Friedreichs Ataxia (FA) is a rare genetic disease caused by mutations that prevent production of the mitochondrial matrix protein frataxin (FXN), which functions in mitochondrial iron homeostasis, notably in the de novo biosynthesis of iron-sulfur cluster proteins. In its absence, free iron accumulates in mitochondria, iron-sulfur proteins lose activity and energy production fails through damage to the electron transport chain. The lead investigator has developed a protein replacement approach that uses a cell-penetrant peptide to deliver functional FXN to the mitochondrial matrix. Protein replacement therapy is a well-established approach to metabolic diseases, such as diabetes, lysosomal storage disorders and hemophilia. Work in patient-derived cellular and animal models has demonstrated that replacement of functional FXN using the peptide TAT can correct the FA disease phenotype. In a mouse model, TAT-FXN extends lifespan, corrects histology and biochemical defects, and improves cardiac and neurological function. Moreover, this TAT-protein delivery platform could be extended beyond FA, representing a technology with the potential to treat multiple mitochondrial disorders for which there are no current therapies. The TRND project team are collaborating on the development of the recombinant fusion protein, CTI-1601, conducting additional efficacy and pharmacokinetic studies, and developing and validating the biochemical assays necessary to evaluate CTI-1601. These studies are supporting the preparation and filing of an Investigational New Drug application to the Food and Drug Administration by the lead collaborators.

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National Center for Advancing Translational Sciences
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Rogers, Cynthia E (2014) Here/in this issue there/abstract thinking: healthy moms, healthy babies (and brains). J Am Acad Child Adolesc Psychiatry 53:1143-4