US 12,729,377 B2 · RNAi agents and compositions for inhibiting expression of angiopoietin-like 3 (ANGPTL3), and methods of use

Abstract

The present disclosure relates to RNAi agents, e.g., double stranded RNAi agents, able to inhibit Angiopoietin-like 3 (also called ANGPTL3, ANGPL3, angiopoietin-like protein 3) gene expression, and compositions that include ANGPTL3 RNAi agents. Also disclosed are methods of use of ANGPTL3 RNAi agents and compositions. The ANGPTL3 RNAi agents disclosed herein may be conjugated to targeting ligands to facilitate the delivery to cells, including to hepatocytes. Pharmaceutical compositions that include one or more ANGPTL3 RNAi agents, optionally with one or more additional therapeutics, are described. Delivery of the ANGPTL3 RNAi agents in vivo provides for inhibition of ANGPTL3 gene expression, and can result in lower triglycerides and/or cholesterol levels in the subject. The RNAi agents can be used in methods of treatment of ANGPTL3-related diseases and disorders, including cardiometabolic diseases such as hypertriglyceridemia and hyperlipidemia.

Claims24

Dependent claims

An RNAi agent for inhibiting expression of an ANGPTL3 gene, comprising an antisense strand and a sense strand, wherein the antisense strand is 21 nucleotides in length and comprises the modified nucleotide sequence (5′→3′):

usAfscsUfgAfuCfaAfaUfaUfgUfuGfaGfsc (SEQ ID NO:2);
and
the sense strand is 21 nucleotides in length and comprises the modified nucleotide sequence (5′→3′):
gcucaacaUfa_2NUfuugaucagua (SEQ ID NO:18);
wherein a represents 2′-O-methyl adenosine, c represents 2′-O-methyl cytidine, g represents 2′-O-methyl guanosine, u represents 2′-O-methyl uridine, Af represents 2′-fluoro adenosine, Cf represents 2′-fluoro cytidine, Gf represents 2′-fluoro guanosine, Uf represents 2′-fluoro uridine, a 2N represents 2′-O-methyl-2-aminoadenosine, and s represents a phosphorothioate linkage;
and wherein the sense strand of the RNAi agent is linked to a targeting ligand comprising N-acetyl-galactosamine.

3 more elements

Dependencies are inferred from the claim text.

RNAi agents and compositions for inhibiting expression of angiopoietin-like 3 (ANGPTL3), and methods of use

Life of this patent

RNAi agents and compositions for inhibiting expression of angiopoietin-like 3 (ANGPTL3), and methods of use

Life of this patent

Abstract

Claims24