Journal Article

Severe cardiac and skeletal manifestations in DMD-edited microminipigs: an advanced surrogate for Duchenne muscular dystrophy

Akihisa Kangawa, Kinuyo Ozaki, Koichi Kimura, Satoko Enya, Yoshitsugu Aoki, Masayoshi Otake, Michihiro Imamura, Etsuro Ono, Masatoshi Shibata

2024

Overview

Duchenne muscular dystrophy (DMD) is an intractable X-linked muscular dystrophy caused by mutations in the DMD gene. While many animal models have been used to study the disease, translating findings to humans has been challenging. Microminipigs, with their pronounced physiological similarity to humans and notably compact size amongst pig models, could offer a more representative model for human diseases. Here, we accomplished precise DMD modification in microminipigs by co-injecting embryos with Cas9 protein and a single-guide RNA targeting exon 23 of DMD . The DMD -edited microminipigs exhibited pronounced clinical phenotypes, including perturbed locomotion and body-wide skeletal muscle weakness and atrophy, alongside augmented serum creatine kinase levels. Muscle weakness was observed as of one month of age, respiratory and cardiac dysfunctions emerged by the sixth month, and the maximum lifespan was 29.9 months. Histopathological evaluations confirmed dystrophin deficiency and pronounced dystrophic pathology in the skeletal and myocardial tissues, demonstrating that these animals are an unprecedented model for studying human DMD. The model stands as a distinct and crucial tool in biomedical research, offering deep understanding of disease progression and enhancing therapeutic assessments, with potential to influence forthcoming treatment approaches. The authors present DMD -edited microminipigs showing severe Duchenne muscular dystrophy symptoms; their human-like physiology and small size make them ideal for developing new treatments.

• Publisher: Springer Science and Business Media LLC,Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/90 / 45/41 / 631/337/4041/3196 / 692/308/1426 / 82/1 / 82/51 / Animal models / Animals / Atrophy / Biology (General) / Biomedical and Life Sciences / Creatine / Creatine kinase / Disease Models, Animal / Duchenne's muscular dystrophy / Dystrophin / Dystrophin - genetics / Dystrophin - metabolism / Embryos / Gene Editing / Humans / Kinases / Life Sciences / Life span / Locomotion / Male / Medical research / Muscle, Skeletal - metabolism / Muscle, Skeletal - pathology / Muscular dystrophy / Muscular Dystrophy, Duchenne - genetics / Muscular Dystrophy, Duchenne - pathology / Muscular Dystrophy, Duchenne - physiopathology / Phenotype / Phenotypes / QH301-705.5 / Skeletal muscle / Swine / Swine, Miniature