Antisense compounds targeting genes associated with cystic fibrosis
Inventors
Assignees
Rosalind Franklin University of Medicine and Science
Publication Number
US-12042508-B2
Publication Date
2024-07-23
Expiration Date
2036-02-17
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Abstract
The present disclosure relates generally to compounds comprising oligonucleotides complementary to a cystic fibrosis transmembrane conductance regulator (CFTR) RNA transcript. Certain such compounds are useful for hybridizing to a CFTR RNA transcript, including but not limited to a CFTR RNA transcript in a cell. In certain embodiments, such hybridization results in modulation of splicing of the CFTR transcript. In certain embodiments, such compounds are used to treat one or more symptoms associated with Cystic Fibrosis.
Core Innovation
The invention discloses compounds comprising oligonucleotides complementary to a cystic fibrosis transmembrane conductance regulator (CFTR) RNA transcript. These antisense oligonucleotides (ASOs) are designed to specifically hybridize with regions of the human or murine CFTR transcript, including exons and introns, to modulate pre-mRNA splicing events. By targeting specific sequences, the ASOs alter the splicing of CFTR transcripts, leading to mRNAs that encode proteins which fully or partially restore CFTR function.
The problem addressed by this invention is the lack of effective therapies for cystic fibrosis, a genetic disorder caused by mutations in both copies of the CFTR gene. Current treatments do not cure the disease or sufficiently address the splicing defects and nonsense mutations that disrupt production of functional CFTR protein. Many CF patients have mutations that result in aberrant splicing or nonsense mutations leading to non-functional proteins.
Through the use of modified ASOs, the invention enables the correction of aberrant splicing caused by various mutations, including exon skipping of CFTR exons with nonsense mutations, or restoration of the open reading frame. The ASOs can be chemically modified to enhance stability and effectiveness. Compounds and compositions described in this patent can be used to modulate CFTR transcript splicing or expression both in vitro and in vivo, and are suitable for treating animals, including humans or mice, with symptoms associated with cystic fibrosis.
Claims Coverage
There are four independent inventive features described in the patent claims.
Compound of SEQ ID NO:127 modified antisense oligonucleotide
A compound comprising a modified antisense oligonucleotide consisting of the sequence of SEQ ID NO:127. - The oligonucleotide includes at least one modified nucleoside selected from a modified sugar moiety, a 2′-substituted sugar moiety, 2′-OMe, 2′-F, 2′-MOE, a bicyclic sugar moiety, LNA, cEt, a sugar surrogate, morpholino, or modified morpholino. - The compound may contain at least 5 to at least 25 modified nucleosides, each independently comprising a modified sugar moiety. - The oligonucleotide may contain no more than 4 contiguous naturally occurring nucleosides and may have at least one modified internucleoside linkage.
Pharmaceutical composition with SEQ ID NO:127 antisense compound
A pharmaceutical composition comprising the compound according to SEQ ID NO:127 and a pharmaceutically acceptable carrier or diluent. - The composition may further comprise one or more antisense compounds, enabling potential combination therapies or formulation flexibility.
Method of modulating splicing or expression of CFTR transcript
A method of modulating splicing or expression of a CFTR transcript in a cell comprising contacting the cell with the compound according to SEQ ID NO:127. - The method is applicable for both in vitro or in vivo cells.
Treatment of cystic fibrosis using SEQ ID NO:127 antisense oligonucleotide
A method of treating cystic fibrosis comprising administering the compound according to SEQ ID NO:127, or a pharmaceutical composition containing it, to an animal. - The administration can be by inhalation, parenteral injection or infusion, oral, subcutaneous or intramuscular injection, buccal, transdermal, transmucosal, or topical routes. - The treated animal may be a human or mouse. - Additional methods cover administration of oligonucleotides having 14 to 30 linked nucleosides with at least 14 nucleosides of SEQ ID NO:127, where the oligonucleotide is at least 80% complementary to an equal-length region of CFTR.
The independent claims focus on modified antisense oligonucleotides targeting CFTR, particularly SEQ ID NO:127, compositions containing these compounds, methods of modulating CFTR splicing or expression, and methods of treating cystic fibrosis through administration of these agents.
Stated Advantages
The invention provides compounds and methods that restore partial or full function of CFTR protein by correcting aberrant splicing or enabling translation of in-frame mRNA, leading to increased levels of properly localized and functioning CFTR protein.
The compounds enable the treatment or amelioration of one or more symptoms associated with cystic fibrosis by targeting splicing mutations and nonsense mutations in the CFTR gene.
The antisense oligonucleotides offer a potential therapeutic benefit by enabling correction of specific CFTR gene mutations found in cystic fibrosis patients, where previous therapies were inadequate.
Documented Applications
Treatment of cystic fibrosis by administering modified antisense oligonucleotides or pharmaceutical compositions to an animal in need thereof.
Modulation of CFTR transcript splicing or expression in vitro or in vivo by contacting cells with the disclosed antisense compounds.
Therapeutic correction of specific CFTR splicing mutations (e.g., 2789+5G>A, 3849+10kbC>T, 3272-26A>G) in patient-derived lymphoblast or epithelial cells.
Use of antisense compounds to induce skipping of exons with nonsense mutations in CFTR to restore the reading frame and produce partially functional CFTR protein.
Administration of the compounds to humans or mice by routes including inhalation, parenteral injection or infusion, oral, subcutaneous or intramuscular injection, buccal, transdermal, transmucosal, and topical delivery.
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