DMD exon 44 skipping program / Wave Life Sciences - LARVOL DELTA

Single-swap editing for the correction of common Duchenne muscular dystrophy mutations. (PubMed, Mol Ther Nucleic Acids) - "Furthermore, an adeno-associated virus delivery method for base editing components can efficiently restore dystrophin production locally and systemically in skeletal and cardiac muscles of a DMD mouse model containing a deletion of Dmd exon 44. Our studies demonstrate single-swap editing as a potential gene editing therapy for common DMD mutations."

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

Exon Skipping and Dystrophin Production with ENTR-601-45, a Novel EEV-Conjugated, Exon 45 Skip Amenable PMO in Preclinical Models of DMD (ASGCT 2023) - "Furthermore, a single intravenous dose of ENTR-601-44 (a DMD exon 44 splice modulating EEV-PMO) showed durable exon skipping in skeletal and cardiac muscle in human dystrophin-expressing (hDMD) mice and non-human primates for at least 12 weeks post-dose...Additionally, a single IV dose of ENTR-601-45 resulted in high levels of exon skipping in hDMD mouse skeletal and cardiac muscle after 1 week. These results demonstrate the therapeutic potential of ENTR-601-45 and suggest potential for further study in patients with DMD amenable to exon 45 skipping."

Preclinical • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Modeling Gene Editing Outcomes in Microphysiological Human Tissue System Models of Duchenne Muscular Dystrophy (ASGCT 2023) - "To further demonstrate the utility of this model, we created an additional myobundle line lacking DMD exon 44 and evaluated two exon skipping strategies: an adenine base editor and SpCas9 targeted to the exon 45 splice acceptor...Together, these results suggest that restoration of dystrophin reverses the functional deficits seen in dystrophic human myobundles.Collectively, this foundational work shows that 3D microphysiological muscle tissue models can be used to perform safety, efficacy, and functional assays in a model that accurately captures human muscle physiology, directly addressing a need in the gene editing field that has been unmet by 2D cell culture and animal models. Additionally, improvements to the model, including the incorporation of immune cells and vasculature, may continue to increase its ability to accurately predict the safety and efficacy of gene therapies in patients."

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

Development of a novel, EEV-Conjugated PMO for Duchenne muscular dystrophy (WMS 2022) - "Based on these findings, we examined the therapeutic potential of a DMD exon 44 splice modulating EEV-PMO (ENTR-601-44)...Additionally, ENTR-601-44 demonstrated robust exon skipping in skeletal muscle and the heart of nonhuman primates. Together, these findings suggest potential for further study of ENTR-601-44 in patients with DMD amenable to exon 44 skipping."

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

AAV.U7.ex44 Mediates Efficient Exon Skipping, Protein Restoration & Phenotype Rescue -Pre-Clinical Intramuscular & Dose Escalation Study for a Mutational Hotspot of the Duchenne Muscular Dystrophy (DMD) (ASGCT 2022) - "To conclude, our lead candidate induces efficient DMD exon 44 skipping, resulting in dystrophin production and muscle strength improvement in major muscle groups affected in DMD. This AAV.U7-exon 44 skipping vector represents a promising candidate for ~6-12% of DMD patients."

Preclinical • Duchenne Muscular Dystrophy • Fibrosis • Genetic Disorders • Immunology • Inflammation • 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