SRP-4044 / Sarepta Therap - LARVOL DELTA

North Star Ambulatory Assessment changes in ambulant Duchenne boys amenable to skip exons 44, 45, 51, and 53: A 3 year follow up. (PubMed, PLoS One) - "Our results confirm different progression of disease in subgroups of patients with deletions amenable to skip different exons. This information is relevant as current long term clinical trials are using the NSAA in these subgroups of mutations."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

[VIRTUAL] Genotype-related respiratory progression in Duchenne Muscular Dystrophy – multicentre international study (EAN 2021) - "Exon44 had the slowest (2.7%/ year) and skip51 the fastest (5.9%/year) annual FVC% decline... The identification of genotype-related respiratory progression in DMD boys is valuable for prognosis and for evaluation of exon skipping treatments."

Clinical • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • TRIB3

Early Gross Motor Milestones in Duchenne Muscular Dystrophy. (PubMed, J Neuromuscul Dis) - "Our results showed that the risk of a delay in sitting and walking was increasingly high in patients with mutations predictive of the involvement of different brain dystrophin isoforms."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

[VIRTUAL] Adenine Base Editing to Modulate mRNA Splicing as a Therapeutic Strategy for Duchenne Muscular Dystrophy (ASGCT 2021) - "In order to test the effect of splice site disruption on exon skipping, we generated a human iPSC line harboring a deletion of dystrophin exon 44...To facilitate in vivo editing, we evaluated both ABE8e and ABE8.17m in AAV-compatible split intein designs. Future studies will evaluate the functional impact this single base pair change can make on the DMD dystrophic phenotype."

Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

[VIRTUAL] In Vivo Delivery of AAV.U7 Induce Efficient Exon Skipping for a Mutational Hotspot of the DMD Gene Results in Protein Restoration & Force Improvement in Skeletal Muscles, Heart & Diaphragm (ASGCT 2021) - "To conclude, our lead candidate can induce efficient DMD exon 44 skipping, resulting into dystrophin production and muscle strength improvement in major muscle groups affected in DMD. This AAV.U7-exon 44 skipping vector represent a promising candidate that could help ~6-8% of DMD patients."

Preclinical • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Genotype characterization and delayed loss of ambulation by glucocorticoids in a large cohort of patients with Duchenne muscular dystrophy. (PubMed, Orphanet J Rare Dis) - "Genotype variation influences clinical progression in certain DMD groups. Beneficial responses to GC treatment were observed among all DMD genotypes. Compared with other genotypes, deletions amenable to skipping exon 44 had a lower hazard ratio, which may indicate a stronger protective effect of GC treatments on this subgroup. These data are valuable for designing future clinical trials, as clinical outcomes may be influenced by the genotypes."

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

[VIRTUAL] Delay in Duchenne Muscular Dystrophy Progression with Eteplirsen: Longer Time to Loss of Ambulation Versus Standard of Care (MDA 2021) - "A sensitivity analysis included all genotyped CINRG patients who were ambulatory at baseline, excluding skip exon-44 and del_3-7, in the SOC group (n=278). Time to LOA from birth was significantly longer in patients treated with eteplirsen than with SOC."

Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Proteasome inhibitors reduce thrombospondin-1 release in human dysferlin-deficient myotubes. (PubMed, BMC Musculoskelet Disord) - "Our findings indicate that the ubiquitin-proteasome system might not be the main mechanism of mutant dysferlin degradation. However, its inhibition could help to improve muscle inflammation by reducing TSP-1 release."

Journal • Immunology • Inflammation • Muscular Dystrophy • Targeted Protein Degradation • Myogenin • THBS1

Longitudinal natural history in young boys with Duchenne muscular dystrophy. (PubMed, Neuromuscul Disord) - "Similarly, patients with mutations downstream exon 44, had lower baseline scores and lower magnitude of changes compared to those with mutations located at the 5' end of the gene (p < 0,001). Very few boys achieved the age appropriate maximum score. These results provide useful information for the assessment and counselling of young DMD boys and for the design of clinical trials in this age group."

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

Repurposing Pathogenic Variants of DMD Gene and its Isoforms for DMD Exon Skipping Intervention. (PubMed, Curr Genomics) - "Exon 44/45 variations were found to be the most prominent among single exon variations, whereas exon 49/50 was found to be the most frequently mutated locations in single/multiple exon variations...A major proportion of DMD subjects (80%) could be diagnosed by the MLPA technique. The data generated from our study may be beneficial for strengthening of mutation database in the North Indian population."

Journal • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy • Spectrin

Phenotype-genotype correlations in a pseudodominant Stargardt disease pedigree due to a novel ABCA4 deletion-insertion variant causing a splicing defect. (PubMed, Mol Genet Genomic Med) - "This work demonstrates the intrafamilial phenotypic variability in a pseudodominant Stargardt disease pedigree and the use of patient-derived fibroblasts to evaluate the effect of a novel ABCA4 delins variant on splicing to complement in silico pathogenicity assessment."

Journal • Age-related Macular Degeneration • Gene Therapies • Inherited Retinal Dystrophy • Macular Degeneration • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa

[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

CRISPR-Cas9 corrects Duchenne muscular dystrophy exon 44 deletion mutations in mice and human cells. (PubMed, Sci Adv) - "Using AAV9 encoding Cas9 and single guide RNAs, we also demonstrate the importance of the dosages of these gene editing components for optimal gene correction in vivo. Our findings represent a significant step toward possible clinical application of gene editing for correction of DMD."

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

Cardiopulmonary phenotypic discordance is common in Duchenne muscular dystrophy. (PubMed, Pediatr Pulmonol) - "In our cohort of DMD patients, discordant cardiopulmonary function was common (present in one-third of our patients), and the dystrophin genotype did not reliably predict a patient's cardiopulmonary phenotype. If confirmed by larger, multi-center studies, our findings have significant implications for predicting patient prognosis, evaluating DMD therapies, and designing new DMD therapies."

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