Compositions and methods for inhibiting gene expression of alpha-1 antitrypsin
Inventors
Wooddell, Christine I. • Lewis, David L. • Wakefield, Darren H. • Almeida, Lauren • Kanner, Steven B.
Assignees
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Publication Number
US-12188017-B2
Publication Date
2025-01-07
Expiration Date
Abstract
The invention relates to a RNA interference triggers for inhibiting the expression of an AAT gene through the mechanism of RNA interference. The invention also relates to a pharmaceutical composition comprising the AAT RNAi trigger together with an excipient capable of improving delivery of the RNAi trigger to a liver cell in vivo. Delivery of the AAT RNAi trigger to liver cells in vivo provides for inhibition of AAT gene expression and treatment of alpha 1-antitrypsin deficiency and associated diseases.
Core Innovation
The invention relates to an RNA interference (RNAi) trigger molecule capable of inhibiting the expression of an alpha-1 antitrypsin gene. The RNAi trigger molecule comprises a sense strand sequence and an antisense strand sequence that form either a sequence pair of SEQ ID NOs: 16/28 or a sequence meroduplex of SEQ ID NOs: 16/29/44.
The described RNAi trigger molecule includes optional design features including targeting moieties conjugated to a strand, specific sense/antisense sequence pairs or meroduplexes, and modified nucleotides or nucleotide mimics. The document describes strand extensions and nucleotide modifications such as 2′-O-methyl, 2′-fluoro, locked nucleic acids, UNA/unlocked nucleic acids, and phosphorothioate linkages, together with targeting moieties including cholesterol/cholesteryl derivatives and GalNAc/N-acetylgalactosamine.
A delivery approach is described using an MLP (melittin-like peptide) membrane-active delivery polymer that is reversibly masked by an ASGPr-ligand maleamate to form an MLP delivery polymer. The masking agent is described as an ASGPr-ligand maleamate, including a CDM-NAG example, that restores activity after cleavage, thereby enabling liver-directed delivery of the RNAi trigger molecule.
Claims Coverage
The provided material identifies one independent claim. It covers an RNAi trigger molecule defined by specific sense/antisense sequence arrangements that inhibit expression of an alpha-1 antitrypsin gene, with dependent claims refining targeting, modifications, delivery, and disease indications.
RNAi trigger molecule for inhibiting alpha-1 antitrypsin gene expression via defined sequence pair or meroduplex
An RNA interference (RNAi) trigger molecule capable of inhibiting the expression of an alpha-1 antitrypsin gene, wherein the RNAi trigger molecule comprises a sense strand sequence and an antisense strand sequence that form a sequence pair of SEQ ID NOs: 16/28 or a sequence meroduplex of SEQ ID NOs: 16/29/44.
5′-end conjugation of a targeting moiety to the RNAi trigger molecule
A targeting moiety is conjugated to the 5′ end of the sense strand of the RNAi trigger molecule.
Cholesteryl or N-acetylgalactosamine targeting moiety
The targeting moiety comprises either a cholesteryl group or an N-acetyl-galactosamine.
Modified nucleotide selection for the RNAi trigger molecule
A modified nucleotide is selected from an enumerated list including 2′-O-methyl, 2′-fluoro, phosphorothioate-linked nucleotides, locked nucleic acids, UNA/unlocked nucleic acids, inverted deoxythymidine, and other nucleotide or nucleotide mimic categories.
Pharmaceutical composition including an MLP delivery polymer
A pharmaceutical composition that includes the RNAi trigger molecule and an MLP delivery polymer.
Treatment for specified alpha-1 antitrypsin deficiency-related diseases
The pathological condition and disease resulting from alpha-1 antitrypsin deficiency is selected from chronic hepatitis, cirrhosis, hepatocellular carcinoma, or fulminant hepatic failure.
The claim coverage centers on an RNAi trigger molecule defined by SEQ ID-specific sense/antisense arrangements for inhibiting alpha-1 antitrypsin gene expression, with dependent features for 5′-end targeting moiety conjugation, specified targeting moieties, nucleotide modifications, MLP delivery polymer inclusion, and narrowed alpha-1 antitrypsin deficiency-related disease indications.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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