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Novel antioxidant therapies in a mouse model of Barth syndrome

Novel antioxidant therapies in a mouse model of Barth syndrome
Colin Phoon, MD, MPhil, Associate Professor, New York University School of Medicine, New York, NY

Award—US $50,000 over 2-year period

*Funding for this award was provided by the Paula & Woody Varner Fund


A rare X-linked, multisystem mitochondrial disease, Barth syndrome is characterized by cardiomyopathy, skeletal myopathy, neutropenia, and growth delay. Barth syndrome is caused by mutations in tafazzin (taz). Tafazzin is a transacylase that remodels the mitochondrial phospholipid cardiolipin into its mature, functional form. Tafazzin deficiency leads to abnormal cardiolipin profiles, leading to damage of the structural integrity and functioning of mitochondria. Cardiomyopathies are a leading cause of death and disability in Barth syndrome. In this IDEA proposal, we will investigate new potential long-term therapies for the cardiomyopathy in Barth syndrome. A taz knockdown (TAZKD) transgenic mouse is currently our best model of the human condition; the findings of cardiomyopathy, skeletal myopathy, and mitochondrial structural and functional abnormalities appear similar to human Barth syndrome. Several research laboratories have now revealed a critical role of reactive oxygen species (ROS) in the pathogenesis of the cardiomyopathy in Barth syndrome. Preliminary data from ours and other laboratories point to the therapeutic potential of reduction of mitochondrial ROS. The mechanisms are not clear, but may be independent of bioenergetics or normalization of cardiolipin. We propose to investigate two specific molecules that possess or enhance a cell’s ROS-scavenging properties in the TAZKD mouse model of Barth syndrome: 1) N- acetylcysteine, which increases glutathione stores within the mitochondria and is used in several disease conditions and being tested in others; 2) MitoQ10, a synthetic conjugated molecule that selectively enters and accumulates within mitochondria; once there, MitoQ10 is reduced to its active ubiquinol form to act as a powerful antioxidant, which has been used to prevent mitochondrial oxidative damage and treat disease conditions in animal models and patients. This study will focus on treatment of adult mice that have already developed the cardiomyopathy and thus mimic treatment of patients with existing cardiac dysfunction. These preclinical data should help pave the way to clinical trials for patients with Barth syndrome.

Associated Publications to Date:

Xu Y, Phoon CK, Berno B, D'Souza K, Hoedt E, Zhang G, Neubert TA, Epand RM, Ren M, Schlame M. Loss of protein association causes cardiolipin degradation in Barth syndrome. Nat Chem Biol. 2016 Jun 27. doi: 10.1038/nchembio.2113. [Epub ahead of print] (PubMed Abstract)

Associated Presentations to Date:

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

Recapitulating the Barth cardiomyopathy in the inducible mouse model of tafazzin deficiency

BSF 2016 Conference
July 22, 2016 ~ Clearwater Beach, FL

Mitochondria and Barth syndrome

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

Cardiomyopathy and myocardial noncompaction in Barth syndrome

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