Unlocking Sulforaphane's Potential in Friedreich Ataxia: Further Evidence from Preclinical Investigations Using...

Friedreich ataxia (FRDA) is a neurodegenerative disorder typically caused by autosomal recessive inheritance of expanded guanine-adenine-adenine (GAA) repeats (>56) in both alleles of the frataxin (FXN) gene, leading to FXN protein deficiency. Omaveloxolone (Omav) is the only approved therapy. Therefore, further therapeutic options are essential. Previously, we showed that sulforaphane (SF) increases FXN expression and modulates epigenetic, inflammatory, and oxidative stress pathways in sensory neurons from a patient induced pluripotent stem cells (iPSCs) with 550 GAA1 repeats (FA2). Here, we compared SF, Omav, and dimethyl fumarate (DMF) treatment in sensory neurons derived from three patient iPSC lines with varying GAA1 repeats: FA1 (867), FA2, and FA3 (450).

In FA1, SF treatment improved cell viability and reduced oxidative stress and inflammation. In FA3, SF increased cell viability, FXN protein levels, and gene and protein expression of redox markers, while targeting dysregulated epigenetic mechanisms and inflammation. All three lines showed SF's consistent anti-oxidant and anti-inflammatory effects. Responses to Omav and DMF varied across the FA lines with less pronounced effects than when treated with SF. Overall, SF was more effective than Omav and DMF in improving cell viability and regulating FXN expression and epigenetic, redox, and inflammatory pathways.

These findings reveal variability in drug responses based on FRDA genetic profiles and position SF as a promising drug to address multiple pathological processes.

Our preclinical data support SF as a strong FRDA drug candidate. Clinical evaluation is warranted to confirm its full therapeutic potential. Antioxid. Redox Signal. 00, 000-000.