Antisense compounds targeting genes associated with cystic fibrosis
Inventors
Assignees
Rosalind Franklin University of Medicine and Science
Publication Number
US-10525076-B2
Publication Date
2020-01-07
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 present disclosure provides compounds comprising oligonucleotides that are complementary to a cystic fibrosis transmembrane conductance regulator (CFTR) RNA transcript. These compounds, such as antisense oligonucleotides (ASOs), hybridize specifically to regions of the CFTR transcript, including both human and murine sequences. In certain embodiments, this hybridization results in modulation of splicing of the CFTR transcript, which can generate mRNAs coding for proteins that partially or fully restore CFTR function.
The problem being addressed is that cystic fibrosis is caused by mutations in both copies of the CFTR gene, and current treatments are not curative. Many CF-causing mutations disrupt the normal splicing or reading frame of CFTR mRNA, resulting in non-functional or absent CFTR protein, which leads to severe clinical symptoms. Existing therapies address symptoms but do not correct the genetic defects underlying the disease.
The core invention is the use of chemically-modified oligonucleotides, designed to target specific regions—including exons and introns—of the CFTR pre-mRNA. By either correcting aberrant splicing caused by mutations or inducing exon skipping in exons containing mutations, these ASOs can restore the open reading frame of the CFTR mRNA, allowing production of a functional or partially functional CFTR protein. The modifications to the ASO backbones, sugars, and nucleobases enhance their stability and efficacy, facilitating their use in pharmaceutical compositions for the treatment of cystic fibrosis.
Claims Coverage
The patent contains several independent claims, each defining a distinct inventive feature related to modified antisense oligonucleotides targeting CFTR transcripts and their use in modulating splicing and treating cystic fibrosis.
Modified oligonucleotide complementary to CFTR transcript
A compound comprising a modified oligonucleotide of 22 to 30 linked nucleosides and having a nucleobase sequence comprising at least 22 contiguous nucleosides of SEQ ID NO:150, where the oligonucleotide has a complementary region of at least 22 contiguous nucleobases complementary to an equal-length portion of a CFTR transcript.
Pharmaceutical composition of modified oligonucleotide
A pharmaceutical composition comprising at least one compound that is a modified oligonucleotide with sequence as described above and a pharmaceutically acceptable carrier or diluent.
Method of modulating CFTR splicing or expression in a cell
A method of modulating splicing or expression of a CFTR transcript in a cell by contacting the cell with the described modified oligonucleotide compound.
Method of administration to an animal
A method comprising administering at least one compound or the pharmaceutical composition as described to an animal.
Method of treating cystic fibrosis
A method of treating cystic fibrosis comprising administering at least one compound or the pharmaceutical composition as described to an animal in need thereof.
These inventive features cover the composition, formulation, cellular use, administration in vivo, and therapeutic application of modified antisense oligonucleotides specifically targeting the CFTR transcript for cystic fibrosis.
Stated Advantages
Allows correction of aberrant CFTR splicing caused by disease-related mutations, resulting in mRNAs that code for functional or partially functional CFTR protein.
Can restore the reading frame and produce CFTR isoforms with at least partial function when inducing exon skipping of mutated exons.
Enables the amelioration of at least one symptom of cystic fibrosis by increasing the amount of functional CFTR protein.
May prevent or delay onset of cystic fibrosis symptoms by modulating RNA splicing or expression.
Documented Applications
Treatment of cystic fibrosis by administering antisense oligonucleotides to patients with CFTR mutations.
Use in modulating splicing or expression of CFTR transcript in vitro or in vivo.
Use in pharmaceutical compositions for research, diagnostic, or therapeutic purposes targeting CFTR RNA transcripts.
Application in animals, including mice and humans, to correct CFTR splicing defects and ameliorate cystic fibrosis symptoms.
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