Pigs with δ-sarcoglycan deficiency exhibit traits of genetic cardiomyopathy

Author:

Matsunari Hitomi,Honda Michiyo,Watanabe Masahito,Fukushima Satsuki,Suzuki Kouta,Miyagawa Shigeru,Nakano Kazuaki,Umeyama Kazuhiro,Uchikura Ayuko,Okamoto Kazutoshi,Nagaya Masaki,Toyo-oka Teruhiko,Sawa Yoshiki,Nagashima Hiroshi

Abstract

AbstractGenetic cardiomyopathy is a group of intractable cardiovascular disorders involving heterogeneous genetic contribution. This heterogeneity has hindered the development of life-saving therapies for this serious disease. Genetic mutations in dystrophin and its associated glycoproteins cause cardiomuscular dysfunction. Large animal models incorporating these genetic defects are crucial for developing effective medical treatments, such as tissue regeneration and gene therapy. In the present study, we knocked out the δ-sarcoglycan (δ-SG) gene (SGCD) in domestic pig by using a combination of efficient de novo gene editing and somatic cell nuclear transfer. Loss of δ-SG expression in the SGCD knockout pigs caused a concomitant reduction in the levels of α-, β-, and γ-SG in the cardiac and skeletal sarcolemma, resulting in systolic dysfunction, myocardial tissue degeneration, and sudden death. These animals exhibited symptoms resembling human genetic cardiomyopathy and are thus promising for use in preclinical studies of next-generation therapies.

Funder

Japan Agency for Medical Research and Development

Publisher

Springer Science and Business Media LLC

Subject

Cell Biology,Molecular Biology,Pathology and Forensic Medicine

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