Journal Article

Pigs with δ-sarcoglycan deficiency exhibit traits of genetic cardiomyopathy

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

2020

Overview

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. Gene δ-sarcoglycan was knocked out in pigs via gene editing and somatic cell cloning. Loss of expression led to α-, β-, and γ-sarcoglycan depletion in the cardiac and skeletal sarcolemma. Pigs exhibiting systolic dysfunction, myocardial tissue degeneration, and sudden death are promising for studying next-generation therapies for human genetic cardiomyopathy.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/109 / 42/41 / 45/23 / 631/1647/1511 / 631/61/17/1511 / 82/51 / Animal models / Animals / Cardiomyopathies - genetics / Cardiomyopathies - metabolism / Cardiomyopathies - pathology / Cardiomyopathy / Cloning / Degeneration / Depletion / Domestic animals / Dystrophin / Female / Frameshift Mutation - genetics / Gene Knockout Techniques / Gene therapy / Genetic modification / Genome editing / Glycoproteins / Heart / Heterogeneity / Hogs / Laboratory Medicine / Male / Medical treatment / Medicine / Medicine & Public Health / Mutation / Myocardium - chemistry / Myocardium - metabolism / Myocardium - pathology / Nuclear transfer / Pathology / Regeneration / Sarcoglycans - deficiency / Sarcoglycans - genetics / Sarcolemma / Signs and symptoms / Somatic cell nuclear transfer / Swine / technical-report / Tissue engineering / Tissues