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Reversal of cardiolipin deficiency in Barth syndrome mouse model

Reversal of cardiolipin deficiency in Barth syndrome mouse model
Trudy M. Forte, PhD, Director of Research, Lypro Biosciences, Inc., Berkeley, CA

Award—US $49,997 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 recessive disorder characterized by cardiomyopathy, skeletal muscle weakness and neutropenia. Consistent with findings of mitochondrial ultrastructure changes, the disorder is associated with alterations in the content and composition of the unique phospholipid, cardiolipin, which is abundant in the inner membrane of mitochondria. The molecular shape and physical properties of cardiolipin appear to be critical for optimal function of this highly specialized, protein-rich, membrane. Inherited mutations in the tafazzin (TAZ) gene are associated with Barth syndrome. Studies have revealed that the TAZ encodes a phospholipid transacylase that is localized to mitochondria and functions in cardiolipin acyl chain remodeling. While cardiac tissue is normally comprised of > 90 % tetra-linoleoyl cardiolipin (CL), subjects with Barth syndrome show characteristic differences in cardiolipin acyl chain composition, including decreased levels of total cardiolipin, decreased levels of tetra- linoleoyl cardiolipin and increased levels of monolysocardiolipin.

Recently, we developed a water-soluble cardiolipin transport vehicle termed cardiolipin nanodisks (CL-ND). These unique particles are made up solely of a scaffold protein, apolipoprotein A-I, and cardiolipin. Our proposed research will employ the TAZ shRNA knockdown mouse model that manifests cardiolipin deficiency, cardiomyopathy, skeletal muscle weakness, mitochondrial respiratory chain dysfunction and low weight. The following Aim describes experiments designed to test the ability of CL-ND injected daily versus once a week as a bolus to bypass or compensate for TAZ knockdown dependent effects.

Associated Publications to Date:

Ikon N, Hsu FF, Shearer J, Forte TM, Ryan RO. Evaluation of cardiolipin nanodisks as lipidreplacement therapy for Barth syndrome. J Biomed Res. 2017 Nov 1. doi: 10.7555/JBR.32.20170094. [Epub ahead of print] (PubMed - Open Access)*

Ikon N, Su B, Hsu FF, Forte TM, Ryan RO. Exogenous cardiolipin localizes to mitochondria and prevents TAZ knockdown-induced apoptosis in myeloid progenitor cells. Biochem Biophys Res Commun. 2015 Jul 8. pii: S0006-291X(15)30243-6. doi: 10.1016/j.bbrc.2015.07.012. [Epub ahead of print] (PubMed - Open Access)*

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