Sulforaphane Targets Multiple Pathological Processes in Friedreich Ataxia Patient-Induced Pluripotent Stem Cell-Derived Sensory Neurons

<b><i>Aims:</i></b> In Friedreich ataxia (FRDA), early motor discoordination stems from dysfunctional sensory neurons in the spinal cord driven by epigenetic dysregulation, frataxin (FXN) deficiency, oxidative stress, and inflammation. Omaveloxolone, a nuclear factor erythroid 2-related factor-2 (NRF2) inducer, is the only treatment available. In various chronic disease models, sulforaphane (SF) can target NRF2 and the above processes. This study compared the effects of SF with omaveloxolone and dimethyl fumarate (DMF) in sensory neurons generated from FRDA patient-induced pluripotent stem cells and their isogenic control. <b><i>Results:</i></b> The successful generation of the FRDA and isogenic control sensory neurons was confirmed by the positive expression of β-III TUBULIN, BRN3A, ISLET1, PERIPHERIN, and tropomyosin receptor kinase C. In comparison with the isogenic control, FRDA sensory neurons displayed an aberrant gene expression profile alike to that reported in patients. None of the drugs affected the viability of the isogenic control sensory neurons. SF treatment improved the viability of FRDA sensory neurons by up to 61% versus the untreated control. DMF treatment showed a modest 35% increase, while omaveloxolone lacked an effect. SF-treated FRDA sensory neurons demonstrated increased reduced glutathione/oxidized glutathione ratio and expression of FXN and redox markers, and a reduced expression of selected epigenetic enzymes and inflammatory cytokines, at the respective gene and protein levels. DMF and omaveloxolone treatments only modulated some of these biomarkers. <b><i>Innovation:</i></b> We revealed the therapeutic potential of SF and how it performs in comparison with omaveloxolone and DMF, in a physiologically and genetically relevant <i>in vitro</i> FRDA model. <b><i>Conclusion:</i></b> SF offers a multipronged approach to alleviating the different cellular events underlying FRDA. <i>Antioxid. Redox Signal.</i> 43, 308-327.