Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich’s Ataxia Pre-Clinical Models and Clinical Trials

Abstract

Friedreich’s ataxia (FRDA) is an autosomal, recessive, inherited neurodegenerative disease caused by the loss of activity of the mitochondrial protein frataxin (FXN), which primarily affects dorsal root ganglia, cerebellum, and spinal cord neurons. The genetic defect consists of the trinucleotide GAA expansion in the first intron of FXN gene, which impedes its transcription. The resulting FXN deficiency perturbs iron homeostasis and metabolism, determining mitochondrial dysfunctions and leading to reduced ATP production, increased reactive oxygen species (ROS) formation, and lipid peroxidation. These alterations are exacerbated by the defective functionality of the nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor acting as a key mediator of the cellular redox signalling and antioxidant response. Because oxidative stress represents a major pathophysiological contributor to FRDA onset and progression, a great effort has been dedicated to the attempt to restore the NRF2 signalling axis. Despite this, the beneficial effects of antioxidant therapies in clinical trials only partly reflect the promising results obtained in preclinical studies conducted in cell cultures and animal models. For these reasons, in this critical review, we overview the outcomes obtained with the administration of various antioxidant compounds and critically analyse the aspects that may have contributed to the conflicting results of preclinical and clinical studies.

Clinical Approaches for Mitochondrial Diseases

“…Even Raxone (Idebenone), which has demonstrated therapeutic effects for LHON disease in numerous case studies, has not yet received FDA approval. While Omaveloxolone is the first FDA-approved treatment for mitochondrial disease, there are conflicting opinions on its clinical effects, and the strength of the supporting efficacy data is still debatable [208].…”

Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8-800 murine model of Friedreich’s ataxia

“…To date, there is no cure for FRDA. Despite enormous efforts made to develop effective therapeutic strategies, the only treatment for symptom management, Omaveloxolone, was approved by the U.S. Food and Drug Administration in 2023 [18,19]. Therefore, to continue deciphering all the pathological mechanisms underlying the disease and testing other potentially effective drugs, we need to count with in vitro and in vivo models of the disease that resemble the human pathology as faithfully as possible.…”