Modulators of diacyglycerol acyltransferase 2 (DGAT2)

Inventors

Swayze, Eric E.

Assignees

Ionis Pharmaceuticals Inc

Abstract

The present embodiments provide methods, compounds, and compositions useful for inhibiting DGAT2 expression, which may be useful for treating, preventing, or ameliorating a disease associated with DGAT2.

Core Innovation

The invention relates to DGAT2-targeting therapeutic embodiments for NAFLD, NASH, hepatic steatosis, lipodystrophy, and partial lipodystrophy. The described approach administers a compound comprising or consisting of a modified oligonucleotide intended to reduce or inhibit triglyceride synthesis, lipid synthesis and/or insulin resistance in the liver or white adipose tissue.

A central feature is the use of antisense oligonucleotide compositions that are DGAT2-specific inhibitors and that target DGAT2 nucleic acids. The disclosure includes modified oligonucleotide chemical architectures with modified sugars such as 2′-O-methoxyethyl, phosphorothioate internucleoside linkages, and 5-methylcytosine, together with optional GalNAc conjugates and sequence- or region-defined DGAT2-targeting compounds.

The document further ties the therapeutic effect to improvement of insulin signaling, insulin sensitivity, and/or cardiovascular risk profile in the individual. The partial content also references specific lead ASO/ISIS numbers, including ISIS 484137, and includes claims-related chemical-structure constraints for the modified oligonucleotide compounds.

Claims Coverage

The partial content provides two independent method claims, each directed to treating, preventing, or ameliorating NAFLD, NASH, lipodystrophy, or partial lipodystrophy using a DGAT2-targeting modified oligonucleotide. Across the independent claims, there are three main inventive elements: administering the modified oligonucleotide compound, requiring effects on triglyceride and/or lipid pathways and insulin-related outcomes, and linking those effects to the treatment outcome for the listed conditions.

Overall, the independent claims cover methods that administer a modified oligonucleotide compound for treating, preventing, or ameliorating NAFLD, NASH, lipodystrophy, or partial lipodystrophy, with required functional effects on triglyceride synthesis, lipid synthesis, and insulin resistance, and in one claim also improvement of insulin signaling/sensitivity and/or cardiovascular risk profile.

Stated Advantages

Documented Applications