-11-01 2004-09-16 The Trustees Of The University Of Pennsylvania Compositions and methods for siRNA inhibition of HIF-1 alpha
US20070031844A1 (en) * 2002-11-14 2007-02-08 Anastasia Khvorova Functional and hyperfunctional siRNA
US20040248299A1 (en) * 2002-12-27 2004-12-09 Sumedha Jayasena RNA interference
US20050181382A1 (en) * 2003-06-02 2005-08-18 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of RNAi
US20050186586A1 (en) * 2003-06-02 2005-08-25 University Of Massachusetts Methods and compositions for enhancing the efficacy and specificity of RNAi

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10125369B2 (en) 2012-12-05 2018-11-13 Alnylam Pharmaceuticals, Inc. PCSK9 iRNA compositions and methods of use thereof

Also Published As

Publication number Publication date
US7589191B2 (en) 2009-09-15
US7569684B2 (en) 2009-08-04
US8138329B2 (en) 2012-03-20
US20090191625A1 (en) 2009-07-30
US7745610B2 (en) 2010-06-29
US20070260050A1 (en) 2007-11-08
US20080071073A1 (en) 2008-03-20
US20140094390A1 (en) 2014-04-03
US7521191B2 (en) 2009-04-21
US20130210676A1 (en) 2013-08-15
US8907077B2 (en) 2014-12-09
US7632939B2 (en) 2009-12-15
US20120252873A1 (en) 2012-10-04
US20110003714A1 (en) 2011-01-06
US20110319297A1 (en) 2011-12-29
US20080097092A1 (en) 2008-04-24
US20080139799A1 (en) 2008-06-12
US20070276136A1 (en) 2007-11-29
US8461326B2 (en) 2013-06-11
US20080113376A1 (en) 2008-05-15
US8658784B2 (en) 2014-02-25
US20070276135A1 (en) 2007-11-29
US20100099578A1 (en) 2010-04-22
US20070185320A1 (en) 2007-08-09
US20070255051A1 (en) 2007-11-01
US20070185318A1 (en) 2007-08-09
US20070134698A1 (en) 2007-06-14
US20070255048A1 (en) 2007-11-01
US20110039734A1 (en) 2011-02-17
US20100144552A1 (en) 2010-06-10
US20070293664A1 (en) 2007-12-20
US20100279896A1 (en) 2010-11-04
US7632938B2 (en) 2009-12-15
US20100069261A1 (en) 2010-03-18
US7662950B2 (en) 2010-02-16
US20070128641A1 (en) 2007-06-07
US8633306B2 (en) 2014-01-21
US20070260047A1 (en) 2007-11-08
US20100062951A1 (en) 2010-03-11
US7855186B2 (en) 2010-12-21
US20080015114A1 (en) 2008-01-17
US20080085998A1 (en) 2008-04-10
US20130059760A1 (en) 2013-03-07
US20070213521A1 (en) 2007-09-13
US7741470B2 (en) 2010-06-22
US20120258888A1 (en) 2012-10-11
US7709629B2 (en) 2010-05-04
US7582746B2 (en) 2009-09-01
US20070249819A1 (en) 2007-10-25
US7615541B2 (en) 2009-11-10
US20070185319A1 (en) 2007-08-09
US20070265438A1 (en) 2007-11-15
US20100234583A1 (en) 2010-09-16
US20090325818A1 (en) 2009-12-31
US20100267587A1 (en) 2010-10-21
US20100087334A1 (en) 2010-04-08
US20080039617A1 (en) 2008-02-14
US7635771B2 (en) 2009-12-22
US20110281769A1 (en) 2011-11-17
US7598369B2 (en) 2009-10-06
US20080113377A1 (en) 2008-05-15
US7833989B2 (en) 2010-11-16
US7645870B2 (en) 2010-01-12
US20070260048A1 (en) 2007-11-08
US20080086002A1 (en) 2008-04-10
US20120065250A1 (en) 2012-03-15
US7829696B2 (en) 2010-11-09
US20080113374A1 (en) 2008-05-15
US8293887B2 (en) 2012-10-23
US20080113370A1 (en) 2008-05-15
US8217162B2 (en) 2012-07-10
US20110034349A1 (en) 2011-02-10
US20110319296A1 (en) 2011-12-29
US20120270926A1 (en) 2012-10-25
US20100004141A1 (en) 2010-01-07
US7678896B2 (en) 2010-03-16
US20100113761A1 (en) 2010-05-06
US8222395B2 (en) 2012-07-17
US20070255047A1 (en) 2007-11-01
US20100022413A1 (en) 2010-01-28
US8575329B2 (en) 2013-11-05
WO2006006948A3 (en) 2007-11-15
US20070179286A1 (en) 2007-08-02
US7605252B2 (en) 2009-10-20
US7550572B2 (en) 2009-06-23
US20080113373A1 (en) 2008-05-15
US20080113369A1 (en) 2008-05-15
US20130023446A1 (en) 2013-01-24
US20070134697A1 (en) 2007-06-14
US20070225486A1 (en) 2007-09-27
US8030476B2 (en) 2011-10-04
US20120015850A1 (en) 2012-01-19
US20070255052A1 (en) 2007-11-01
US20080132691A1 (en) 2008-06-05
US20070128640A1 (en) 2007-06-07
US8883998B2 (en) 2014-11-11
US20120010106A1 (en) 2012-01-12
US8039610B2 (en) 2011-10-18
US20080027216A1 (en) 2008-01-31
US20110003713A1 (en) 2011-01-06
US20080113378A1 (en) 2008-05-15
US20100234582A1 (en) 2010-09-16
US20070260049A1 (en) 2007-11-08
US20080027215A1 (en) 2008-01-31
US20070260052A1 (en) 2007-11-08
US20070299253A1 (en) 2007-12-27
US8268985B2 (en) 2012-09-18
US20090156797A1 (en) 2009-06-18
US7737267B2 (en) 2010-06-15
US20120184463A1 (en) 2012-07-19
US20070244312A1 (en) 2007-10-18
US8022199B2 (en) 2011-09-20
US7795421B2 (en) 2010-09-14
US20070185317A1 (en) 2007-08-09
US20080085997A1 (en) 2008-04-10
US20110077173A1 (en) 2011-03-31
US8067576B2 (en) 2011-11-29
US7807820B2 (en) 2010-10-05
US8247169B2 (en) 2012-08-21
US20070238868A1 (en) 2007-10-11
US7999097B2 (en) 2011-08-16
US7666853B2 (en) 2010-02-23
US7816512B2 (en) 2010-10-19
US8071754B2 (en) 2011-12-06
US8314229B2 (en) 2012-11-20
US7897754B2 (en) 2011-03-01
US7595388B2 (en) 2009-09-29
US20100113760A1 (en) 2010-05-06
US20100069622A1 (en) 2010-03-18
US7655789B2 (en) 2010-02-02
US7541453B2 (en) 2009-06-02
US20080081904A1 (en) 2008-04-03
US20100113306A1 (en) 2010-05-06
US20110021382A1 (en) 2011-01-27
US20120283311A1 (en) 2012-11-08
US20080076908A1 (en) 2008-03-27
US20080113371A1 (en) 2008-05-15
US20130225447A1 (en) 2013-08-29
US20100016176A1 (en) 2010-01-21
US7598370B2 (en) 2009-10-06
US8022198B2 (en) 2011-09-20
US20070265437A1 (en) 2007-11-15
US20090253776A1 (en) 2009-10-08
US7935813B2 (en) 2011-05-03
WO2006006948A2 (en) 2006-01-19
US7592443B2 (en) 2009-09-22
US20070255046A1 (en) 2007-11-01
US20080064865A1 (en) 2008-03-13
US8445668B2 (en) 2013-05-21
US20070141602A1 (en) 2007-06-21
US20120258889A1 (en) 2012-10-11
US8426579B2 (en) 2013-04-23
US20070213520A1 (en) 2007-09-13
US20100010206A1 (en) 2010-01-14
US20080090997A1 (en) 2008-04-17
US20100022763A1 (en) 2010-01-28
US20080045703A1 (en) 2008-02-21
US20080113375A1 (en) 2008-05-15
US8222396B2 (en) 2012-07-17
US20070255050A1 (en) 2007-11-01
US20080097091A1 (en) 2008-04-24
US20080097089A1 (en) 2008-04-24
US7638621B2 (en) 2009-12-29
US20070219362A1 (en) 2007-09-20
US20080113372A1 (en) 2008-05-15
US20120283142A1 (en) 2012-11-08
US8232386B2 (en) 2012-07-31
US8304528B2 (en) 2012-11-06
US20080086001A1 (en) 2008-04-10
US20120270751A1 (en) 2012-10-25
US20100190971A1 (en) 2010-07-29
US8236942B2 (en) 2012-08-07
US20100240554A1 (en) 2010-09-23
US20070255049A1 (en) 2007-11-01
US7608706B2 (en) 2009-10-27
US20070287833A1 (en) 2007-12-13
US7745612B2 (en) 2010-06-29
US8658785B1 (en) 2014-02-25
US7579458B2 (en) 2009-08-25
US7638622B2 (en) 2009-12-29
US20070232797A1 (en) 2007-10-04
US20080071075A1 (en) 2008-03-20

Similar Documents

Publication Publication Date Title
Takeshita et al. Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo
Wang et al. DNA ligase III as a candidate component of backup pathways of nonhomologous end joining
Du et al. A systematic analysis of the silencing effects of an active siRNA at all single-nucleotide mismatched target sites
Milligan et al. Current concepts in antisense drug design
Dorsett et al. siRNAs: applications in functional genomics and potential as therapeutics
Hansen et al. Circular RNA and miR-7 in cancer
Lal et al. miR-24 Inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to “seedless” 3′ UTR microRNA recognition elements
Shirane et al. Enzymatic production of RNAi libraries from cDNAs
Heidel et al. Potent siRNA inhibitors of ribonucleotide reductase subunit RRM2 reduce cell proliferation in vitro and in vivo
Bramsen et al. Improved silencing properties using small internally segmented interfering RNAs
Nakamura et al. Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone morphogenetic protein signaling
JP5066095B2 (en) Regulation of gene expression by oligomers targeted to chromosome dna
Portnoy et al. Small RNA and transcriptional upregulation
Mann et al. Improved antisense oligonucleotide induced exon skipping in the mdx mouse model of muscular dystrophy
AU2004257167B2 (en) Inhibition of Syk kinase expression
Dallas et al. RNAi: A novel antisense technology and its therapeutic potential.
Paddison et al. Short hairpin activated gene silencing in mammalian cells
Piao et al. CCR4-NOT deadenylates mRNA associated with RNA-induced silencing complexes in human cells
CA2504926C (en) Compositions and methods for sirna inhibition of hif-1 alpha
EP1608733B1 (en) Modified polynucleotides for use in rna interference
DK2602322T3 (en) Induction of exon skipping in eukaryotic cells
KR101201664B1 (en) Further novel forms of interfeing RNA molecules
JP2019062909A (en) Method of sequence-specific inhibition of short chain rna function
Mook et al. Evaluation of locked nucleic acid–modified small interfering RNA in vitro and in vivo
Elbashir et al. Analysis of gene function in somatic mammalian cells using small interfering RNAs

Legal Events

Date Code Title Description
AS Assignment

Owner name: DHARMACON, INC., COLORADO

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KHVOROVA, ANASTASIA;REYNOLDS, ANGELA;LEAKE, DEVIN;AND OTHERS;REEL/FRAME:019484/0743;SIGNING DATES FROM 20070416 TO 20070521

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION