DMD exon 52 skipping program / Wave Life Sciences - LARVOL DELTA

Highly Efficient and Durable AAV‐mediated Skipping of DMD Exon 53 in hDMDdel52/mdx Mice Results in Sustained Therapeutic Levels of Dystrophin (ESGCT 2023) - "The lead construct (AAV.3XU7.Ex53.3AS) was evaluated in immortalized human myoblasts derived from a patient with a deletion of DMD exon 52 and found to promote up to 80% skipping of exon 53 and robust expression of dystrophin.Next, we performed in vivo proof-of-concept studies in hDMDdel52/mdx mice, which express a human dystrophin mRNA without exon 52 and are amenable to exon 53-skipping therapies...3XU7.Ex51, which provided similar results in patient myoblasts in terms of skipping efficiency and dystrophin restoration and in vivo evaluation of this vector in hDMDdel52/mdx mice is ongoing. Altogether, our results provide compelling proof-of-concept data supporting the development of vectorized exon-skipping therapies for the treatment of DMD."

Preclinical • Duchenne Muscular Dystrophy • Fibrosis • Genetic Disorders • Immunology • Muscular Dystrophy • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • HSP90AA1

Prevention of early-onset cardiomyopathy in Dmd exon 52-54 deletion mice by CRISPR-Cas9-mediated exon skipping. (PubMed, Mol Ther Methods Clin Dev) - "Here we employed CRISPR-Cas9 delivered intravenously by adeno-associated virus (AAV) vectors to restore functional dystrophin expression via excision or skipping of exon 55. Remarkably, our exon skipping approach completely prevented onset of the cardiac phenotype in treated mice up to 12 weeks. Thus, our results demonstrate that intravenous delivery of a single-cut CRISPR-Cas9-mediated exon skipping therapy can prevent heart dysfunction in DMD in vivo."

Journal • Preclinical • Cardiomyopathy • Cardiovascular • Duchenne Muscular Dystrophy • Fibrosis • Genetic Disorders • Immunology • Muscular Dystrophy

Systemic deletion of DMD exon 51 rescues clinically severe Duchenne muscular dystrophy in a pig model lacking DMD exon 52. (PubMed, Proc Natl Acad Sci U S A) - "Our findings indicate that ubiquitous deletion of DMD exon 51 in DMDΔ52 pigs largely rescues the rapidly progressing, severe muscular dystrophy and the reduced cardiac function of this model. Long-term follow-up studies of DMDΔ51-52 pigs will show if they develop symptoms of the milder BMD."

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

Pig models for Duchenne muscular dystrophy - from disease mechanisms to validation of new diagnostic and therapeutic concepts. (PubMed, Neuromuscul Disord) - "The first porcine DMD model was generated by deletion of DMD exon 52 (DMDΔ52) in cultured kidney cells, which were used for somatic cell nuclear transfer to produce DMDΔ52 offspring...In this overview, we summarize how porcine DMD models have been used for dissecting disease mechanisms, for validating multispectral optoacoustic tomography as an imaging modality for monitoring fibrosis, and for preclinical testing of a CRISPR/Cas9 based approach to restore an intact DMD reading frame. Particular advantages of porcine DMD models include their targeted design and the rapid disease progression with early cardiac involvement, facilitating translational studies in reasonable time frames."

Journal • Preclinical • Review • Duchenne Muscular Dystrophy • Fibrosis • Genetic Disorders • Immunology • Muscular Dystrophy

A scalable, clinically severe pig model for Duchenne muscular dystrophy. (PubMed, Dis Model Mech) - "Pigs cloned from male cells lacking DMD exon 52 (DMDΔ52) resemble molecular, clinical and pathological hallmarks of DMD, but die before sexual maturity and cannot be propagated by breeding...Furthermore, behavioral tests provided evidence for impaired cognitive ability. Our breeding cohort of DMDΔ52 pigs and standardized tissue repositories provide important resources for studying DMD disease mechanisms and for testing novel treatment strategies."

Clinical • Journal • Preclinical • Duchenne Muscular Dystrophy • Fibrosis • Genetic Disorders • Immunology • Muscular Dystrophy

[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