Friedreich’s ataxia is a rare inherited disease that causes damage to the nervous system and worsening muscle coordination over time, often beginning in childhood. It affects about 1 in 50,000 people of both sexes. People with the disease must use a wheelchair within 10 to 20 years of diagnosis and in later stages can be totally incapacitated. Life expectancy may be shortened, and heart disease is the most common cause of death. Friedreich’s ataxia has no cure or effective treatment, but the symptoms can be treated to allow optimal functioning for as long as possible. The disease is caused by mutations in the FXN gene, which codes for frataxin, a protein essential for assembling iron and sulfur molecules. The researchers are developing a drug for the treatment of Friedreich’s ataxia. This drug acts as an antioxidant to help counter the oxidative destruction of brain, spinal cord and muscle cells seen in patients with this disease.
Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative and cardiodegenerative disorder caused by decreased function of the protein frataxin. Frataxin is important for the assembly of iron-sulfur clusters in mitochondrial respiratory-chain complexes. Although the biochemical basis of FRDA is being further elucidated, current knowledge allows the development of new therapeutic approaches for effective treatment. Despite the diverse functions that mitochondria carry out, genetic defects that are nonlethal manifest themselves with relatively common biochemical phenocopies. Hallmarks of many of these diseases include decreased ATP product, increased oxidative stress and increased lactate formation. These biochemical alterations are most remarkable in respiratory chain diseases. Considerable evidence suggests that redox-coupling defects underlie the observed biochemical manifestations of select mitochondrial diseases, including FRDA. Specifically, evidence suggests that genetic defects giving rise to structural changes within the respiratory chain may alter the physical-chemical properties of redox centers, impairing electron flux and giving rise to the aforementioned observations. As a means to develop new therapeutic approaches to the treatment of mitochondrial diseases, we hypothesized that compounds that restore electrochemical coupling between defective redox centers may result in (partial) restoration of redox flux and improvement. EPI-A0001, a redox encrypted bioisostere of CoQ10, has been identified through a proprietary biodesign-guided chemical mining approach and evaluated in functional assays of FRDA. The preliminary developability assessment of EPI-A0001 is favorable.
University of Pennsylvania, Philadelphia
Robert B. Wilson, M.D., Ph.D.
Friedreich’s Ataxia Research Alliance, Downington, Pennsylvania
Public Health Impact
There are currently no approved drugs for Friedreich’s ataxia, a life-shortening, highly debilitating disease. The market is such that this disease, with an orphan designation, has not warranted sufficient commercial interest on the part of large pharmaceutical companies. Inroads into therapeutic development in Friedreich’s ataxia are likely to benefit other, larger affected patient populations, such as Parkinson’s disease patients, that possess potential shared disease mechanisms.
Work on this project is complete. The investigator successfully filed an Investigational New Drug (IND) application using BrIDGs data and initiated clinical testing. EPI-A0001 eventually entered Phase II clinical trials in patients with Friedreich’s ataxia.
- Synthesis of Good Manufacturing Practice (GMP) and non-GMP material
- Formulation development
- Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies
- Investigational New Drug (IND)-directed toxicology