Antisense compounds targeting genes associated with cystic fibrosis
Inventors
Assignees
Rosalind Franklin University of Medicine and Science
Publication Number
US-11116785-B2
Publication Date
2021-09-14
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 provides compounds comprising modified oligonucleotides that are complementary to specific regions of the cystic fibrosis transmembrane conductance regulator (CFTR) RNA transcript. These antisense oligonucleotides (ASOs) are designed to hybridize with CFTR RNA in cells, modulate its splicing, or otherwise alter the expression of CFTR, leading to mRNAs that code for proteins which fully or partially restore CFTR function.
The problem addressed is the lack of effective treatments for cystic fibrosis, a genetic disorder caused by mutations in the CFTR gene leading to defective or insufficient protein function. Existing therapies only manage symptoms and do not address the underlying genetic defects, particularly in cases with splicing or nonsense mutations, where current interventions are not fully effective or curative.
The disclosed ASOs can be tailored to target a wide variety of CFTR gene regions, including exons and introns implicated in disease-causing mutations. By inducing specific pre-mRNA splicing events or correcting aberrant splicing, these compounds can either restore the reading frame or correct mis-spliced transcripts, resulting in mRNA isoforms that produce functional or partially functional CFTR proteins. Methods of treatment include direct administration to animals or humans with cystic fibrosis, either as a compound or in pharmaceutical compositions.
Claims Coverage
There are five primary independent inventive features claimed.
Compound comprising a modified oligonucleotide with defined sequence and complementarity
A compound comprising a modified oligonucleotide of 21 to 30 linked nucleosides, the nucleobase sequence comprising at least 21 nucleosides of SEQ ID NO:126, wherein the oligonucleotide consists of at least 21 contiguous nucleobases and is at least 80% complementary to an equal-length portion of a target region of a CFTR transcript.
Pharmaceutical composition comprising the modified oligonucleotide and a pharmaceutically acceptable carrier
A pharmaceutical composition containing at least one of the described modified oligonucleotides and a pharmaceutically acceptable carrier or diluent.
Method of modulating splicing or expression of a CFTR transcript in a cell
A method where the cell is contacted with at least one of the specified modified oligonucleotides to modulate splicing or expression of a CFTR transcript, either in vitro or in vivo.
Method of treating cystic fibrosis by administering the modified oligonucleotide
A method of treating cystic fibrosis comprising administering at least one of the specified modified oligonucleotides to an animal in need thereof, including administration by various routes.
Compound comprising a modified oligonucleotide having specified length and sequence
A compound comprising a modified oligonucleotide having 25 to 30 linked nucleosides and a nucleobase sequence comprising SEQ ID NO:126.
The independent claims focus on compounds of specified modified oligonucleotide sequences, pharmaceutical compositions containing these compounds, methods for modulating CFTR transcript splicing or expression, and methods for treating cystic fibrosis through administration of these oligonucleotides.
Stated Advantages
The antisense oligonucleotides provided can induce specific splicing events or correct aberrant splicing in the CFTR gene transcript, resulting in the production of mRNAs coding for CFTR proteins that fully or partially restore normal function.
The compounds and methods can be used to treat cystic fibrosis by ameliorating one or more symptoms associated with the disease.
The invention enables modulation of splicing of CFTR transcripts to restore reading frames or skip disease-causing exons, resulting in functional or partially functional CFTR protein production.
The disclosed oligonucleotides are applicable to a range of CFTR mutations, including common splicing, nonsense, and frame-shift mutations, thereby expanding therapeutic coverage.
Administration of certain antisense oligonucleotides can rescue cellular phenotype, delay onset, or prevent onset of cystic fibrosis symptoms.
Documented Applications
Treatment of cystic fibrosis in animals or humans by administering the antisense oligonucleotide compounds or their pharmaceutical compositions.
Modulation of CFTR transcript splicing or expression in cells, either in vitro or in vivo.
Correction of aberrant splicing of CFTR transcripts caused by mutations such as 2789+5G>A, 3849+10kbC>T, or 3272-26A>G, restoring functional CFTR mRNA.
Induction of exon skipping of mutated exons in the CFTR gene to restore the open reading frame and allow production of partially functional CFTR protein.
Rescue of CFTR function in patient-derived epithelial cells through treatment with specific antisense oligonucleotides.
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