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

Tiberi J, Segatto M, Fiorenza MT, La Rosa P. Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich's Ataxia Pre-Clinical Models and Clinical Trials. Biomedicines. 2023 Apr;11(5):1293. DOI: 10.3390/biomedicines11051293. PMID: 37238963.

 The issues discussed here indicate that there are still many dark spots that require elucidation in order for FRDA patients to benefit from effective antioxidant therapy. However, although the relationship between the lack of FXN in FRDA and the benefits of NRF2–ARE axis activation have not yet been fully elucidated, it is important to highlight the significant correlation found between FXN expression and NRF2 activity, which is associated with the presence of three highly conserved ARE sequences on the FXN gene promoter, which are crucial for the binding of the NRF2–sMaf complex to promote the transcription of detoxification and antioxidant genes [105,106]. In light of this, by addressing the limitations that currently separate pre-clinical models from patient trials and improving early diagnostic systems, it is auspicial that new treatments or molecules, especially in conjunction with other therapeutic approaches (i.e., lentivirus-mediated FXN gene delivery [228] or human embryonic stem cell (hESC) therapy [229]), may pave the way for effective treatments of this pathology.