Compositions and methods for modulating PNPLA3 expression
Inventors
SAXENA, Utsav • Dudek, Henryk T. • Abrams, Marc • Turanov, Anton • Brown, Bob Dale
Assignees
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Publication Number
US-12084662-B2
Publication Date
2024-09-10
Expiration Date
Abstract
Oligonucleotides and compositions including the same are disclosed for inhibiting or reducing patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene expression. Methods of making and using the oligonucleotides also are disclosed, particularly uses relating to treating diseases, disorders and/or conditions associated with PNPLA3 expression.
Core Innovation
The invention relates to RNAi oligonucleotides comprising a sense strand and an antisense strand that form a duplex region for reducing patatin-like phospholipase domain-containing protein 3 (PNPLA3) expression. The duplex targets PNPLA3 mRNA, including variants such as PNPLA3 I148M, to suppress PNPLA3 mRNA and PNPLA3 protein expression.
The RNAi oligonucleotides are defined with specific nucleotide and internucleotide chemical modifications on both strands. These include 2′-O-methyl and 2′-fluoro modifications, phosphorothioate internucleotide linkages, and additional chemistry on the antisense strand including a 4′-phosphate analog comprising 5′-methoxyphosphonate-4′-oxy, together with sense-strand incorporation of adem-GalNAc-modified nucleotides.
The oligonucleotides further incorporate GalNAc targeting ligands directed to ASGPR, including adem-GalNAc formats, and are described as suitable for liver-targeted PNPLA3 suppression. Pharmaceutical composition and treatment method frameworks are provided for administration to individuals to reduce PNPLA3 expression, and the document describes use across liver cardiometabolic diseases including NAFLD/NASH, ALD, cirrhosis, hepatocellular carcinoma, and cholangiopathies.
Claims Coverage
The provided claim set includes one independent claim covering a specific RNAi oligonucleotide structure for reducing PNPLA3 expression, with dependent claims refining the subject matter to pharmaceutical composition aspects. The independent claim is supported by five inventive features focused on duplex formation, strand-specific chemical modifications, and GalNAc targeting via adem-GalNAc.
RNAi duplex for reducing PNPLA3 expression
An RNAi oligonucleotide comprising a sense strand and an antisense strand that form a duplex region, wherein the oligonucleotide is for reducing patatin-like phospholipase domain-containing protein 3 (PNPLA3) expression.
Sense-strand chemical modification pattern
The sense strand is defined by a specified sequence comprising nucleotides modified with 2′-O-methyl, nucleotides modified with 2′-fluoro, a phosphorothioate linkage, and nucleotides modified with adem-GalNAc.
Antisense-strand chemical modification pattern
The antisense strand is defined by a specified sequence comprising nucleotides modified with 2′-O-methyl and 2′-fluoro, phosphorothioate internucleotide linkages, and a nucleotide that is a 4′-phosphate analog comprising 5′-methoxyphosphonate-4′-oxy.
Pharmaceutical composition with acceptable carrier, delivery agent, or excipient
A pharmaceutical composition comprising the RNAi oligonucleotide and a pharmaceutically acceptable carrier, delivery agent, or excipient.
Phosphate buffered saline as a carrier component
A pharmaceutical composition in which the carrier includes phosphate buffered saline.
Across the independent claim and its refinements, coverage is directed to an RNAi duplex for reducing PNPLA3 expression, with a defined sense-strand modification scheme including adem-GalNAc, a defined antisense-strand modification scheme including a 4′-phosphate analog comprising 5′-methoxyphosphonate-4′-oxy, and downstream pharmaceutical composition formulations including pharmaceutically acceptable carriers and phosphate buffered saline.
Stated Advantages
Reducing PNPLA3 expression (PNPLA3 mRNA/protein) is explicitly stated as the purpose of the RNAi oligonucleotide.
Documented Applications
Treating liver cardiometabolic diseases by liver-targeted suppression of PNPLA3 expression, including ALD, NAFLD/NASH, cirrhosis, hepatocellular carcinoma (HCC), and PSC/other cholangiopathies.
Using RNAi oligonucleotide administration to individuals to reduce PNPLA3 expression is described at a treatment-method level in the provided content.
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