A Protein Replacement Drug for Friedreich’s Ataxia

Friedreich’s ataxia (FA) is a rare, progressive condition affecting multiple systems in the body. The disease typically begins in mid-childhood, leading to an inability to stand or walk within 15 years of onset. Patients experience progressive loss of voluntary muscle control and coordination, debilitating scoliosis (abnormal curvature of the spine), and heart failure leading to premature death by age 50. Some patients also develop diabetes and suffer loss of hearing and vision. There are no approved treatments for FA other than supportive care. The lead collaborator has developed a technology to deliver functional frataxin protein to patients. The purpose of this project is to support the development of this protein replacement therapy.

Scientific Synopsis

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.

Lead Collaborator

Chondrial Therapeutics, LLC, Indianapolis
R. Mark Payne, M.D.

Public Health Impact

There are no approved treatments for FA. The disease strikes in childhood, is progressively debilitating and leads to premature death by age 50.


TRND scientists conducted additional efficacy and toxicology studies and developed and validated the biochemical assays necessary to evaluate the drug product. These studies supported the preparation and filing of an Investigational New Drug (IND) application with the Food and Drug Administration by the lead collaborators. The IND was cleared by the FDA, allowing clinical trials to begin. See ClinicalTrials.gov, NCT04176991.