RNAi agents for inhibiting expression of mucin 5AC (MUC5AC), compositions thereof, and methods of use
Inventors
Bush, Erik W. • Nicholas, Anthony • Schienebeck, Casi M.
Assignees
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Publication Number
US-12365897-B2
Publication Date
2025-07-22
Expiration Date
Abstract
Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of a Mucin 5AC (MUC5AC) gene. The MUC5AC RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of an MUC5AC gene. Pharmaceutical compositions that include one or more MUC5AC RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described MUC5AC RNAi agents to pulmonary epithelial cells, in vivo, provides for inhibition of MUC5AC gene expression and a reduction in MUC5AC production, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including mucoobstructive lung disease such as severe asthma and various cancers.
Core Innovation
An RNAi agent is provided for inhibiting expression of a Mucin 5AC gene (MUC5AC). The RNAi agent includes an antisense strand comprising the nucleobase sequence SEQ ID NO:379 and a sense strand comprising a nucleotide sequence that is at least partially complementary to the antisense strand. The disclosure also describes strand length limitations, complementarity criteria, and optional inverted abasic residues in the sense strand.
The disclosed RNAi agents include chemically modified and unmodified strand designs, with strand identifiers and sequence-ID mapping. The disclosure further defines permissible nucleotide modifications and structural rules for nucleotides, including phosphorothioate linkages, inverted abasic deoxyribonucleotide-5′-phosphate motifs, and representative modified nucleotides, capping moieties, and linking group motifs.
The invention also describes pharmaceutical compositions containing the MUC5AC-targeting RNAi agents and conjugate concepts in which the RNAi duplex is combined with non-nucleotide groups, including targeting groups, linkers, PK/PD modulators, and delivery polymers or vehicles. The targeting is described using integrin αvβ6 targeting ligands, and the document includes pulmonary delivery context oriented to inhibiting MUC5AC expression in the lung.
Claims Coverage
The independent claim coverage centers on an RNAi agent that inhibits MUC5AC gene expression using a defined antisense sequence and a complementary sense strand. Across the provided claim set, the inventive features include sequence definition, sense strand complementarity, strand-length constraints, optional inverted abasic residues, modified-nucleotide chemistry, targeting-ligand linkage, and a pulmonary deposited dose constraint.
MUC5AC RNAi agent with SEQ ID NO:379 antisense and complementary sense strand
An RNAi agent for inhibiting expression of a Mucin 5AC gene comprising an antisense strand comprising the nucleobase sequence SEQ ID NO:379 and a sense strand comprising a nucleotide sequence that is at least partially complementary to the antisense strand.
Permitted modified nucleotide chemistries
The RNAi agent includes a modified nucleotide selected from a defined group including 2′-O-methyl nucleotide, 2′-fluoro nucleotide, 2′-deoxy nucleotide, 2′,3′-seco nucleotide mimic, locked nucleotide, 2′-F-arabino nucleotide, 2′-methoxyethyl nucleotide, abasic nucleotide, ribitol, inverted nucleotide, inverted 2′-O-methyl nucleotide, inverted 2′-deoxy nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, vinyl phosphonate-containing nucleotide, cyclopropyl phosphonate-containing nucleotide, and 3′-O-methyl nucleotide.
Sense and antisense strands sized within an 18 to 30 nucleotide window
The sense strand and the antisense strand each have a length between 18 and 30 nucleotides.
Sense strand includes one or two inverted abasic residues
The sense strand includes one or two inverted abasic residues.
Targeting-ligand linkage to the RNAi agent
The RNAi agent is linked to a targeting ligand.
Pulmonary deposited dose administration range
Administering the RNAi agent to a subject as a pulmonary deposited dose ranging from 0.01 mg/kg to 5.0 mg/kg of body weight.
The claim set requires an RNAi agent with a specified MUC5AC-targeting antisense sequence and a sense strand that is at least partially complementary. Dependent claims further refine strand length, optional inverted abasic residues in the sense strand, permitted modified nucleotides, linkage to a targeting ligand, and a defined pulmonary deposited dose range.
Stated Advantages
Inhibiting expression of a Mucin 5AC gene.
Enables treatment of mucoobstructive lung diseases and other respiratory-related disease contexts described as associated with MUC5AC expression.
Documented Applications
Pulmonary delivery to epithelial cells using pharmaceutical compositions and administration routes described as particularly inhalation-related, for inhibiting MUC5AC expression.
Inhibiting MUC5AC gene expression in mucoobstructive lung disease, including severe asthma, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), and primary ciliary dyskinesia (PCD).
Potential cancer-related indications including lung adenocarcinoma, pancreatic cancer, breast cancer, and ovarian cancer.
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