Inhibition of Rho-associated kinases ROCK1 and ROCK2 as a Therapeutic Strategy to Reactivate the Repressed FXN Gene in Friedreich Ataxia

Inhibition of Rho-associated kinases ROCK1 and ROCK2 as a Therapeutic Strategy to Reactivate the Repressed FXN Gene in Friedreich Ataxia. Minggang Fang, Shahid Banday, Sara K. Deibler, Tessa M. Simone, Madison Coleman, Emerald O’Connor, Rui Li, Lihua Julie Zhu, Michael R. Green, Journal of Neuroscience 22 May 2025, e2307242025; DOI: 10.1523/JNEUROSCI.2307-24.2025 

 Through an RNA interference screen, we identified ROCK1 and ROCK2 kinases as critical repressors of FXN expression, making them promising therapeutic targets for upregulating FXN in patient-derived cells. Treatment with small-molecule ROCK inhibitors, including the FDA-approved drug belumosudil and clinically advanced fasudil, restores frataxin levels, alleviates mitochondrial defects, and improves disease phenotypes in cells and animal models. These findings establish ROCK kinases as targets for Friedreich ataxia therapy and open new avenues for repurposing existing ROCK inhibitors, warranting clinical exploration.

Inhibition of Rho-associated kinases ROCK1 and ROCK2 as a Therapeutic Strategy to Reactivate the Repressed FXN Gene in Friedreich Ataxia