Friedreich’s ataxia (FA) is a debilitating inherited disorder, where progressive damage to the nervous system causes impaired muscle control as well as heart and spine problems. Currently, there are no FA-specific treatments and no cure available for the disease. However, with ongoing research, there is a range of therapies in the pipeline and in clinical trials for the prevention and treatment of FA. Some of the examples of investigative therapies are discussed below.
Currently, we know that FA is caused by the lack of a protein called frataxin, which is normally present in the mitochondria (the part of a cell involved in producing energy). The more the exact role of frataxin and how its absence causes the symptoms of FA is understood, the more and better drugs can be designed to specifically target aspects of these pathways that are more likely to be effective in treating or even preventing FA.
The loss of frataxin may increase oxidative stress, which can result in the damage and death of cells such as nerve and muscle cells. Oxidative stress is caused by free radicals, which are produced by the mitochondria during energy production. Based on this, it is thought that antioxidants, or substances that can reduce the levels of free radicals, may help treat FA.
Multiple clinical trials have been carried out testing the safety and efficacy of various antioxidants in people with FA, however, the results do not suggest a clinical benefit for the treatment of the disease. For example, a clinical trial of idebenone compared to a placebo (NCT00905268) suggested no clinical benefit.
Further research into different or modified antioxidants is planned.
Protein replacement therapy
As FA is believed to be caused by the lack of functioning frataxin protein, one therapeutic aim is to directly provide the patients with the missing protein. This is called protein replacement therapy.
For example, Chondrial Therapeutics is developing CTI-1601 (TAT-Frataxin), a synthetic frataxin protein combined with a system called trans-activator of transcription (TAT) to deliver it to the mitochondria. This has been tested in preclinical studies in mice and results published in the scientific journal Human Molecular Genetics suggest that it may have a significant clinical benefit as it reduced the signs of FA and increased the lifespan of the animals. Chondrial Therapeutics aims to file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) in order to proceed to Phase 1 clinical trials in FA patients.
Gene replacement therapy
Gene replacement therapy aims to deliver a healthy copy of the FXN gene to the body. There are multiple companies researching gene replacement therapy as a potential cure for FA. For example, Agilis Biotherapeutics, Voyager Therapeutics, and AAVLife are researching this possibility, however, no clinical trials in humans are planned yet.
Epigenetic factors can influence how much of a protein is made. Normally, a gene (which contains the instructions to make a protein) is first copied into a messenger molecule called messenger RNA (or mRNA), which is “read” by the protein-making machinery of the cells. Epigenetic factors can, for example, reduce the production of mRNA or prevent the mRNA from being used to make proteins. Approaches taken to alter these may increase the levels of frataxin protein, and treat FA.
Current approaches include:
- Inhibiting the histone deacetylase complex (HDAC), which is involved in “silencing” genes such as FXN so less mRNA is made. RepliGen developed RG2833, an HDAC inhibitor, which was sold to BioMarin for continued development as an FA therapy.
- Using RNA and DNA that are targeted to bind and block the mutation in the frataxin gene, which stops the protein from being made. Trials carried out in human cells have demonstrated that the concept can work, and the therapy can increase the production of frataxin protein. These results are published in the scientific journal Nature Communications.
There are many Friedreich’s ataxia experimental treatments either about to enter or already in clinical trials. These target different aspects of the disease.
For example, RTA 408 (omaveloxolone), developed by Reata Pharmaceuticals, is currently in Phase 2 clinical trials (NCT02255435). RTA 408 acts to activate Nrf2, an enzyme that has decreased activity in FA patients. Nrf2 is a transcriptional activator or a protein that increases the production of proteins involved in reducing oxidative stress and may boost energy production by the mitochondria. Another potential drug that targets Nrf2 is CAT-4001 (by Catabasis).
EPI-743 (by BioElectron) aims to improve mitochondrial energy production and reduce oxidative stress. The potential drug showed clinical benefit in a small open-label trial. It was also tested in two Phase 2 clinical trials (NCT01728064 and NCT01962363).
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