SRP-4052 / Sarepta Therap - LARVOL DELTA

[VIRTUAL] Biological Efficacy of the Peptide-Conjugated Phosphorodiamidate Morpholino Oligomer SRP-5051 in Preclinical Models of Duchenne Muscular Dystrophy (MDA 2021) - "In vivo systems included a disease-relevant, humanized DMD mouse model, hDMD del52/mdx, that contains a DMD transgene with exon 52 deleted on an mdx mouse background (lacking endogenous dystrophin), and a primate model using healthy male cynomolgus monkeys. SRP-5051 showed dose-dependent efficacy in preclinical models. These data justify the monthly SRP-5051 dosing regimen used in ongoing clinical studies, and support further clinical investigation of this PPMO."

Preclinical • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • HSP90AA1

Detailed genetic and functional analysis of the hDMDdel52/mdx mouse model. (PubMed, PLoS One) - "Long-read sequencing revealed a partial deletion of exon 52 (first 25 bp), and a 2.3 kb inversion in intron 51 in both copies...This revealed a clear and highly significant difference in overall gait between hDMDdel52/mdx mice and C57BL6/J controls. The motor deficit detected in the model confirms its suitability for preclinical testing of exon skipping AONs for human DMD at both the functional and molecular level."

Journal • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • HSP90AA1

[VIRTUAL] DEVELOPING AN EFFECTIVE EXONS 45-55 SKIPPING THERAPY FOR DUCHENNE MUSCULAR DYSTROPHY (CCC Canada 2020) - "Various PMO combinations were transfected into immortalized patient-derived DMD exon 52-deleted myotubes 3 days post-differentiation; total RNA and protein were extracted 2 days later. We developed an exons 45-55 skipping cocktail effective in restoring dystrophin synthesis in patient-derived myotubes, and have identified a peptide to enhance the in vivo efficacy of this cocktail. Future work will test the effects of this DG9-conjugated cocktail on a novel DMD mouse model we are currently characterizing."

Cardiovascular • Congestive Heart Failure • Duchenne Muscular Dystrophy • Genetic Disorders • Heart Failure • Muscular Dystrophy

Characterizing Exon Skipping Efficiency in DMD Patient Samples in Clinical Trials of Antisense Oligonucleotides. (PubMed, J Vis Exp) - "The morpholino AON viltolarsen (code name: NS-065/NCNP-01) has been shown to induce exon 53 skipping, restoring the reading frame for patients with exon 52 deletions. In this methods article, we present the molecular characterization of dystrophin expression using Sanger sequencing, RT-PCR, and western blotting in the clinical trial. The characterization of dystrophin expression was fundamental in the study for showing the efficacy since no functional outcome tests were performed."

Clinical • Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Dominant collagen XII mutations cause a distal myopathy. (PubMed, Ann Clin Transl Neurol) - "This study characterizes a distal myopathy phenotype in adults with dominant COL12A1 pathogenic variants, further defining the phenotypic spectrum and natural history of COL12A1-related myopathies. This work also provides proof of concept of a precision medicine treatment approach by proposing and validating allele-specific knockdown using siRNAs specifically designed to target a patient's dominant COL12A1 disease allele."

Journal • Myositis

[VIRTUAL] 27 years of molecular diagnosis of dystrophinopathies by multiplex PCR in Morocco (EAN 2020) - "73% of the deletions were found in the 5’ hotspot (Exon 44 to Exon 52), 18% were located on the 3’ hotspot (Exon 3 to Exon 19) and only 6% of deletions spanned both hotspots. We report here our experience in the molecular diagnosis of dystrophinopathies by the multiplex PCR technique. It is a good first-line strategy in our public health due to its low- cost with a good cost-to-benefit ratio."

Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy • PCR

The spectrum of deletions and duplications in the dystrophin (DMD) gene in a cohort of patients with Duchenne muscular dystrophy in Sri Lanka. (PubMed, Neurol India) - "The most common deletion was the deletion spanning from exon 45 to exon 52, which was seen in 6 (12%) children...The least common region fell within exons 56 to 79 (4%). The deletion/duplication pattern seen in this cohort of children with DMD was similar to that reported among other global populations."

Clinical • Journal