Antisense compounds targeting genes associated with cystic fibrosis
Inventors
Assignees
Rosalind Franklin University of Medicine and Science
Publication Number
US-9840709-B2
Publication Date
2017-12-12
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) hybridize to CFTR pre-mRNA and modulate splicing events, resulting in mRNA transcripts that code for fully or partially functional CFTR proteins. This hybridization can induce skipping of exons that contain mutations, thereby restoring the open reading frame and permitting production of an internally deleted, yet functional, CFTR protein.
The background problem addressed by the invention is the lack of effective therapies for cystic fibrosis, a genetic autosomal recessive disorder caused by mutations in the CFTR gene. These mutations lead to dysfunctional CFTR protein and thickened secretions in multiple organs, especially the lungs, resulting in severe morbidity and reduced life expectancy. Current treatments manage symptoms but do not cure or adequately restore CFTR function. Therefore, there is a need for therapeutics that enhance or restore CFTR protein function by correcting aberrant splicing caused by CFTR gene mutations.
Claims Coverage
The patent includes multiple independent claims focused on compounds and methods involving modified oligonucleotides targeting CFTR transcripts to modulate splicing or expression in order to treat cystic fibrosis.
Modified oligonucleotide complementary to CFTR transcript
The compound comprises a modified oligonucleotide of 19 to 30 linked nucleosides with a nucleobase sequence having at least 19 contiguous nucleobases complementary to SEQ ID NO:65 of the CFTR transcript, where each internucleoside linkage is a phosphorothioate modified internucleoside linkage.
Chemical modifications of the oligonucleotide
The modified oligonucleotide contains at least one modified nucleoside, including modified sugar moieties such as 2'-OMe, 2'-F, 2'-MOE, bicyclic sugars like LNA and cEt, sugar surrogates such as morpholino or modified morpholino. It has between 5 to 25 such modified nucleosides, forming contiguous modified regions of 5 to 20 nucleosides with uniform or varying modifications.
Pharmaceutical composition containing the modified oligonucleotide
A pharmaceutical composition comprising at least one of the modified oligonucleotide compounds described and a pharmaceutically acceptable carrier or diluent such as sterile saline.
Methods of modulating CFTR transcript splicing or expression
Methods of modulating splicing or expression of CFTR transcripts by contacting cells, in vitro or in vivo, with the modified oligonucleotide compound, resulting in changes such as exon skipping or correction of splicing defects.
Methods of treatment of cystic fibrosis
Administration of the modified oligonucleotide compounds or pharmaceutical compositions to animals, including humans and mice, by various routes including inhalation, parenteral injection, or topical administration, to treat cystic fibrosis or ameliorate its symptoms.
Overall, the claims cover the design of modified oligonucleotides complementary to specific CFTR RNA regions, with chemical modifications to enhance function and stability, compositions comprising these oligonucleotides, and their methods of use for splicing modulation and treatment of cystic fibrosis.
Stated Advantages
The compounds selectively modulate splicing of CFTR transcripts to produce mRNAs coding for fully or partially functional CFTR protein.
The use of chemically modified oligonucleotides increases stability and binding affinity, enhancing therapeutic potential.
The ability to induce exon skipping allows correction of frame-shift mutations, restoring functional protein expression.
Administration via inhalation or other routes allows targeted delivery to affected tissues, potentially improving treatment efficacy.
Documented Applications
Treatment of cystic fibrosis by modulating splicing or expression of CFTR transcripts to increase levels of functional CFTR protein.
Use of antisense oligonucleotides to correct aberrant splicing caused by CFTR gene mutations such as 2789+5G>A, 3849+10 kbC>T, and 3272-26A>G.
Induction of exon skipping in CFTR exons containing nonsense mutations (e.g., exons 4, 23, and 24) to restore reading frame and protein function.
Use in animals including humans and mice to ameliorate symptoms associated with cystic fibrosis.
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