Pigs with δ-sarcoglycan deficiency exhibit traits of genetic cardiomyopathy

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

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Abstract

Genetic 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.

Original languageEnglish
JournalLaboratory Investigation
DOIs
Publication statusAccepted/In press - 1 Jan 2020

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Matsunari, H., Honda, M., Watanabe, M., Fukushima, S., Suzuki, K., Miyagawa, S., Nakano, K., Umeyama, K., Uchikura, A., Okamoto, K., Nagaya, M., Toyo-oka, T., Sawa, Y., & Nagashima, H. (Accepted/In press). Pigs with δ-sarcoglycan deficiency exhibit traits of genetic cardiomyopathy. Laboratory Investigation. https://doi.org/10.1038/s41374-020-0406-7