Although German physician Nikolaus Friedreich first recognized Friedreich’s ataxia in 1863, it was not until 1996 that two scientific teams discovered the underlying cause of the disease: a mutation in the gene for frataxin protein. Since that time, researchers have identified two types of mutations that cause Friedreich’s ataxia and are working harder than ever to develop treatments and cures for the condition.
Some of the most basic treatments of Friedreich’s ataxia are antioxidants. The theory behind treating Friedreich’s ataxia with antioxidants is to mitigate the free radical damage accrued from dysfunctional mitochondria resulting from frataxin deficiency. “Without frataxin to handle iron safely and efficiently, mitochondria are no longer able to generate the iron-sulfur clusters (ISCs) and heme,” stated a report from Muscular Dystrophy Association. “Because the mitochondria are unable to direct the binding of iron with proteins to make the complexes necessary for ISC or heme synthesis, iron is left ‘free,’ able to induce the conversion of energy-production byproducts into toxic chemicals called free radicals.”
Other basic means of treatment include iron chelation, physical and speech therapy, and dietary restrictions. While these therapeutic options may be beneficial to reduce symptoms, patients will likely require medical interventions that restore mitochondrial function or replenish frataxin protein. To accomplish these goals, a handful of preclinical and investigational new drugs and more advanced treatments are in the development pipeline. As illustrated by Friedreich’s Ataxia Research Alliance, at least 26 compounds are in the stages of development, with the majority in the discovery and phase 2 clinical trial stages.
The most advanced therapeutic is EPI-743, a compound developed by Edison Pharmaceuticals to treat a range of mitochondrial myopathies, including Friedreich’s ataxia. EPI-743 counteracts cell redox stress, synchronizing energy generation in mitochondria. In May 2014, the FDA granted fast track status to EPI-743 for Friedreich’s ataxia after successful phase 1 and phase 2 clinical trials were completed. “Fast Track designation will facilitate Edison’s clinical development of EPI-743 for patients with Friedreich’s ataxia,” said Guy Miller, MD, PhD, CEO of Edison Pharmaceuticals, in a news release from the company. “We are fully committed to delivering the first approved drug for this highly debilitating and lethal disease for which there are no FDA-approved therapies.”
A few other phase 2-level treatments include ALCAR from University of South Florida, Resveratrol from Murdoch Children’s Research Institute in Australia, Nicotinamide from Imperial College in London, interferon gamma from Horizon, and erythropoietin (EPO) from a variety of research groups. Yet every successful drug target seems to be coupled with a greater number of unsuccessful treatments. At least seven therapeutics were removed from the Friedreich’s ataxia pipeline after demonstrating intolerable adverse events in patients or showing no statistically significant difference in patients’ health, and even more drug targets may have never even made it past synthesis to be tested in the laboratory.
Perhaps a more ideal approach directly considers the root cause of Friedreich’s ataxia: the frataxin gene. Gene therapy approaches can perform a variety of functions based on the end goal. Removing the gene defect by deleting the GAA repeat expansion, inserting a normal copy of the gene, or delivering RNA necessary for synthesizing frataxin protein may all contribute to a therapeutic effect for patients. As described by a report from Ataxia UK, a few basic research studies have shown success with genetic approaches. Starting at a cellular level, researchers at Children’s Medical Research Institute increased frataxin expression in Friedreich’s ataxia patient cells, increasing the cells’ resistance to oxidative stress. Going into mouse models of disease, an Ataxia UK-funded research group treated mice with frataxin DNA and saw an increase in frataxin protein levels.
As scientists learn more and more about Friedreich’s ataxia, they are able to direct their research efforts to creating treatments that show the greatest possible potential for treating Friedreich’s ataxia. Although the road from basic research in the laboratory to treating patients in the clinic is long and winding, researchers have made immense progress in the field.