Abstract: One aspect of the present invention relates to a double stranded iRNA agent comprising an antisense strand which is complementary to a target gene; a sense strand which is complementary to said antisense strand; and one or more lipophilic moieties conjugated to one or more internal positions on at least one strand, optionally via a linker or carrier. Another aspect of the invention relates to a method of gene silencing, comprising administering to a cell or a subject in need thereof a therapeutically effective amount of the lipophilic moieties-conjugated double-stranded iRNAs.

Abstract: One aspect of the present invention relates to a double stranded iRNA agent comprising an antisense strand which is complementary to a target gene; a sense strand which is complementary to said antisense strand; and one or more lipophilic moieties conjugated to one or more internal positions on at least one strand, optionally via a linker or carrier, which provides for targeting to, and uptake by, tissues and cells of the CNS, and in particular the striatum. Another aspect of the invention relates to a method of gene silencing in tissues and cells of the CNS, and in particular the striatum, that includes administering to a tissue/cell or a subject in need thereof a therapeutically effective amount of the lipophilic moieties-conjugated double-stranded iRNAs.

Abstract: Disclosed herein is a modular composition comprising 1) an oligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), which may be the same or different; optionally, 3) one or more linkers, which may be the same or different; 4) one or more peptides independently selected from Table 3, which may be the same or different; and optionally, 5) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.

Abstract: The invention relates to a method of gene silencing, comprising administering to a cell or a subject in need thereof a therapeutically effective amount of the lipophilic moieties-conjugated double-stranded iRNAs at one or more internal positions on at least one strand, optionally via a linker or carrier.

Abstract: Disclosed herein is a modular composition comprising 1) an oligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), which may be the same or different; optionally, 3) one or more linkers, which may be the same or different; 4) one or more peptides independently selected from Table 3, which may be the same or different; and optionally, 5) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.

Abstract: One aspect of the present invention relates to double-stranded RNA (dsRNA) agent capable of inhibiting the expression of a target gene. Other aspects of the invention relate to pharmaceutical compositions comprising these dsRNA molecules suitable for therapeutic use, and methods of inhibiting the expression of a target gene by administering these dsRNA molecules, e.g., for the treatment of various disease conditions.

Abstract: Disclosed herein is a method for inhibiting expression of a gene of a subject comprising administering (1) a composition comprising R-(L)a-(G)b; wherein R is an oligonucleotide selected from the group consisting of DNA, RNA, siRNA, and microRNA; L is a linker and each occurrence of L is independently selected from Table 3; G is a targeting ligand and each occurrence of G is independently selected from Table 4; each of a and b is independently 0, 1, 2, 3 or 4; and (2) a composition comprising (P)c-(L)d-(G)e; wherein P is a peptide and each occurrence of P is independently selected from Table 2; L is a linker and each occurrence of L is independently selected from Table 3; G is a targeting ligand and each occurrence of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6. Compositions in (1) and (2) can be co-administered or sequentially administered.

Abstract: Disclosed herein is a modular composition comprising 1) an oligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), which may be the same or different; optionally, 3) one or more linkers, which may be the same or different; 4) one or more peptides independently selected from Table 3, which may be the same or different; and optionally, 5) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.

Abstract: Disclosed herein is a peptide containing conjugate comprising (P)c-(L)d-(G)e, wherein P is a peptide and each occurance of P is independently selected from Table 2; L is an optional linker and each occurance of L, if present, is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6. The conjugate can be administered to a subject either alone or in combination with a composition comprising R-(L)a-(G)b, wherein R is an oligonucleotide as defined herein, to inhibit expression of a gene of the subject.

Abstract: Disclosed herein is a modular composition comprising 1) an oligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), which may be the same or different; optionally, 3) one or more linkers, which may be the same or different; 4) one or more peptides independently selected from Table 3, which may be the same or different; and optionally, 5) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.

Abstract: Disclosed herein is a method for inhibiting expression of a gene of a subject comprising administering (1) a composition comprising R-(L)a-(G)b; wherein R is an oligonucleotide selected from the group consisting of DNA, RNA, siRNA, and microRNA; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; each of a and b is independently 0, 1, 2, 3 or 4; and (2) a composition comprising (P)c-(L)d-(G)e; wherein P is a peptide and each occurance of P is independently selected from Table 2; L is a linker and each occurance of L is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6. Compositions in (1) and (2) can be co-administered or sequentially administered.

Abstract: Disclosed herein is a method for inhibiting expression of a gene of a subject comprising administering (1) a composition comprising R-(L)a-(G)b; wherein R is an oligonucleotide selected from the group consisting of DNA, RNA, siRNA, and microRNA; L is a linker and each occurrence of L is independently selected from Table 3; G is a targeting ligand and each occurrence of G is independently selected from Table 4; each of a and b is independently 0, 1, 2, 3 or 4; and (2) a composition comprising (P)c-(L)d-(G)e; wherein P is a peptide and each occurrence of P is independently selected from Table 2; L is a linker and each occurrence of L is independently selected from Table 3; G is a targeting ligand and each occurrence of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6. Compositions in (1) and (2) can be co-administered or sequentially administered.

Abstract: Disclosed herein is a modular composition comprising 1) an oligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), which may be the same or different; optionally, 3) one or more linkers, which may be the same or different; 4) one or more peptides independently selected from Table 3, which may be the same or different; and optionally, 5) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.

Abstract: Disclosed herein is a modular composition comprising 1) an oligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), which may be the same or different; optionally, 3) one or more linkers, which may be the same or different; 4) one or more peptides independently selected from Table 3, which may be the same or different; and optionally, 5) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.

Abstract: Disclosed herein is a modular composition comprising 1) an oligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), which may be the same or different; optionally, 3) one or more linkers, which may be the same or different; 4) one or more peptides independently selected from Table 3, which may be the same or different; and optionally, 5) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.

Abstract: Disclosed herein is a method for inhibiting expression of a gene of a subject comprising administering (1) a composition comprising R-(L)a-(G)b; wherein R is an oligonucleotide selected from the group consisting of DNA, RNA, siRNA, and microRNA; L is a linker and each occurrence of L is independently selected from Table 3; G is a targeting ligand and each occurrence of G is independently selected from Table 4; each of a and b is independently 0, 1, 2, 3 or 4; and (2) a composition comprising (P)c-(L)d-(G)e; wherein P is a peptide and each occurrence of P is independently selected from Table 2; L is a linker and each occurrence of L is independently selected from Table 3; G is a targeting ligand and each occurrence of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6. Compositions in (1) and (2) can be co-administered or sequentially administered.

Abstract: Disclosed herein is a modular composition comprising 1) an oligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), which may be the same or different; optionally, 3) one or more linkers, which may be the same or different; 4) one or more peptides independently selected from Table 3, which may be the same or different; and optionally, 5) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.

Abstract: Disclosed herein is a peptide containing conjugate comprising (P)c-(L)d-(G)e, wherein P is a peptide and each occurance of P is independently selected from Table 2; L is an optional linker and each occurance of L, if present, is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6. The conjugate can be administered to a subject either alone or in combination with a composition comprising R-(L)a-(G)b, wherein R is an oligonucleotide as defined herein, to inhibit expression of a gene of the subject.

Abstract: The present invention provides membrane lytic poly(amido amine) polymers, polyconjugates, compositions and methods for the delivery of oligonucleotides for therapeutic purposes.

Abstract: Disclosed herein is a modular composition comprising 1) an oligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), which may be the same or different; optionally, 3) one or more linkers, which may be the same or different; 4) one or more peptides independently selected from Table 3, which may be the same or different; and optionally, 5) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.