Authors: Suya Wang , Yifei Li , Yang Xu , Qing Ma , Zhiqiang Lin , Michael Schlame , Vassilios J. Bezzerides , Douglas Strathdee , and William T. Pu
Summary: Rationale: Barth syndrome (BTHS) is an X-linked cardiac and skeletal myopathy caused by mutation of the gene Tafazzin (TAZ). Currently there is no targeted treatment for BTHS. Lack of a proper genetic animal model that recapitulates the features of BTHS has hindered understanding of disease pathogenesis and therapeutic development.
Objective: We characterized murine germline (TAZ-KO) and cardiac specific (TAZ-CKO) Taz knockout models and tested the efficacy of AAV-mediated TAZ gene replacement therapy.
Methods and Results: TAZ-KO caused embryonic and neonatal lethality, impaired growth, dilated cardiomyopathy, and skeletal myopathy. TAZ-KO mice that survived the neonatal period developed progressive, severe cardiac dysfunction and fibrosis. Cardiomyocyte specific inactivation of floxed Taz in CMs using Myh6-Cre caused progressive dilated cardiomyopathy without fetal or perinatal loss. Using both constitutive and conditional knockout models, we tested the efficacy and durability of Taz replacement by AAV gene therapy. Neonatal AAV-TAZ rescued neonatal death, cardiac dysfunction, and fibrosis in TAZ-KO mice, and both prevented and reversed established cardiac dysfunction in TAZ-KO and TAZ-CKO models. However, both neonatal and adult therapies required high CM transduction (~70%) for durable efficacy.
Conclusions: TAZ-KO and TAZ-CKO mice recapitulate many of the key clinical features of BTHS. AAV-mediated gene replacement is efficacious when a sufficient fraction of CMs are transduced.
Source: Circulation Research, Mar 2020