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Enzyme replacement therapy in heart failure associated with tafazzin deficiency

Enzyme replacement therapy in heart failure associated with tafazzin deficiency
Michael T. Chin, MD, PhD, Associate Professor, University of Washington, Seattle, WA

Award—US $50,000 over 1-year period

*Funding for this award was provided by the Will McCurdy Fund for the Advancement of Therapies for Barth Syndrome


Barth syndrome is an X-linked disorder resulting from defects in the gene encoding Tafazzin, an acyltransferase that modifies cardiolipin to the tetralinoleoyl form and is essential for mitochondrial respiration. The clinical manifestations of Barth syndrome include muscular hypotonia, cardiomyopathy and neutropenia. At present, no effective therapy exists for affected individuals. The main issue that this project will address is whether the mechanism by which heart failure develops involves excessive production of mitochondrial reactive oxygen species (ROS) from defective electron transport that then predisposes to cardiac myocyte hypertrophy and apoptosis. We will also assess whether treatment with exogenous tafazzin can suppress reactive oxygen species generation and thereby prevent hypertrophy, apoptosis and heart failure. We have obtained a mouse model of Barth syndrome from Jackson laboratories. We have also generated recombinant tafazzin protein expressed in E. coli that is modified to contain a cellular permeability peptide, purified it to homogeneity and verified its ability to enter cells and correct respiration defects. We have found that that tafazzin-deficient myocytes produce ROS at higher levels than control cells, and that exogenous tafazzin protein suppresses this excess ROS generation. In this proposal, we will examine whether induction of hypertrophy by transverse aortic constriction accelerates hypertrophy, apoptosis and heart failure in tafazzin-deficient cells or animals through excessive production of ROS and then whether exogenously administered recombinant tafazzin is sufficient to ameliorate these responses. These findings will help us understand whether recombinant tafazzin can provide a treatment for cardiomyopathy in Barth syndrome patients.

Associated Publications to Date:

Dinca AA, Chien WM, Chin MT. Identification of novel mitochondrial localization signals in human Tafazzin, the cause of the inherited cardiomyopathic disorder Barth syndrome. J Mol Cell Cardiol. 2017 Nov 9. pii: S0022-2828(17)30340-1. doi:10.1016/j.yjmcc.2017.11.005. [Epub ahead of print] (PubMed Absract)*

Dinca A, Chien WM, Chin MT. Intracellular delivery of proteins with cell-penetrating peptides for therapeutic uses in human disease. Int J Mol Sci. 2016 Feb 22;17(2):263. doi:10.3390/ijms17020263. Review. (PubMed - Open Access)*

Associated Presentations to Date:

BSF 2016 Conference
July 21, 2016 ~ Clearwater Beach, FL

Tafazzin enzyme replacement therapy for Barth syndrome

BSF 2014 Conference
June 27, 2014 ~ Clearwater Beach, FL

Tafazzin enzyme replacement therapy in a mouse model of Barth syndrome

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