Antisense compounds targeting genes associated with cystic fibrosis
Inventors
Assignees
Rosalind Franklin University of Medicine and Science
Publication Number
US-10544417-B2
Publication Date
2020-01-28
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 relates to compounds comprising oligonucleotides that are complementary to a cystic fibrosis transmembrane conductance regulator (CFTR) RNA transcript. These modified oligonucleotides can hybridize to CFTR transcripts in cells and modulate the splicing of CFTR pre-mRNA, leading to changes in mRNA that code for proteins that fully or partially restore CFTR function. The compounds may include specific modifications to sugar moieties, internucleoside linkages, and may incorporate chemical motifs such as 2'-OMe, 2'-F, 2'-MOE, LNA, cEt, morpholino, or modified morpholino.
Cystic fibrosis is a genetic disorder primarily affecting the lungs and other organs, caused by mutations in both copies of the CFTR gene. Current therapies such as antibiotics, enzyme replacements, and lung transplants manage symptoms but do not cure the disease, and more effective therapies are needed. The patent addresses the problem by providing antisense oligonucleotides that induce specific splicing changes in CFTR gene transcripts, either by correcting aberrant splicing caused by mutations or skipping mutated exons, restoring or improving CFTR protein function.
The invention further provides pharmaceutical compositions comprising these antisense oligonucleotides and methods for modulating splicing or expression of CFTR transcripts in vitro or in vivo. The methods include administration of the compounds to animals, including humans, for treating or ameliorating symptoms associated with cystic fibrosis. Examples include targeting specific CFTR mutations such as 2789+5G>A, 3849+10kbC>T, and others by using sequence-specific oligonucleotides to redirect splicing or restore functional mRNA and protein.
Claims Coverage
There are three broad independent inventive features claimed.
Modified oligonucleotide targeting CFTR transcript
A compound comprising a modified oligonucleotide of 25 to 30 linked nucleosides and having a nucleobase sequence comprising at least 25 contiguous nucleobases of SEQ ID NOs: 128 or 129. The oligonucleotide contains a complementary region of at least 25 contiguous nucleobases complementary to an equal-length region of a CFTR transcript. The compound features at least one modified nucleoside selected from modified sugar moieties, including 2'-OMe, 2'-F, 2'-MOE, LNA, cEt, morpholino, or modified morpholino. The modified oligonucleotide can include at least 5 to 25 modified nucleosides with modified sugar moieties, at least one modified internucleoside linkage (including phosphorothioate linkage), and may contain at least one conjugate.
Pharmaceutical composition comprising the modified oligonucleotide
A pharmaceutical composition comprising at least one compound consisting of the aforementioned modified oligonucleotide, combined with a pharmaceutically acceptable carrier or diluent.
Methods of modulating splicing or expression and treating cystic fibrosis
Methods including: - Modulating splicing or expression of a CFTR transcript in a cell by contacting the cell with at least one compound as described. - Administering at least one such compound or the pharmaceutical composition to an animal, including delivery methods such as inhalation, injection, infusion, oral, subcutaneous, intramuscular, buccal, transdermal, transmucosal, or topical. - Treating cystic fibrosis in an animal in need by administering at least one such compound or pharmaceutical composition.
The claims provide broad protection for modified oligonucleotide compounds that specifically target and modulate CFTR RNA transcripts, their pharmaceutical compositions with carriers or diluents, and methods for modulating splicing or expression of CFTR as well as treating cystic fibrosis across various administration routes.
Stated Advantages
The compounds can modulate splicing of the CFTR transcript, resulting in mRNAs that code for proteins that fully or partially restore CFTR function.
Such antisense oligonucleotides can be used to treat or ameliorate one or more symptoms associated with cystic fibrosis.
The invention enables the correction of aberrant splicing caused by mutations or allows for skipping of mutated exons, potentially restoring the reading frame and generating a CFTR isoform with partial function.
Documented Applications
Treatment of cystic fibrosis by administering antisense oligonucleotides that modulate splicing or expression of the CFTR transcript in animals, including humans.
Use of the oligonucleotide compounds as pharmaceutical compositions for amelioration of symptoms or treating cystic fibrosis.
Modulation of splicing or expression of CFTR transcripts in cells in vitro or in vivo using the described compounds.
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