2. Academic Validation
  3. Phase 1/2 trial of brogidirsen: Dual-targeting antisense oligonucleotides for exon 44 skipping in Duchenne muscular dystrophy

Phase 1/2 trial of brogidirsen: Dual-targeting antisense oligonucleotides for exon 44 skipping in Duchenne muscular dystrophy

  • Cell Rep Med. 2025 Jan 21;6(1):101901. doi: 10.1016/j.xcrm.2024.101901.
Hirofumi Komaki 1,  Eri Takeshita 2,  Katsuhiko Kunitake 3,  Takami Ishizuka 4,  Yuko Shimizu-Motohashi 2,  Akihiko Ishiyama 2,  Masayuki Sasaki 2,  Chihiro Yonee 5,  Shinsuke Maruyama 5,  Eisuke Hida 6,  Yoshitsugu Aoki 7
Affiliations

Affiliations

  • 1 Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187-8551, Japan; Translational Medical Center, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187-8502, Japan.
  • 2 Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187-8551, Japan.
  • 3 Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187-8502, Japan.
  • 4 Translational Medical Center, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187-8502, Japan.
  • 5 Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima City, Kagoshima 890-8520, Japan.
  • 6 Department of Biostatistics and Data Science, Graduate School of Medicine, Osaka University, Suita-Shi, Osaka 565-0871, Japan.
  • 7 Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo 187-8502, Japan. Electronic address: [email protected].
PMID: 39793573 DOI: 10.1016/j.xcrm.2024.101901
Abstract

Duchenne muscular dystrophy (DMD) is a severe muscle disorder caused by mutations in the DMD gene, leading to Dystrophin deficiency. Antisense oligonucleotide (ASO)-mediated exon skipping offers potential by partially restoring Dystrophin, though current therapies remain mutation specific with limited efficacy. To overcome those limitations, we developed brogidirsen, a dual-targeting ASO composed of two directly connected 12-mer sequences targeting exon 44 using phosphorodiamidate morpholino oligomers. An open-label, dose-escalation, phase 1/2 trial assessed the safety, pharmacokinetics, and efficacy of brogidirsen in six ambulant patients with DMD amenable to exon 44 skipping. Following dose escalation, extended 24-week treatment with 40 mg/kg and 80 mg/kg yielded dose-dependent increases in Dystrophin (16.63% and 24.47% of normal). Functional assessments indicated motor stabilization, and plasma proteomics revealed reductions in peptidyl arginine deiminase 2 (PADI2), titin (TTN), and myomesin 2 (MYOM2), highlighting potential biomarkers. Brogidirsen's efficacy was supported in vitro using urine-derived cells from patients with DMD. These promising results warrant a subsequent trial for DMD. This study was registered at ClinicalTrials.gov (NCT04129294).

Keywords

DMD; Duchenne; antisense oligonucleotides; dual targeting; dystrophin; exon 44; exon skipping; morpholino; plasma proteomics; urine-derived cells.

Figures
Products