Compositions and methods for inhibiting GYS2 expression
Inventors
Brown, Bob D. • PURSELL, Natalie • Dudek, Henryk T. • Lai, Cheng
Assignees
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Publication Number
US-12534730-B2
Publication Date
2026-01-27
Expiration Date
Abstract
This disclosure relates to oligonucleotides, compositions and methods useful for reducing GYS2 expression, particularly in hepatocytes. Disclosed oligonucleotides for the reduction of GYS2 expression may be double-stranded or single-stranded, and may be modified for improved characteristics such as stronger resistance to nucleases and lower immunogenicity. Disclosed oligonucleotides for the reduction of GYS2 expression may also include targeting ligands to target a particular cell or organ, such as the hepatocytes of the liver, and may be used to treat glycogen storage diseases (e.g., GSDIa, GSDIII, GSDIV, GSDVI, and GSDIX) and related conditions.
Core Innovation
The disclosure provides oligonucleotide therapies for reducing expression of glycogen synthase 2 (GYS2) and relates to RNAi oligonucleotide and antisense approaches. The target is GYS2 mRNA, including hotspots identified by specific sequences designated by SEQ ID NOs 599-608. The core oligonucleotide concept is an antisense strand and a sense strand with sequences selected from explicitly listed SEQ ID NOs.
The oligonucleotides are described in formats such as nicked tetraloop stem-loop extensions and tetraloop including GAAA. The document also describes a range of nucleotide and structural design parameters and modified nucleotides used in these oligonucleotides, together with chemical modification and targeting strategies for the antisense and sense strands.
The disclosure further describes 2′ sugar modifications and modified internucleotide linkages and phosphate analogs such as oxymethylphosphonate, vinylphosphonate, and malonylphosphonate. It also describes conjugation to targeting ligands including GalNAc, with GalNAc moieties having monovalent, bivalent, trivalent, or tetravalent valency, and compositions and delivery concepts for use in hepatocytes.
Claims Coverage
The independent claim covers an antisense/sense oligonucleotide pair defined by explicitly enumerated SEQ ID NOs for the antisense strand and for the sense strand. The dependent claims refine the covered subject matter by specifying particular sense/antisense SEQ ID pairings, structural and chemical features on the strands, GalNAc conjugation parameters, and a formulated composition including an excipient.
Enumerated antisense/sense sequence pairing
An oligonucleotide comprising an antisense strand and a sense strand, wherein the antisense strand comprises a sequence set forth in any one of SEQ ID NOs: 595, 577, 579, 580, 590, 594, 596 and 597, and wherein the sense strand comprises a sequence set forth in any one of SEQ ID NOs: 583, 399, 571, 573, 574, 582, 584 and 585.
Selected antisense/sense SEQ ID combinations
The oligonucleotide wherein the sense and antisense strand sequences are selected as defined by one of several paired combinations of SEQ ID numbers.
GalNAc conjugate with constrained GAAA nucleotide count
The oligonucleotide wherein a specified number of GAAA nucleotides are conjugated to a GalNAc moiety of a defined valency.
Phosphate analog at the 4′-carbon of the sugar
The oligonucleotide wherein the 4′-carbon of the sugar of the 5′-nucleotide contains a phosphate analog selected from oxymethylphosphonate, vinylphosphonate, or malonylphosphonate.
GalNAc moiety valency range
An oligonucleotide wherein the GalNAc moiety can be monovalent, bivalent, trivalent, or tetravalent.
Composition including an excipient
A composition provided that includes the oligonucleotide along with an excipient.
Overall, the claim coverage centers on a defined antisense/sense oligonucleotide pair specified by enumerated SEQ ID NOs, with dependent refinements adding specific strand combination constraints, chemical and structural features, GalNAc targeting conjugation parameters, and a formulated composition comprising an excipient.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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