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Development of mitochondria-targeted peptide compounds as Barth syndrome therapeutics

Nathan Alder, PhD, Associate Professor, University of Connecticut, Storrs, CT

Cardiolipin is a phospholipid that is required for the proper structure and function of mitochondrial membranes. The biosynthesis and compositional remodeling of cardiolipin requires a number of specialized enzymes. Barth syndrome is caused by dysfunction in one of these enzymes, tafazzin, resulting in reduced levels cardiolipin with the proper composition and a buildup of a biosynthetic intermediate, monolysocardiolipin. There are no cures for mitochondrial diseases, including Barth syndrome. However, Szeto-Schiller (SS) peptides are among the most promising compounds under investigation for mitochondrial dysfunction. Indeed, the recent TAZPOWER clinical trial conducted with the lead compound SS-31 (elamipretide) revealed strong promise for the treatment of Barth syndrome. The twofold objective of this research is: (i) to better understand how SS peptides work at the molecular level to improve mitochondrial function in Barth syndrome models, and (ii) to leverage this mechanistic information for the development of more efficacious compounds to treat Barth syndrome. To achieve these goals, we will use a number of experimental systems (model membranes and isolated mitochondria) coupled with advanced biochemical and biophysical methods to understand how SS-31 may alter the properties of membranes with normal cardiolipin composition vs. those with a lipid composition characterized by Barth syndrome. We will then test a rationally designed library of compound analogs for their ability to restore membrane properties and mitochondrial function of Barth syndrome models. The result of this one-year research program will be a detailed understanding of how these peptide compounds act to restore the membrane defects caused by dysfunctional cardiolipin remodeling and the identification of novel compound variants that will pave the way for the development of more effective next-generation Barth syndrome therapeutics. 

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