Complement component C3 iRNA compositions and methods of use thereof for treating or preventing complement component C3-associated diseases
The present invention provides iRNA agents, e.g., double stranded iRNA agents, that target the complement component C3 gene and methods of using such iRNA agents for treating or preventing C3-associated ocular diseases or C3-associated neurodegenerative diseases.
1 . A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C3, or a salt thereof,
wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein each strand is no more than 30 nucleotides in length,
wherein the sense strand comprises a nucleotide sequence comprising at least 17 contiguous nucleotides from the nucleotide sequence 5′-GAGCCGUUCUCUACAAUUACU-3′ of SEQ ID NO:471, and the antisense strand comprises a nucleotide sequence comprising at least 17 contiguous nucleotides from the nucleotide sequence 5′-AGUAAUUGUAGAGAACGGCUCGG-3′ of SEQ ID NO:496, and
wherein one or more lipophilic moieties are conjugated to one or more internal positions on the sense strand.
2 . The dsRNA agent, or salt thereof, of claim 1 , wherein at least one nucleotide of the dsRNA agent comprises a nucleotide modification.
3 . The dsRNA agent, or a salt thereof, of claim 2 , wherein at least one of the nucleotide modifications is selected from the group consisting of a deoxy-nucleotide modification, a 3′-terminal deoxythymidine (dT) nucleotide modification, a 2′-O-methyl modified nucleotide modification, a 2′-fluoro modified nucleotide modification, a 2′-deoxy-modified nucleotide modification, a locked nucleotide modification, an unlocked nucleotide modification, a conformationally restricted nucleotide modification, a constrained ethyl nucleotide modification, an abasic nucleotide modification, a 2′-amino-nucleotide modification, a 2′-O-allyl nucleotide modification, 2′-C-alkyl-nucleotide modification, a 2′-methoxyethyl nucleotide modification, a 2′-O-alkyl nucleotide modification, a morpholino nucleotide modification, a phosphoramidate nucleotide modification, a non-natural base comprising nucleotide modification, a tetrahydropyran nucleotide modification, a 1,5-anhydrohexitol nucleotide modification, a cyclohexenyl nucleotide modification, a 5′ phosphate or 5′ phosphate mimic nucleotide modification, a vinyl phosphonate nucleotide modification, an adenosine-glycol nucleic acid (GNA) nucleotide modification, a thymidine-glycol nucleic acid (GNA) S-Isomer nucleotide modification, a 2-hydroxymethyl-tetrahydrofurane-5-phosphate nucleotide modification, a 2′-deoxythymidine-3′phosphate nucleotide modification, a 2′-deoxyguanosine-3′-phosphate nucleotide modification, and a nucleotide modification wherein a terminal nucleotide is linked to a cholesteryl derivative and a dodecanoic acid bisdecylamide group; and combinations thereof.
4 . The dsRNA agent, or a salt thereof, of claim 3 , further comprising at least one phosphorothioate internucleotide linkage.
5 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the internal positions exclude a cleavage site region of the sense strand.
6 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the one or more lipophilic moieties are conjugated to one or more of the internal positions selected from the group consisting of positions 5, 6, 7, 15, and 17 on the sense strand counting from the 5′ end.
7 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the lipophilic moiety contains a saturated or unsaturated C4-C30 hydrocarbon chain, and an optional functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne.
8 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the lipophilic moiety is conjugated via a carrier that replaces one or more nucleotide(s) in the internal position(s) or the double stranded region.
9 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the lipophilic moiety is conjugated to a nucleobase, sugar moiety, or internucleosidic linkage.
10 . The dsRNA agent, or a salt thereof, of claim 1 , further comprising a phosphate or phosphate mimic at the 5′-end of the antisense strand.
11 . An isolated cell containing the dsRNA agent, or salt thereof, of claim 1 .
12 . A pharmaceutical composition for inhibiting expression of a gene encoding C3, comprising the dsRNA agent, or salt thereof, of claim 1 .
13 . A method of inhibiting expression of a complement component C3 gene in a cell, the method comprising:
(a) contacting the cell with the dsRNA agent, or salt thereof, of claim 1 ; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of the complement component C3 gene, thereby inhibiting expression of the complement component C3 gene in the cell.
14 . A method of treating a subject diagnosed with a complement component C3-associated neurodegenerative disease, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent, or salt thereof, of claim 1 , thereby treating the subject, wherein the complement component C3-associated neurodegenerative disease is selected from the group consisting of Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Parkinson's disease (PD), and Creutzfeldt-Jakob disease (CJD).
15 . The method of claim 14 , wherein the subject is human.
16 . The method of claim 14 , wherein the dsRNA agent, or salt thereof, is administered to the subject intrathecally.
17 . A method of treating a subject having a disorder that would benefit from reduction in complement component C3 expression in an ocular tissue, comprising administering to the subject a therapeutically effective amount of the dsRNA agent, or salt thereof, of claim 1 , thereby treating the subject having the disorder that would benefit from reduction in complement component C3 expression, wherein the disorder that would benefit from reduction in complement component C3 expression in an ocular tissue is selected from the group consisting of dry macular degeneration, wet macular degeneration, Basal Laminar drusen, diabetic retinopathy, diabetic macular edema, and retinal vein occlusion.
18 . A kit comprising the dsRNA agent, or salt thereof, of claim 1 .