COMPLEMENT COMPONENT C5 iRNA COMPOSITIONS AND METHODS OF USE
The invention relates to iRNA, e.g., double-stranded ribonucleic acid (dsRNA), compositions targeting the complement component C5 gene, and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of C5 and to treat subjects having a complement component C5-associated disease, e.g., Alzheimer's disease, atherosclerosis, or inflammation of the choroid plexus (ChP).
1 . A double-stranded ribonucleic acid (dsRNA) agent for use in inhibiting expression of complement component C5 for the prevention or treatment of Alzheimer's disease, atherosclerosis, or inflammation of the choroid plexus (ChP), wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the nucleotide sequence of the sense strand comprises 5′-UGACAAAAUAACUCACUAUAA-3′ and the nucleotide sequence of the antisense strand comprises 5′-UUAUAGUGAGUUAUUUUGUCAAU-3′, wherein substantially all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a modification.
2 . (canceled)
3 . The dsRNA agent of claim 1 , wherein substantially all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a modification.
4 . The dsRNA agent of claim 3 , wherein substantially all of the nucleotides of the sense strand are modified nucleotides selected from the group consisting of a 2′-O-methyl modification, a 2′-fluoro modification, and a 3′-terminal deoxy-thymine (dT) nucleotide.
5 . The dsRNA agent of claim 4 , wherein all of the nucleotides of the sense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification, a 2′-fluoro modification, and a 3′-terminal deoxy-thymine (dT) nucleotide.
6 . The dsRNA agent of claim 3 , wherein all of the nucleotides of the antisense strand are modified nucleotides selected from the group consisting of a 2′-O-methyl modification, a 2′-fluoro modification, and a 3′-terminal deoxy-thymine (dT) nucleotide
7 . The dsRNA agent of claim 1 , wherein the sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus, and the antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus.
8 . The dsRNA agent of claim 1 , wherein the sense strand is conjugated to a ligand comprising one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3′-terminus.
9 . (canceled)
10 . (canceled)
11 . (canceled)
12 . The dsRNA agent of claim 1 , wherein each strand is independently 21-30 nucleotides in length.
13 . (canceled)
14 . (canceled)
15 . The dsRNA agent of claim 8 , wherein the ligand is
16 . The dsRNA agent of claim 15 , wherein the sense strand is conjugated to the ligand as shown in the following schematic
and, wherein X is O or S.
17 . The dsRNA agent of claim 16 , wherein X is O.
18 . A pharmaceutical composition for use in preventing or treating Alzheimer's disease, atherosclerosis, or inflammation of the choroid plexus (ChP), comprising a double-stranded ribonucleic acid (dsRNA) agent which inhibits expression of complement component C5, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the nucleotide sequence of the sense strand comprises 5′-UGACAAAAUAACUCACUAUAA-3′ and the nucleotide sequence of the antisense strand comprises 5′-UUAUAGUGAGUUAUUUUGUCAAU-3′.
19 . The pharmaceutical composition of claim 18 , wherein the pharmaceutical composition is formulated for subcutaneous administration.
20 - 25 . (canceled)
26 . A method of preventing or treating Alzheimer's disease, atherosclerosis, or inflammation of the choroid plexus (ChP) in a subject, comprising administering to the subject an effective amount of a double-stranded ribonucleic acid (dsRNA) agent which inhibits expression of complement component C5, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the nucleotide sequence of the sense strand comprises 5′-UGACAAAAUAACUCACUAUAA-3′ and the nucleotide sequence of the antisense strand comprises 5′-UUAUAGUGAGUUAUUUUGUCAAU-3′, thereby preventing or treating the subject having Alzheimer's disease, atherosclerosis, or inflammation of the choroid plexus (ChP).
27 . The method of claim 26 , wherein the dsRNA agent is administered subcutaneously.
28 . The method of claim 26 or 27 , wherein the subject is human.
29 - 33 . (canceled)