Targeting a Novel Site in Exon 51 with Antisense Oligonucleotides Induces Enhanced Exon Skipping in a Mouse Model of Duchenne Muscular Dystrophy DOI Creative Commons

Todd Oppeneer,

Yulan Qi,

Joshua Henshaw

et al.

Nucleic Acid Therapeutics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Exon skipping with antisense oligonucleotides (ASOs) can correct disease-causing mutations of Duchenne muscular dystrophy (DMD) through RNA-targeted splice correction. This correction restores the reading frame and supports expression near full-length dystrophin. First-generation exon 51-skipping ASOs targeted same binding site, limited clinical efficacy. We characterized a novel site within 51 that induced highly efficient skipping. A precursor ASO (AON-C12) (BMN 351) were designed using 2'-O-methyl-modified phosphorothioate (2'OMePS) RNA locked nucleic acids. hDMDdel52/mdx mice given AON-C12 or BMN 351 for 13 weeks evaluated molecular phenotypic dystrophin deficiency. treatment durable, dose-dependent levels production in all muscles evaluated. In heart, 8 after last dose at 18 mg/kg, exon-skipped transcripts remained 44.3% total, 21.8% wild type. reached higher tissue concentrations percent heart than clinically relevant peptide-conjugated phosphorodiamidate morpholino oligomer comparator. also improved gait scores anatomical muscle pathology parameters compared vehicle-treated mice. The pharmacologic activity safety warrant further nonclinical development.

Language: Английский

BMN 351-Induced Exon Skipping and Dystrophin Expression in Skeletal and Cardiac Muscle Lead to Preservation of Motor Function in a Mouse Model of Exon 51 Skip-Amenable Duchenne Muscular Dystrophy DOI

Todd Oppeneer,

Yulan Qi,

Joshua Henshaw

et al.

Nucleic Acid Therapeutics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Duchenne muscular dystrophy (DMD) is caused by mutations of the DMD gene that prevent expression functional dystrophin protein. BMN 351 an antisense oligonucleotide (ASO) designed to induce skipping exon 51 pre-mRNA and production internally deleted but dystrophin. We determined whether extended-term dosing leads skipping, production, improved motor function in hDMDdel52/mdx mice containing a human 52-deleted transgene. Weekly intravenous doses vehicle, 6 mg/kg 351, or 18 were administered for 25 weeks, samples analyzed 4 12 weeks post-dosing. produced dose-dependent levels heart quadriceps muscles, accompanied increases mean 17% 55% Compared with vehicle-treated mice, ameliorated DMD-related histopathologic changes gastrocnemius muscle heart. Both preserved fine kinematics, which was worse compared wild-type Liver demonstrated findings consistent ASO accumulation, are considered especially sensitive humans other non-clinical species. These results support further clinical development 351.

Language: Английский

Citations

2
Targeting a Novel Site in Exon 51 with Antisense Oligonucleotides Induces Enhanced Exon Skipping in a Mouse Model of Duchenne Muscular Dystrophy DOI Creative Commons

Todd Oppeneer,

Yulan Qi,

Joshua Henshaw

et al.

Nucleic Acid Therapeutics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Exon skipping with antisense oligonucleotides (ASOs) can correct disease-causing mutations of Duchenne muscular dystrophy (DMD) through RNA-targeted splice correction. This correction restores the reading frame and supports expression near full-length dystrophin. First-generation exon 51-skipping ASOs targeted same binding site, limited clinical efficacy. We characterized a novel site within 51 that induced highly efficient skipping. A precursor ASO (AON-C12) (BMN 351) were designed using 2'-O-methyl-modified phosphorothioate (2'OMePS) RNA locked nucleic acids. hDMDdel52/mdx mice given AON-C12 or BMN 351 for 13 weeks evaluated molecular phenotypic dystrophin deficiency. treatment durable, dose-dependent levels production in all muscles evaluated. In heart, 8 after last dose at 18 mg/kg, exon-skipped transcripts remained 44.3% total, 21.8% wild type. reached higher tissue concentrations percent heart than clinically relevant peptide-conjugated phosphorodiamidate morpholino oligomer comparator. also improved gait scores anatomical muscle pathology parameters compared vehicle-treated mice. The pharmacologic activity safety warrant further nonclinical development.

Language: Английский

Citations

0