Friedreich ataxia (FA) is a rare, inherited, neurodegenerative disease caused by an intronic guanine-adenine-adenine (GAA) trinucleotide expansion in the FXN gene, which encodes the frataxin (FXN) protein. FXN insufficiency impairs iron metabolism within the mitochondria, leading to accumulation and deposition of iron and oxidative stress.
Generally, the clinical phenotype of patients with FA includes gait and limb ataxia, dysarthria, scoliosis, and sensory deficits. Secondary diseases, such as cardiomyopathy and diabetes, may also occur.
The management of the disease thus requires a multidisciplinary approach, combining pharmacological treatment with physical, occupational, and speech therapies, along with surgery to manage the symptoms and disease-related complications of FA as needed.
Here, we will present the molecular approaches with encouraging evidence for treating FA, as discussed by Yang and colleagues in Drug Discovery Today.
Read more about FA treatment
As result of numerous efforts, the US Food and Drug Administration (FDA) has recently approved omaveloxolone (Skyclarys™), a nuclear factor erythroid-derived 2-related factor 2 activator, as the first treatment for FA. According to the clinical trial data, omaveloxolone slows disease progression, thereby lessening disease burden.
However, omaveloxolone does not provide a definitive cure for FA, and the search for therapeutic options for patients with FA remains a difficult path. There are other promising molecular therapeutic interventions, but the translation of promising preclinical findings into consistent clinical studies is challenging.
“Although many promising therapeutic agents are under investigation for the treatment or cure of FA, most have been tested in small clinical trials or in tissue types or models that do not fully recapitulate the multisystemic nature of the disease,” Yang and colleagues said.
Additional antioxidants with demonstrated potential as FA treatments are EPI-743, a vatiquinone redox therapy, and RT001, a stabilized deuterated linoleic acid homolog.
EPI-743 was found to be safe and to improve neurological function over a 24-month period in a double-blind, placebo-controlled FA trial. However, it appears to be less effective in improving cardiac function and visual acuity.
RT001 enhanced cardiopulmonary function, but not neurological function, in a phase 1/2, double-blind trial with patients with FA. According to the results of the trial, a total maximum dose of 9.0 g/day was well tolerated. However, RT001 comes with caveats as it needs to be metabolized into soluble substances that can penetrate brain tissue and it may lead to gastrointestinal side effects when a single dose of more than 9.0 g is taken.
Theoretically, idebenone, a free radical scavenger, might be useful in treating patients with FA at early stages. However, a phase 3 study found no significant improvement in cardiac status and neurological function in pediatric patients treated with idebenone. These results could be, nevertheless, limited by selection bias and a relatively short observational period.
Read more about diagnosing FA
Dimethyl fumarate and resveratrol were shown to modulate FXN expression levels in certain cell types derived from patients with FA. However, further studies are needed to ascertain their potential role as FA therapies.
Iron chelators, such as deferoxamine and deferiprone, aim to prevent iron accumulation in the mitochondria of FXN-deficient cells.
Deferiprone in particular has been demonstrated to rescue cardiomyocytes from iron accumulation in several models of FA. However, a 6-month, randomized, placebo-controlled trial found no neurological improvement in patients treated with deferiprone. These patients even worsened their clinical scores when treated with doses of 40 mg/kg. On the other hand, cardiac symptoms were attenuated with lower doses.
More recently, ferroptosis inhibitors, such as lipophilic methylene violet analogs, have emerged as compounds with therapeutic potential in FA but further studies are warranted.
Histone deacetylase inhibitors, such as 2-aminobenzamide, have been shown to upregulate FXN expression. However, 2-aminobenzamide showed suboptimal brain penetrability and caused gastrointestinal toxicity in animal models. Therefore, alternative compounds, such as Click-1, are currently under investigation.
Nicotinamide (also known as vitamin B3) also upregulates FXN expression as demonstrated in animal studies and in a small open-label trial enrolling patients with FA. However, despite being well tolerated, nicotinamide did not improve patients’ clinical rating scales after 8 weeks of treatment. Furthermore, a study performed in induced pluripotent stem cell-derived neurons from patients with FA has demonstrated that nicotinamide-induced FXN upregulation could not be sustained.
Read more about guidelines for monitoring and managing FA
Sulforaphane, a small lipophilic isothiocyanate product, was able to restore FXN expression in FA fibroblasts. Moreover, it has potent antioxidant and anti-inflammatory properties. However, further studies are needed to establish the therapeutic potential of sulforaphane in FA.
Given the genetic background of FA, gene therapy has emerged as an attractive therapeutic option for the disease. Different delivery tools, such as an FXN-expressing adeno-associated virus and a zinc finger-mediated editing approach, have been successfully applied to restore FXN expression in cellular models. However, both methodologies have limitations.
More recently, researchers used the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene-editing tool to remove the GAA expansion site in FXN of mice models and human cells. Despite the promising results, there are concerns regarding transplant rejection, the toxicity of overexpressing FXN, and the accumulation of double-strand DNA breaks from gene editing, which delays cell proliferation.
Several protein-based approaches have been investigated in the context of FA. These include synthetic oligonucleotides, such as anti-AAG gapmer oligonucleotides, which may have improved binding affinity and potency compared with other compounds. However, studies assessing their toxicity are still lacking.
Another approach involves FXN fusion protein replacement using a trans-activator of transcription cationic peptides as a vehicle. Such an approach was successfully applied in rodent models of FA, leading to increased life span. In terms of limitations, it shows a relatively low recovery rate in aconitase activity and its efficacy depends on disease stage. Future studies in a more suitable FA neuron model are of utmost importance to determine its potential as an FA therapy.
Complementary synthetic transcription elongation factor (Syn-TEF1) and interferon (IFN)-c-1b, a recombinant cytokine, have also emerged as molecular approaches with potential application in FA treatment.
Syn-TEF1 allows for FXN transcription under GAA repeat expansion-induced pausing of RNA polymerase II activity. Studies in several FA cell models recapitulating different stages of the disease, as well as in a mouse model, supported its specificity and efficacy. The safety, brain penetrability, and efficacy of Syn-TEF1 remains to be explored in further in vivo studies and clinical trials.
Read more about the complications of FA
The ability of IFN-c-1b to enhance FXN expression has been demonstrated in various cell types with promising therapeutic outcomes in animal studies. However, a 6-month, double-blind trial failed to show improvement in modified Friedreich’s Ataxia Rating Scale scores and FXN levels vs placebo.
“The heterogenetic nature of FA might well dictate the need to use a combination of treatment modalities for effective and individualized treatment of patients,” said Yang and colleagues.
The investigation of combination therapies is still in its very early stages. Current studies only tested the combination of deferiprone with idebenone, and none revealed any significant beneficial outcomes in alleviating neurological dysfunction and cardiac complications. Only 1 study demonstrated a slight improvement in reducing cardiac lesions in patients with FA. However, all studies were limited by small sample size and selection bias.
Further studies are required to confirm the potential added value of this and other combination therapies in FA.
Yang W, Thompson B, Kwa FAA. Molecular approaches for the treatment and prevention of Friedreich’s ataxia. Drug Discov Today. 2022;27(3):866-880. doi:10.1016/j.drudis.2021.11.003
FDA approves first treatment for Friedreich’s ataxia. News release. U.S Food & Drug Administration; February 28, 2023.