RNAi agents for inhibiting expression of PNPLA3, pharmaceutical compositions thereof, and methods of use
Inventors
Nicholas, Anthony • Pei, Tao • XU, Zhao • Schienebeck, Casi • Ding, Zhi-Ming
Assignees
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Publication Number
US-12054718-B2
Publication Date
2024-08-06
Expiration Date
Abstract
Described are RNAi agents, e.g., double stranded RNAi agents, for inhibiting patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene expression. Also disclosed are pharmaceutical compositions that include PNPLA3 RNAi agents and methods of use thereof. The PNPLA3 RNAi agents disclosed herein may be conjugated to targeting ligands to facilitate the delivery to cells, including to hepatocytes. Delivery of the PNPLA3 RNAi agents in vivo provides for inhibition of PNPLA3 gene expression. The RNAi agents can be used in methods of treatment of PNPLA3-related diseases and disorders, including non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatic fibrosis, and alcoholic or non-alcoholic liver diseases, including cirrhosis.
Core Innovation
The invention relates to an RNAi agent for inhibiting expression of a PNPLA3 gene. The agent comprises an antisense strand comprising SEQ ID NO: 95 and a sense strand that is at least partially complementary to the antisense strand, and nucleotides 1-19 are complementary to a PNPLA3 mRNA region comprising nucleotides 2180-2198 of SEQ ID NO: 1.
The antisense strand incorporates specific nucleotide modifications and linkage chemistry. The symbols a, g, and u represent 2′-O-methyl adenosine, 2′-O-methyl guanosine, and 2′-O-methyl uridine, respectively, Af, Gf, and Uf represent 2′-fluoro adenosine, 2′-fluoro guanosine, and 2′-fluoro uridine, respectively, and s represents a phosphorothioate linkage.
The invention further describes RNAi agent compositions with pharmaceutically acceptable excipients and related delivery and therapeutic context directed to inhibiting PNPLA3 gene expression. The disclosed disease context includes NAFLD, NASH, hepatic fibrosis, alcoholic fatty liver disease, and cirrhosis, and includes cellular and in vivo delivery in hepatocytes.
Claims Coverage
The independent claim coverage in the provided material covers an RNAi agent for inhibiting PNPLA3 gene expression, defined by a specified modified antisense strand complementary to a PNPLA3 mRNA region, and an at least partially complementary sense strand. Three inventive features are identified.
RNAi agent for inhibiting PNPLA3 gene expression
An RNAi agent for inhibiting expression of a PNPLA3 gene, comprising an antisense strand comprising SEQ ID NO: 95 and a sense strand at least partially complementary to the antisense strand.
Antisense strand complementarity to PNPLA3 mRNA region
The antisense strand nucleotides 1-19 are complementary to the PNPLA3 mRNA region comprising nucleotides 2180-2198 of SEQ ID NO: 1.
Specific modified nucleotides and phosphorothioate linkage
In the antisense strand, a, g, and u represent 2′-O-methyl adenosine, 2′-O-methyl guanosine, and 2′-O-methyl uridine, respectively; Af, Gf, and Uf represent 2′-fluoro adenosine, 2′-fluoro guanosine, and 2′-fluoro uridine, respectively; and s represents a phosphorothioate linkage.
Coverage centers on a PNPLA3-targeting RNAi agent defined by a specified chemically modified antisense strand complementary to a defined PNPLA3 mRNA region, together with an at least partially complementary sense strand.
Stated Advantages
Inhibits PNPLA3 gene expression, including at least about 30% in certain embodiments.
Treating PNPLA3-related diseases including NAFLD, NASH, hepatic fibrosis, alcoholic fatty liver disease, and cirrhosis.
Demonstrated reduction of SEAP functional readout in the PNPLA3-SEAP mouse model relative to vehicle.
Substantial PNPLA3 mRNA knockdown in cynomolgus monkeys based on liver biopsy measurements, including cytoplasmic hepatocyte-specific reduction after a single dosing example.
Documented Applications
Treatment of PNPLA3-related diseases including NAFLD, NASH, hepatic fibrosis, alcoholic fatty liver disease, and cirrhosis using an RNAi agent that inhibits PNPLA3 gene expression.
Use in a PNPLA3-SEAP mouse model for evaluating in vivo efficacy using serum SEAP as a functional readout.
Nonhuman primate evaluation in cynomolgus monkeys using liver biopsy measurements (RT-qPCR and in situ hybridization) to assess PNPLA3 mRNA knockdown after dosing of specific agents.
Nonclinical safety outcomes reported in rats and monkeys.
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