WO2017059223A2 - Compositions and methods for inhibiting gene expression of lpa - Google Patents
Compositions and methods for inhibiting gene expression of lpa Download PDFInfo
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- WO2017059223A2 WO2017059223A2 PCT/US2016/054729 US2016054729W WO2017059223A2 WO 2017059223 A2 WO2017059223 A2 WO 2017059223A2 US 2016054729 W US2016054729 W US 2016054729W WO 2017059223 A2 WO2017059223 A2 WO 2017059223A2
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- seq
- rnai agent
- nucleotide sequence
- lpa
- lpa rnai
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Definitions
- Lipoprotein(a) [ Lp(a)
- LPA apo(a) gene
- Lp(a) levels in humans are genetically defined and do not change significantly with diet, exercise, or other lifestyle changes.
- LPA varies in length depending upon the number of Kringle KIV2 domains present and its expression is inversely correlated with the number of domains present.
- Normal Lp(a) levels range from 0.1-25 mg/dl, with about 25% of the population in the United States of America having Lp(a) levels of 30 mg/dl or higher.
- Lp(a) levels Analysis of Lp(a) levels in multiple studies have implicated high Lp(a) levels as an independent risk factor for cardiovascular disease, stroke, and other related disorders including atherosclerotic stenosis.
- genome-w ide association analyses have also implicated LPA as a genetic risk factor for diseases such as atherosclerotic stenosis.
- LPA also termed apo(a)
- RNAi RNA interference
- compositions containing LPA RNAi agents for selectively and efficiently inhibiting expression of the LPA gene are the name of the gene which encodes apolipoprotein (a) (apo(a)), a key component of the lipoprotein (a) particle (Lp(a)).
- the LPA RNAi agents described herein can be used in the prevention or treatment or the preparation of a medicament for the prevention or treatment of diseases including, but not limited to: Berger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic valve stenosis, aortic valve regurgitation, aortic dissection, retinal artery occlusion, cerebrovascular disease, mesenteric ischemia, superior mesenteric artery occlusion, renal artery stenosis, stable/unstable angina, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperapobetalipoproteinemia, cerebrovascular atherosclerosis, cerebrovascular disease, and venous thrombosis.
- diseases including, but not limited to: Berger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic valve stenosis, aortic valve regurgitation, a
- Each LPA RNAi agent includes at least a sense strand and an antisense strand.
- the sense strand and the antisense strand can be partially, substantially, or fully complementary to each other.
- the length of the RNAi agent sense and antisense strands described herein each can be 17 to 30 nucleotides in length. In some embodiments, the sense and antisense strands are independently 17 to 26 nucleotides in length. The sense and antisense strands can be either the same length or different lengths.
- the RNAi agents described herein upon delivery to a cell expressing the LPA gene, inhibit the expression of the LPA gene in vitro or in vivo.
- a sense strand of an LPA RNAi agent comprises a nucleotide sequence having at least 90% identity over a core stretch of at least 17 consecutive nucleotides to a sequence in an LPA mRNA.
- the sense strand nucleotide sequence having at least 90% identity to a sequence in the LPA mRNA is 17, 18, 19, 20, 21, 22, or 23 nucleotides in length.
- An antisense strand of an LPA RNAi agent comprises a nucleotide sequence having at least 90% complementary over a core stretch of at least 16 consecutive nucleotides to a sequence in the LPA mRNA and the corresponding sense strand.
- the antisense strand nucleotide sequence having at least 90% complementarity to a sequence in the LPA mRNA or the corresponding sense strand is 17, 18, 19, 20, 21, 22, or 23 nucleotides in length.
- one or more LPA RNAi agents are delivered to target cells or tissues using any oligonucleotide delivery technology known in the art.
- Nucleic acid delivery methods include, but are not limited to, by encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres, proteinaceous vectors or Dynamic PolyconjugatesTM (DPCs (see, for example WO 2000/053722, WO 2008/0022309, WO 2011/104169, and WO 2012/083185, each of which is incorporated herein by reference).
- DPCs Dynamic PolyconjugatesTM
- an LPA RNAi agent is conjugated to a targeting group.
- the targeting group can include a cell receptor ligand, such as a galactose cluster, including a galactose cluster comprising an N-acetyl-galactosamine trimer.
- a cell receptor ligand such as a galactose cluster, including a galactose cluster comprising an N-acetyl-galactosamine trimer.
- an LPA RNAi agent is optionally combined with one or more additional (i.e., second, third, etc.) therapeutics.
- An additional therapeutic can be another LPA RNAi agent (e.g., an LPA RNAi agent which targets a different sequence within the LPA target).
- An additional therapeutic can also be a small molecule drug, antibody, antibody fragment, and/or vaccine.
- the LPA RNAi agents, with or without the one or more additional therapeutics, can be combined with one or more excipients to form pharmaceutical compositions.
- compositions for delivering an LPA RNAi agent to a liver cell, particularly hepatocytes, in vivo comprising: an LPA RNAi agent conjugated to a targeting group.
- the targeting group is a asialoglycoprotein ligand.
- the method of treating a subject with an LPA RNAi agent or LPA RNAi agent-containing composition can optionally be combined with one or more steps of administering one or more additional (i.e., second) therapeutics or treatments.
- the LPA RNAi agent and additional therapeutics can be administered in a single composition or they may be administered separately.
- additional therapeutics include, but are not limited to, HMg Co-A reductase inhibitors (statins), ezetimibe, PCSK-9 inhibitors, CTEP inhibitors, therapies targeting ANGPTL3, therapies targeting APOC3, and niacin.
- LPA RNAi agents can be used in methods for therapeutic prevention or treatment of diseases including, but not limited to: Berger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic valve stenosis, aortic valve regurgitation, aortic dissection, retinal artery occlusion, cerebrovascular disease, mesenteric ischemia, superior mesenteric artery occlusion, renal artery stenosis, stable/unstable angina, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperapobetalipoproteinemia, cerebrovascular atherosclerosis, cerebrovascular disease, and venous thrombosis.
- diseases including, but not limited to: Berger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic valve stenosis, aortic valve regurgitation, aortic dissection, retinal artery occlusion,
- Such methods comprise administration of an LPA RNAi agent as described herein to a subject, e.g., a human or animal subject.
- the pharmaceutical compositions can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be made by any way commonly known in the art, such as, but not limited to, topical (e.g., by a transdermal patch), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer, intratracheal, intranasal), epidermal, transdermal, oral or parenteral.
- topical e.g., by a transdermal patch
- pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer, intratracheal, intranasal
- epidermal transdermal, oral or parenteral.
- Parenteral administration includes, but is not limited to, intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; subdermal (e.g., via an implanted device), intracranial, intraparenchymal, intrathecal, and intraventricular, administration.
- the pharmaceutical compositions described herein are administered by subcutaneous injection.
- LPA RNAi agents and/or compositions can be used in methods for therapeutic treatment of diseases, including but not limited to: Berger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic valve stenosis, aortic valve regurgitation, aortic dissection, retinal artery occlusion, cerebrovascular disease, mesenteric ischemia, superior mesenteric artery occlusion, renal artery stenosis, stable/unstable angina, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperapobetalipoproteinemia, cerebrovascular atherosclerosis, cerebrovascular disease, and venous thrombosis.
- Such methods comprise administration of an LPA RNAi agent as described herein to a subject, e.g., a human or animal subject.
- FIG. 1 Graph illustrating serum Lp(a) protein levels in Lp(a) transgenic (Tg) mice following a single subcutaneous administration of 0.5 mg/kg (dashed line) or 2 mg/kg (solid line) of indicated LPA RNAi agent. Lp(a) levels were normalized to day 1 and saline control.
- FIG. 2. Graph illustrating serum Lp(a) protein levels in Lp(a) Tg mice following administration of three subcutaneous doses of 1 mg/kg (dashed line) or 3 mg/kg (solid line) of indicated LPA RNAi agent, administered once a week for three weeks (dose on days 1, 8, and 15). Lp(a) levels were normalized to day 1 and saline control.
- FIG. 3 Graph illustrating Lp(a) particle levels in Cynomolgus monkey serum following administration of a single 2 mg/kg ADO 1196 LPA RNAi agent dosed 1 : 1 (wt/wt) with delivery polymer on day 1. Lp(a) levels were normalized to two pre-dose values (shown as day 0).
- FIG. 4 Graph illustrating Lp(a) particle levels in Cynomolgus monkey serum following administration of 4 mg/kg or 6 mg/kg LPA RNAi agent dosed 1 : 1 (wt/wt) with delivery polymer on day 1 and day 71. Lp(a) levels were normalized to two pre-dose values
- FIG. 5 Graph illustrating Lp(a) particle levels in Cynomolgus monkey serum following three weekly subcutaneous doses of 3 mg/kg of AD02819 LPA RNAi agent on days 1, 8, and 15. Lp(a) levels were normalized to three pre-dose values (shown as day 0).
- FIG. 6 Graph illustrating Lp(a) particle levels in Cynomolgus monkey serum following a single subcutaneous administration of 3 mg/kg of LPA RNAi agent on day 1.
- AD03460 and AD03536 groups received an additional 1 mg/kg dose of LPA RNAi agent on day 48.
- Lp(a) levels were normalized to three pre-dose values (shown as day 0).
- RNAi agents for inhibiting expression of the LPA gene referred to herein as LPA RNAi agents.
- LPA RNAi agents for inhibiting expression of the LPA gene
- the RNAi agents described herein upon delivery to a cell expressing the LPA gene, inhibit or knockdown expression of LPA in vitro and/or in vivo through the biological process of RNA interference (RNAi).
- RNAi RNA interference
- LPA may refer to an LPA gene, an LPA mRNA, or an LP(a) protein, as appropriate.
- An LPA RNAi agent comprises a sense strand and an antisense strand.
- the sense strand and antisense strand each contain a core sequence 17-23 nucleobases in length.
- An antisense strand core sequence is 100% (perfectly) complementary or at least 90% (substantially) complementary to a nucleotide sequence (sometimes referred to, e.g., as a target sequence) present in an LP A mRNA.
- a sense strand core sequence is 100% (perfectly) complementary or at least 90% (substantially) complementary to a sequence in the antisense strand and thus the sense strand core sequence is perfectly identical or at least 90% identical to a nucleotide sequence (target sequence) present in the LPA mRNA.
- a sense strand core sequence can be the same length as a corresponding antisense core sequence or it can be a different length.
- the antisense strand core sequence is 17, 18, 19, 20, 21 , 22, or 23 nucleotides in length.
- the sense strand core sequence is 17, 18, 19, 20, 21 , 22, or 23 nucleotides in length.
- LPA RNAi agent sense and antisense strands anneal to form a duplex.
- a sense strand and an antisense strand of an LPA RNAi agent are partially, substantially, or fully complementary to each other.
- the sense strand core sequence is at least 90% complementary or 100% complementary to the antisense core sequence.
- the sense strand core sequence contains a sequence of at least 17, at least 18, at least 19, at least 20, or at least 21 nucleotides that is at least 90% or 100% complementary to a corresponding 17, 18, 19, 20, or 21 nucleotide sequence of the antisense strand core sequence (i.e., the sense strand and antisense core sequences of an LPA RNAi agent have a region of at least 17, at least 18, at least 19, at least 20, or at least 21 nucleotides that is at least 90% base paired or 100% base paired.)
- first nucleotide sequence e.g., RNAi agent sense strand or LPA mRNA
- second nucleotide sequence e.g., RNAi agent antisense strand
- first nucleotide sequence e.g., RNAi agent sense strand or LPA mRNA
- second nucleotide sequence e.g., RNAi agent antisense strand
- Complementary sequences include Watson-Crick base pairs or non- Watson-Crick base pairs and include natural or modified nucleotides or nucleotide mimics as long as the above requirements with respect to their ability to hybridize are fulfilled.
- Perfectly complementary or “fully complementary” means that all (100%) of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide.
- the contiguous sequence may comprise all or a part of a first or second nucleotide sequence.
- partial complementary means that in a hybridized pair of nucleobase sequences, at least 70% of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide.
- substantially complementary means that in a hybridized pair of nucleobase sequences, at least 85% of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide.
- the sense and antisense strands are 19-26 nucleotides in length.
- the described RNAi agent sense and antisense strands are independently 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 nucleotides in length.
- the sense and antisense strands can be either the same length or they can be different lengths.
- a sense strand and an antisense strand are each 26 nucleotides in length.
- a sense strand is 23 nucleotides in length and an antisense strand is 21 nucleotides in length.
- a sense strand is 22 nucleotides in length and an antisense strand is 21 nucleotides in length.
- a sense strand is 21 nucleotides in length and an antisense strand is 21 nucleotides in length. In some embodiments, a sense strand is 19 nucleotides in length and an antisense strand is 21 nucleotides in length.
- the sense strand and/or the antisense strand may optionally and independently contain an additional 1, 2, 3, 4, 5, or 6 nucleotides (extension) at the 3' end, the 5' end, or both the 3' and 5' ends of the core sequences.
- the antisense strand additional nucleotides, if present, may or may not be complementary to the corresponding sequence in the LPA mRNA.
- the sense strand additional nucleotides, if present, may or may not be identical to the corresponding sequence in the LPA mRNA.
- the antisense strand additional nucleotides, if present may or may not be complementary to the corresponding sense strand's additional nucleotides, if present.
- an extension comprises 1, 2, 3, 4, 5, or 6 nucleotides at the 5' and/or 3' end of the sense strand core sequence and/or antisense strand core sequence.
- the extension nucleotides on a sense strand may or may not be complementary to nucleotides, either core sequence nucleotides or extension nucleotides, in the corresponding antisense strand.
- the extension nucleotides on an antisense strand may or may not be complementary to nucleotides, either core sequence nucleotides or extension nucleotides, in the corresponding sense strand.
- both the sense strand and the antisense strand of an RNAi agent contain 3' and 5' extensions.
- an LPA RNAi agent has an antisense strand having a 3' extension and a sense strand having a 5' extension.
- an LPA RNAi agent comprises an antisense strand having a 3' extension of 1, 2, 3, 4, 5, or 6 nucleotides in length. In other embodiments, an LPA RNAi agent comprises an antisense strand having a 3' extension of 1, 2, or 3 nucleotides in length. In some embodiments, one or more of the antisense strand extension nucleotides comprise uracil or thymidine nucleotides or nucleotides which are complementary to the corresponding LPA mRNA sequence.
- a 3' antisense strand extension includes or consists of, but is not limited to: Ab, AbAb, AUA, UGCUU, CUG, UG, UGCC, CUGCC, CGU, CUU, UGCCUA, CUGCCU, UGCCU, UGAUU, GCCUAU, T, TT (each listed 5' to 3').
- an LPA RNAi agent comprises an antisense strand having a 5' extension of 1, 2, 3, 4, or 5 nucleotides in length. In other embodiments, an LPA RNAi agent comprises an antisense strand having a 5' extension of 1 or 2 nucleotides in length. In some embodiments, one or more of the antisense strand extension nucleotides comprises uracil or thymidine nucleotides or nucleotides which are complementary to the corresponding LPA mRNA sequence. In some embodiments, the 5' antisense strand extension includes or consists of, but is no limited to, UA, TU, U, T, CUC (each listed 5' to 3').
- an antisense strand may have any of the 3' extensions described above in combination with any of the 5' antisense strand extensions described, if present.
- an LPA RNAi agent comprises a sense strand having a 3' extension of 1, 2, 3, 4, or 5 nucleotides in length.
- one or more of the sense strand extension nucleotides comprises adenosine, uracil, or thymidine nucleotides, AT dinucleotide, or nucleotides which correspond to nucleotides in the LPA mRNA sequence.
- the 3' sense strand extension includes or consists of, but is no limited to: T, UUAb, UAb, Ab, UT, TT, UUT, TTT, or TTTT (each listed 5' to 3').
- an LPA RNAi agent comprises a sense strand having a 5' extension of 1, 2, 3, 4, 5, or 6 nucleotides in length.
- one or more of the sense strand extension nucleotides comprise uracil or adenosine nucleotides or nucleotides which correspond to nucleotides in the LPA mRNA sequence.
- the sense strand 5' extension can be, but is not limited to: CA, AUAGGC, AUAGG, AUAG, AUA, A, AA, AC, GCA, GGCA, GGC, UAUCA, UAUC, Ab, UCA, UAU (each listed 5' to 3').
- a sense strand may have a 3' extension and/or a 5' extension.
- nucleotide sequences used in forming LPA RNAi agents are provided in Tables 1, 2A, 2B, 3A, and 3B.
- sequence or “nucleotide sequence” refers to a succession or order of nucleobases, nucleotides, and/or nucleosides, whether modified or unmodified, described with a succession of letters using the standard nucleotide nomenclature and the key for modified nucleotides described herein.
- RNAi agents include, but are not limited to: short interfering RNAs (siRNAs), double-strand RNAs (dsRNA), micro RNAs (miRNAs), short hairpin RNAs (shRNA), and dicer substrates (e.g., U.S. Patent Nos. 8084599, 8349809, and 8513207).
- siRNAs short interfering RNAs
- dsRNA double-strand RNAs
- miRNAs micro RNAs
- shRNA short hairpin RNAs
- dicer substrates e.g., U.S. Patent Nos. 8084599, 8349809, and 8513207.
- Unmodified LPA RNAi agent sense strand and antisense strand sequences are provided in Table 1.
- each of the nucleotides in each of the sequences listed in Table 1 may be a modified nucleotide.
- Table 1 Unmodified LPA RNAi agent antisense strand and sense strand sequences.
- the LPA RNAi agents described herein are formed by annealing an antisense strand with a sense strand.
- a sense strand containing a sequence listed in Table 1 or Table 2B can be hybridized to any antisense strand containing a sequence listed in Table 1 or Table 2A provided the two sequences have a region of at least 90% complementarity over a contiguous 16, 17, 18, 19, 20, or 21 nucleotide sequence.
- an LPA RNAi agent antisense strand comprises a nucleotide sequence of any of the sequences in Table 1. In some embodiments, an LPA RNAi agent antisense strand comprises the sequence of nucleotides 1-17, 2-17, 1-18, 2-18, 1-19, 2-19, 1-20, 2-20, 1-21, 2- 21, 1-22, 2-22, 1-23, 2-23, 1-24, 2-24, 1-25, 2-25, 1-26, or 2-26 of any of the sequences in Table 1. In some embodiments, an LP A RNAi agent sense strand comprises the nucleotide sequence of any of the sequences in Tables 1.
- an LPA RNAi agent sense strand comprises the sequence of nucleotides 1-17, 2-17, 1 -18, 2-18, 1 -19, 2-19, 1-20, 2-20, 1 - 21, 2-21 , 1 -22, 2-22, 1 -23, 2-23, 1-24, 2-24, 1-25, 2-25, 1-26, or 2-26 of any of the sequences in Table 1.
- the sense and antisense strands of the RNAi agents described herein contain the same number of nucleotides. In some embodiments the sense and antisense strands of the RNAi agents described herein contain different numbers of nucleotides. In some embodiments, the sense strand 5' end and the antisense strand 3' end of an RNAi agent form a blunt end. In some embodiments, the sense strand 3' end and the antisense strand 5' end of an RNAi agent form a blunt end. In some embodiments, both ends of an RNAi agent form blunt ends. In some embodiments, neither end of an RNAi agent is blunt-ended.
- a blunt end refers to an end of a double stranded RNAi agent in which the terminal nucleotides of the two annealed strands are complementary (form a complementary base-pair).
- the sense strand 5' end and the antisense strand 3' end of an RNAi agent form a frayed end.
- the sense strand 3' end and the antisense strand 5' end of an RNAi agent form a frayed end.
- both ends of an RNAi agent form a frayed end.
- neither end of an RNAi agent is a frayed end.
- a frayed end refers to an end of a double stranded RNAi agent in which the terminal nucleotides of the two annealed strands from a pair (i.e. do not form an overhang) but are not complementary (i.e. form a non-complementary pair).
- an overhang is a stretch of one or more unpaired nucleotides at the end of one strand of a double stranded RNAi agent.
- the unpaired nucleotides may be on the sense strand or the antisense strand, creating either 3' or 5' overhangs.
- the RNAi agent contains: a blunt end and a frayed end, a blunt end and 5' overhang end, a blunt end and a 3' overhang end, a frayed end and a 5' overhang end, a frayed end and a 3' overhang end, two 5' overhang ends, two 3' overhang ends, a 5' overhang end and a 3' overhang end, two frayed ends, or two blunt ends.
- a nucleotide base is a heterocyclic pyrimidine or purine compound which is a constituent of all nucleic acids and includes adenine (A), guanine (G), cytosine (C), thymine (T), and uracil (U).
- nucleotide can include a modified nucleotide or nucleotide mimic, abasic site (Ab or X), or a surrogate replacement moiety.
- an LPA RNAi agent is prepared or provided as a salt, mixed salt, or a free-acid.
- an LPA RNAi agent contains one or more modified nucleotides.
- a "modified nucleotide” is a nucleotide other than a ribonucleotide (2'-hydroxyl nucleotide). In some embodiments, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the nucleotides are modified.
- Modified nucleotides include, but are not limited to, deoxynucleotides, nucleotide mimics, abasic nucleotides (represented herein as X, Ab), 2'-modified nucleotides, 3' to 3' linkages (inverted) nucleotides (represented herein as invdN, invN, invn, invX, invAb, non-natural base-comprising nucleotides, bridged nucleotides, peptide nucleic acids (PNAs), 2',3'-seco nucleotide mimics (unlocked nucleobase analogues, represented herein as NU A or NUNA), locked nucleotides (represented herein as NLNA or NLNA), 3'-0-Methoxy (2' intemucleoside linked) nucleotides (represented herein as 3'-OMen), 2'-F-Arabino nucleotides (represented herein as NfANA or WANA),
- 2'-modified nucleotides include, but are not limited to, 2'-0-methyl nucleotides (represented herein as a lower case letter 'n' in a nucleotide sequence), 2'-deoxy-2'-fluoro nucleotides (represented herein as Nf, also represented herein as 2'-fluoro nucleotide), 2'-deoxy nucleotides (represented herein as dN), 2'-methoxy ethyl (2'-0-2-methoxylethyl) nucleotides (represented herein as NM or 2'-MOE), 2'-amino nucleotides, and 2'-alkyl nucleotides.
- 2'-0-methyl nucleotides represented herein as a lower case letter 'n' in a nucleotide sequence
- 2'-deoxy-2'-fluoro nucleotides represented herein as Nf, also represented herein as 2'-fluoro nucleot
- LPA RNAi agent sense strands and antisense strands may be synthesized and/or modified by methods known in the art. Modification at one nucleotide is independent of modification at another nucleotide.
- Modified nucleotides also include nucleotides having modified nucleobases.
- Modified nucleobases include, but are not limited to, synthetic and natural nucleobases, 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine, 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2- thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and th
- one or more nucleotides of an LPA RNAi agent are linked by nonstandard linkages or backbones (i.e. modified intemucleoside linkages or modified backbones).
- a modified intemucleoside linkage is a non-phosphate-containing covalent intemucleoside linkage.
- Modified intemucleoside linkages or backbones include, but are not limited to, 5'-phosphorothioate group (represented herein as a lower case 's' before a nucleotide, as in sN, sn, sNf, or sdN), chiral phosphorothioates, thiophosphate, phosphorodithioates, phosphotriesters, aminoalkyl-phosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphorami dates including 3 '-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkyl-phosphonates, thionoalkylphosphotriesters, morpholino linkages, and boranophosphates having normal 3'-5' linkages, 2'-5' linked analogs of these, and those having inverted polarity
- a modified intemucleoside linkage or backbone lacks a phosphorus atom.
- Modified intemucleoside linkages lacking a phosphorus atom include, but are not limited to, short chain alkyl or cycloalkyl inter-sugar linkages, mixed heteroatom and alkyl or cycloalkyl inter-sugar linkages, or one or more short chain heteroatomic or heterocyclic inter-sugar linkages.
- modified intemucleoside backbones include, but are not limited to, siloxane backbones, sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones, methylene formacetyl and thioformacetyl backbones, alkene containing backbones, sulfamate backbones, methyleneimino and methylenehydrazino backbones, sulfonate and sulfonamide backbones, amide backbones; and others having mixed N, O, S, and CH2 component parts.
- a sense strand of an LPA RNAi agent can contain 1, 2, 3, 4 phosphorothioate linkages
- an antisense strand of an LPA RNAi agent can contain 1, 2, 3, or 4 phosphorothioate linkages
- both the sense strand and the antisense strand independently can contain 1, 2, 3, or 4 phosphorothioate linkages.
- an LPA RNAi agent sense strand contains two phosphorothioate intemucleoside linkages.
- the two phosphorothioate internucleoside linkages are between the nucleotides at positions 1 -3 from the 3' end of the sense strand.
- the two phosphorothioate internucleoside linkages are between the nucleotides at positions 1 -3, 2-4, 3-5, 4-6, 4-5, or 6-8 from the 5' end of the sense strand.
- an LPA RNAi agent antisense strand contains four phosphorothioate internucleoside linkages.
- the four phosphorothioate internucleoside linkages are between the nucleotides at positions 1 -3 from the 5' end of the sense strand and between the nucleotides at positions 19-21, 20-22, 21-23, 22-24, 23-25, or 24-26 from the 5' end.
- an LPA RNAi agent contains two phosphorothioate internucleoside linkages in the sense strand and four phosphorothioate internucleoside linkages in the antisense strand.
- an LPA RNAi agent contains one or more modified nucleotides and one or more modified internucleoside linkages. In some embodiments, a 2'-modified nucleotide is combined with modified internucleoside linkage.
- vpdN vinyl phosphonate deoxyribonucleotide
- Each sense strand and/or antisense strand can have any of the above indicated targeting groups or linking groups, as well as other targeting or linking groups, conjugated to the 5' and or 3' end of the sequence.
- the chemical structures for these groups are provided in Table 4.
- LP RNAi agent antisense strands having modified nucleotides.
- AM03824-AS usCfsgUf ANA a UfaAfCfAfauaAfgGfgGfcUfgcscsuAu 679 156 AM03825-AS usCfsgUfaUf ANA aAfCfAfauaAfgGfgGfcUfgcscsuAu 680 156
- AM01181-SS Af cAf cAf a U f gCf u Cf a Gf a Cf gCf a Af ( i n vdT) 857 198
- AM01224-SS AfgAfa UfaCfuAfcCfcAfaAfuGfgAf(invdT) 900 241
- AM01225-SS AfaUfaCfuAfcCfcAfaAfuGfgUfgAf(invdT) 901 242 AM01226-SS Af u Af c Uf a Cf cCf a Af a UfgGf u GfgAf ( i n vdT) 902 243
- AM01229-SS Af uAfcCfa UfgGfa UfcCf cAfgUfgAf ( in vdT) 905 246
- AM01231-SS Af aGf a Af cAf u Gf u Cf a Gf u Cf u UfgAf ( i n vdT) 907 248
- AM02236-SS AfcAfgAfaUfCfAfgGfuGfuCfcUfaAf(invdT) 963 304
- AM03030-SS (Stearyl)uAuAusCfsaGfaAfaCfaGfAfAfuCfaGfgUfgUfcAf(Cll-PEG3-NAG3) 1026 309
- AM03880-SS (NAG4)uscaGfcCfcCfu UfAfUfuGfu UfaUfaCfgsa(invAb) 1116 355
- AM03881-SS (NAG24)uscaGfcCfcCfu UfAfUfuGfuUfa UfaCfgausu(invAb) 1117 354
- AM03882-SS (NAG4)usaguuaucgAfGfGfcucauucucausu(invAb) 1118 356
- AM04138-SS (NAG25)uauausasguuaucgAfGfGfcucauucuc(invdA) 1123 308
- AM04152-SS Alk-PEG5-C6uauausasguuaucgAfGfGfcucauucuCM(invdA) 1124 308
- AM04214-SS Alk-SM PT-C6uauausasguuaucgAfGfGfcucauucuCM(in dA) 1125 308
- AM04233-SS (NAG26)uauausasguuaucgAfGfGfcucauucuCM(invdA) 1126 308
- AM04372-SS (NAG27)uauausasguuaucgAfGfGfcucauucuCM(invdA) 1127 308
- AM04381-SS (NAG25)auauscsagccccu L)fAfUfuguuauacga(invdT) 1128 358
- AM04382-SS (NAG25)uauscsagccccu L)fAfUfuguuauacgau(in dT) 1129 359
- AM04391-SS (NAG25 auausasguuaucgAfGfGfcucauucuca(invdT) 1130 360
- AM04392-SS (NAG25 uausasguuaucgAfGfGfcucauucucau(invdT) 1131 361
- AM04412-SS (NAG25 uauauscsagccccuL)fAfUfuguuauacg(invdA) 1132 310
- AM04416-SS (NAG25 (invAb)uuaucgAfGfGfcucauucucausu(in Ab) 1134 362
- AM04496-SS (NAG25 (invAb)GfcCfcCfu UfAfUfuGfu UfaUfaCfgausu(invAb) 1135 357
- AM04497-SS (NAG29 uauausasguuaucgAfGfGfcucauucuc(invdA) 1136 308
- AM04498-SS (NAG29 uauauaasuuaucgaGfGfcucauucucsa(invAb) 1138 363
- AM04500-SS (NAG30 (invAb)GfcCfcCfu UfAfUfuGfu UfaUfaCfgausu(invAb) 1139 357
- AM04502-SS (NAG25 uauauaasuuaucgaGfGfcucauucucsa(invAb) 1140 363
- AM04535-SS (NAG25 uauaucsasgccccuL)fAfUfuguuauacg(invdA) 1141 310
- AM04536-SS (NAG25 uauaucasgccccuL)fAfUfuguuauacg(invdA) 1142 310
- AM04537-SS (NAG25 uauauasgsuuaucgAfGfGfcucauucuc(invdA) 1143 308
- AM04538-SS (NAG25 uauauagsuuaucgAfGfGfcucauucuc(invdA) 1144 308
- AM04543-SS (NAG30 u scaGf cCf cCf u Uf Af Uf u Gf u Ufa Ufa Cfgsa ( i n vAb) 1145 355
- AM04578-SS (NAG25 ggcsagccccu UfAfUfuguuauacgAMs(invdT)dT 1146 364
- AM04588-SS (NAG25 ggcsagccccu UfAfUfuguuauacgAMsuu(in dT) 1147 365
- AM04579-SS (NAG25 Gu NA gcsagccccuUfAfUfuguuauacgAMs(in dT)dT 1148 364
- AM04580-SS (NAG25 ggcs(invdA)gccccu UfAfUfuguuauacgAMs(invdT)dT 1149 364
- AM04581-SS (NAG25 csagccccuUfAfUfuguuauacgAMs(invdT)dTdTdT 1150 366
- AM04611-SS (NAG31 (invAb)GfcCfcCfu UfAfUfuGfu UfaUfaCfgausu(invAb) 1151 357
- AM04612-SS (NAG32 (invAb)GfcCfcCfu UfAfUfuGfu UfaUfaCfgausu(invAb) 1152 357
- AM04669-SS (NAG25 uauauagsusuaucgAfGfGfcucauucuc(invdA) 1153 308
- AM04670-SS (NAG25 uauauagususaucgAfGfGfcucauucuc(invdA) 1154 308
- AM04671-SS (NAG25 gcgausasguuaucgAfGfGfcucauucuc(invdA) 1155 367
- AM04672-SS (NAG25 ugaausasguuaucgAfGfGfcucauucuc(invdA) 1156 368
- AM04673-SS (NAG25 aucgusasguuaucgAfGfGfcucauucuc(invdA) 1157 369
- AM04674-SS (NAG25 u(invdA)uausasguuaucgAfGfGfcucauucuc(invdA) 1158 308
- AM04675-SS (NAG25 uaua(invdA)sasguuaucgAfGfGfcucauucuc(in dA) 1159 370
- AM04676-SS (NAG25 uauaus(invdA)sguuaucgAfGfGfcucauucuc(invdA) 1160 308
- AM04726-SS (NAG30 aGfcCfcCfuUfAfUfuGfuUfa UfaCfgsa(invAb) 1161 371
- AM04727-SS (NAG30 aaGfcCfcCfu UfAfUfuGfu UfaUfaCfgsa(invAb) 1162 372
- AM04728-SS (NAG30 sasGfcCfcCfu UfAfUfuGfu UfaUfaCfgas(invAb) 1163 371
- AM04729-SS (NAG30 gscaGfcCfcCfuUfAfUfuGfuUfa UfaCfgsa(invAb) 1164 373
- AM04737-SS (NAG25 uauauagsuuaucgaGfGfcucauucucsa(in Ab) 1165 374
- AM04741-SS (NAG30 sgscaGfcCfcCfuUfAfUfuGfuUfa UfaCfgsa(invAb) 1166 373
- AM04742-SS (NAG33 (invAb)GfcCfcCfu UfAfUfuGfu UfaUfaCfgausu(invAb) 1167 357
- AM04744-SS (NAG35 (invAb)GfcCfcCfu UfAfUfuGfu UfaUfaCfgausu(invAb) 1169 357
- AM04803-SS (NAG30 acGfcCfcCfuUfAfUfuGfu Ufa UfaCfgsa(invAb) 1170 375
- AM04804-SS (NAG30 sasaGfcCfcCfu UfAfUfuGfu Ufa UfaCfgas(invAb) 1171 372
- AM04807-SS (NAG30 sascGfcCfcCfu UfAfUfuGfu UfaUfaCfgas(invAb) 1172 375
- AM04806-SS (NAG30 sgscaGfcCfcCfu UfAfUfuGfu Ufa UfaCfgas(invAb) 1173 373
- AM04808-SS (NAG31 sGfcCfcCfuUfAfUfuGfuUfa UfaCfgausu(invAb) 1174 376
- AM04809-SS (NAG31 saGfcCfcCfu UfAfUfuGfuUfa UfaCfgausu(invAb) 1175 377
- AM04810-SS (NAG31)sasaGfcCfcCfu UfAfUfuGfu Ufa UfaCfgas(invAb) 1176 372
- AM04811-SS (NAG31)sasaGfcCfcCfu UfAfUfuGfu Ufa UfaCfgausu(invAb) 1177 378
- AM04812-SS (NAG31)sasaGfcCfcCfuUfAfUfuGfu Ufa UfaCfg(invdA)usu(invAb) 1178 378
- AM04813-SS (NAG31)uauausasguuaucgAfGfGfcucauucuc(invdA) 1179 308
- AM04817-SS (NAG31)uagscsagccccu L)fAfUfuguuauacgs(invdA) 1181 380
- AM04820-SS (NAG31)sgscagccccu L)fAfUfuguuauacgsa(invAb) 1184 373
- AM04862-SS (NAG25)auaagasguuaucgAfGfGfcucauucuc(invdA) 1185 382
- AM04863-SS (NAG25)auaagsasguuaucgAfGfGfcucauucuc(invdA) 1186 382
- AM04868-SS (NAG25)sgsccccuL)fAfUfuguuauacgauus(invAb) 1191 376
- AM05072-SS (NAG25)(invAb)GfcCfcCf(NOTA-dT)UfAfUfuGfu UfaUfaCfgausu(invAb) 1196 1241
- a sense strand containing a sequence listed in Table 2B can be hybridized to any antisense strand containing a sequence listed in Table 2A provided the two sequences have a region of at least 90% complementarity over a contiguous 16, 17, 18, 19, 20, or 21 nucleotide sequence.
- Representative LPA RNAi agents are represented by the Duplex ID Nos. shown in Tables 3A and 3B.
- an LPA RNAi agent comprises of any of the Duplex ID Nos. presented herein. In some embodiments an LPA RNAi agent consists of any of the Duplex ID Nos. presented herein. In some embodiments, an LPA RNAi agent comprises the sense strand and antisense strand nucleotide sequences of any of the Duplex ID Nos. presented herein. In some embodiments, an LPA RNAi agent comprises the sense strand and antisense strand nucleotide sequences of any of the Duplex ID Nos. presented herein and a targeting group and/or linking group wherein the targeting group and/or linking group is covalently linked (i.e. conjugated) to the sense strand or the antisense strand.
- an LPA RNAi agent comprises the sense strand and antisense strand modified nucleotide sequences of any of the Duplex ID Nos. presented herein. In some embodiments, an LPA RNAi agent comprises the sense strand and antisense strand modified nucleotide sequences of any of the Duplex ID Nos. presented herein and a targeting group and/or linking group wherein the targeting group and/or linking group is covalently linked to the sense strand or the antisense strand.
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7718133B2 (en) | 2003-10-09 | 2010-05-18 | 3M Innovative Properties Company | Multilayer processing devices and methods |
WO2017156012A1 (en) * | 2016-03-07 | 2017-09-14 | Arrowhead Pharmaceuticals, Inc. | Targeting ligands for therapeutic compounds |
EP3506913A4 (en) * | 2016-09-02 | 2020-06-10 | Arrowhead Pharmaceuticals, Inc. | Targeting ligands |
TN2020000039A1 (en) * | 2017-09-11 | 2021-10-04 | Arrowhead Pharmaceuticals Inc | Rnai agents and compositions for inhibiting expression of apolipoprotein c-iii (apoc3) |
WO2019079294A1 (en) * | 2017-10-17 | 2019-04-25 | Arrowhead Pharmaceuticals, Inc. | Rnai agents and compositions for inhibiting expression of asialoglycoprotein receptor 1 |
CA3109553A1 (en) * | 2018-09-19 | 2020-03-26 | Arrowhead Pharmaceuticals, Inc. | Rnai agents for inhibiting expression of 17beta-hsd type 13 (hsd17b13), compositions thereof, and methods of use |
WO2022121959A1 (en) * | 2020-12-09 | 2022-06-16 | 纳肽得有限公司 | Sirna molecule and application thereof in treatment of coronary artery diseases |
EP4237561A1 (en) | 2020-12-23 | 2023-09-06 | Argonaute Rna Limited | Treatment of cardiovascular disease |
US11649260B2 (en) | 2021-06-18 | 2023-05-16 | Hongene Biotech Corporation | Functionalized N-acetylgalactosamine nucleosides |
US11692001B2 (en) | 2021-08-30 | 2023-07-04 | Hongene Biotech Corporation | Functionalized n-acetylgalactosamine analogs |
EP4402263A2 (en) | 2021-09-14 | 2024-07-24 | Argonaute Rna Limited | Treatment of cardiovascular disease |
CN116801886A (en) * | 2021-09-18 | 2023-09-22 | 上海金中锘美生物医药科技有限公司 | LPA inhibitors and uses thereof |
WO2023114746A1 (en) | 2021-12-15 | 2023-06-22 | Hongene Biotech Corporation | Functionalized n-acetylgalactosamine analogs |
CN114703184B (en) * | 2022-03-11 | 2024-06-18 | 厦门甘宝利生物医药有限公司 | LPA inhibitors and uses thereof |
WO2024032681A1 (en) * | 2022-08-11 | 2024-02-15 | 益杰立科(上海)生物科技有限公司 | Method for epitope editing target and use |
CN115851723B (en) * | 2022-10-24 | 2023-10-03 | 厦门甘宝利生物医药有限公司 | RNA inhibitor for inhibiting LPA gene expression and application thereof |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL9201440A (en) | 1992-08-11 | 1994-03-01 | Univ Leiden | Triantennary cluster glycosides, their preparation and application. |
US5599706A (en) | 1994-09-23 | 1997-02-04 | Stinchcomb; Dan T. | Ribozymes targeted to apo(a) mRNA |
ATE408699T1 (en) | 1999-03-10 | 2008-10-15 | Phogen Ltd | ADMINISTRATION OF NUCLEIC ACIDS AND PROTEINS TO CELLS |
CZ302719B6 (en) * | 2000-12-01 | 2011-09-21 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Isolated double-stranded RNA molecule, process for its preparation and use |
US7259150B2 (en) | 2001-08-07 | 2007-08-21 | Isis Pharmaceuticals, Inc. | Modulation of apolipoprotein (a) expression |
US7227014B2 (en) | 2001-08-07 | 2007-06-05 | Isis Pharmaceuticals, Inc. | Antisense modulation of apolipoprotein (a) expression |
JP2006523209A (en) | 2003-03-12 | 2006-10-12 | アリゾナ ボード オブ リージェンツ オン ビハーフ オブ ザ ユニバーシティー オブ アリゾナ | Method for modulating angiogenesis by an apelin composition |
US8084599B2 (en) | 2004-03-15 | 2011-12-27 | City Of Hope | Methods and compositions for the specific inhibition of gene expression by double-stranded RNA |
EP2061443A4 (en) | 2006-08-18 | 2013-07-24 | Arrowhead Res Corp | Polyconjugates for in vivo delivery of polynucleotides |
CA3151965A1 (en) | 2008-12-18 | 2010-07-15 | Dicerna Pharmaceuticals, Inc. | Extended dicer substrate agents and methods for the specific inhibition of gene expression |
US20100249214A1 (en) | 2009-02-11 | 2010-09-30 | Dicerna Pharmaceuticals | Multiplex dicer substrate rna interference molecules having joining sequences |
SG183374A1 (en) | 2010-02-24 | 2012-09-27 | Arrowhead Res Corp | Compositions for targeted delivery of sirna |
WO2011141703A1 (en) * | 2010-05-12 | 2011-11-17 | Protiva Biotherapeutics Inc. | Compositions and methods for silencing apolipoprotein b |
US8501930B2 (en) * | 2010-12-17 | 2013-08-06 | Arrowhead Madison Inc. | Peptide-based in vivo siRNA delivery system |
JP2014504295A (en) | 2010-12-17 | 2014-02-20 | アローヘッド リサーチ コーポレイション | galactose cluster for siRNA-pharmacokinetic modulator targeting moiety |
PE20140198A1 (en) | 2010-12-29 | 2014-02-21 | Arrowhead Res Corp | IN VIVO POLYNUCLEOTIDE DELIVERY CONJUGATES HAVING ENZYME SENSITIVE COUPLINGS |
KR20140051357A (en) | 2011-08-26 | 2014-04-30 | 애로우헤드 리서치 코오포레이션 | Poly(vinyl ester) polymers for in vivo nucleic acid delivery |
SI3301177T1 (en) * | 2011-11-18 | 2020-07-31 | Alnylam Pharmaceuticals, Inc. | Rnai agents, compositions and methods of use thereof for treating transthyretin (ttr) associated diseases |
US8933047B2 (en) | 2012-04-18 | 2015-01-13 | Arrowhead Madison Inc. | Poly(acrylate) polymers for in vivo nucleic acid delivery |
DK2855500T3 (en) | 2012-05-24 | 2020-09-14 | Ionis Pharmaceuticals Inc | Methods and compositions for modulating apolipoprotein (A) expression |
RU2650510C2 (en) | 2013-05-01 | 2018-04-16 | Ионис Фармасьютикалз, Инк. | Compositions and methods of modulating apolipoprotein c-iii expression |
US20160272970A1 (en) | 2015-03-17 | 2016-09-22 | Arrowhead Madison Inc. | RNA Interference Agents |
EA201792103A1 (en) | 2015-05-29 | 2018-06-29 | Эрроухэд Фармасьютикалз, Инк. | COMPOSITIONS AND METHODS FOR INHIBITING EXPRESSION OF HIF2ALPH GENES |
CN108138182B (en) * | 2015-07-31 | 2022-08-19 | 阿尔尼拉姆医药品有限公司 | Transthyretin (TTR) iRNA compositions and methods of use thereof to treat or prevent TTR-associated diseases |
WO2017156012A1 (en) | 2016-03-07 | 2017-09-14 | Arrowhead Pharmaceuticals, Inc. | Targeting ligands for therapeutic compounds |
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