RNAi agents for inhibiting expression of Beta-ENaC, compositions thereof, and methods of use
Inventors
Nicholas, Anthony • Schienebeck, Casi M. • Bush, Erik W. • Pei, Tao • XU, Zhao • Li, Zhen • Zhu, Rui
Assignees
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Publication Number
US-12655428-B2
Publication Date
2026-06-16
Expiration Date
Abstract
Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of a beta-ENaC (SCNN1B) gene. The beta-ENaC RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of a beta-ENaC gene. Pharmaceutical compositions that include one or more beta-ENaC RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described beta-ENaC RNAi agents to epithelial cells, such as pulmonary epithelial cells, in vivo, provides for inhibition of beta-ENaC gene expression and a reduction in ENaC activity, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including chronic obstructive pulmonary disease (COPD).
Core Innovation
The document describes an RNAi agent for inhibiting expression of a beta-ENaC gene. The RNAi agent comprises an antisense strand having the nucleotide sequence (5′→3′) cPrpusGfsusUfgAfagaugUfaAfcAfgUfuGfsc (SEQ ID NO: 138) and a sense strand that is at least partially complementary to the antisense strand, wherein all or substantially all of the nucleotides on the sense strand are modified nucleotides.
The agent includes modified nucleotides such as 2′-O-methyl adenosine, 2′-O-methyl cytidine, 2′-O-methyl guanosine, 2′-O-methyl uridine, 2′-fluoro adenosine, 2′-fluoro cytidine, 2′-fluoro guanosine, and 2′-fluoro uridine. cPrpu represents a 5′-cyclopropyl phosphonate-2′-O-methyl uridine and s represents a phosphorothioate linkage.
The broader description also discusses conjugatable and linking concepts for duplexes, including targeting and linking group concepts and optional targeting-ligand conjugation using an αvβ6 integrin ligand. It further refers to duplexes designated by Duplex ID numbers and representative duplexes referenced in tables.
Claims Coverage
The claim coverage centers on one RNAi agent structure for inhibiting beta-ENaC gene expression, with dependent coverage that also includes methods of inhibiting expression in cells and treating a human subject. Three inventive features are reflected in the merged independent and dependent claim content.
Rna i agent for inhibiting beta-enac expression with modified sense strand
An RNAi agent for inhibiting expression of a beta-ENaC gene comprising an antisense strand comprising SEQ ID NO: 138 and a sense strand at least partially complementary to the antisense strand, wherein all or substantially all of the nucleotides on the sense strand are modified nucleotides, including specified 2′-O-methyl and 2′-fluoro nucleotides, a 5′-cyclopropyl phosphonate-2′-O-methyl uridine unit, and a phosphorothioate linkage.
Cell inhibition by introducing the beta-enac RNAi agent
A method of inhibiting expression of a beta-ENaC gene in a cell by introducing an effective amount of the RNAi agent into the cell.
Therapeutic treatment of ena c-associated symptoms or diseases
A method of treating one or more symptoms or diseases linked to enhanced or elevated ENaC activity by administering a therapeutically effective amount of the RNAi agent to a human subject in need.
The claims are directed to an RNAi agent defined by a specific antisense sequence and a complementary sense strand in which all or substantially all sense nucleotides are modified, together with use claims for inhibiting beta-ENaC expression in cells and treating ENaC-linked conditions in humans.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating one or more symptoms or diseases linked to enhanced or elevated ENaC activity in a human subject in need.
Inhibiting expression of a beta-ENaC gene in a cell.
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