Epigenetic reactivation in Friedreich’s ataxia from benzamides to gene‑targeted chimeras

Ansari, F. U., Rojsajjakul, T., Liu, J., Nageshwaran, S. K., & Blair, I. A. (2026). Epigenetic reactivation in Friedreich’s ataxia from benzamides to gene‑targeted chimeras. Expert Opinion on Drug Discovery, 21(7), 779–791. doi:10.1080/17460441.2026.2689723 

 This review summarizes the evolution of FXN protein‑reactivating approaches from first‑generation systemic epigenetic therapies, including class I‑selective benzamide histone deacetylase inhibitors and high‑dose nicotinamide, to emerging locus‑targeted platforms such as anti‑gene oligonucleotides and gene‑targeted chimera small molecules. The authors also examine splice‑modulating strategies aimed at increasing the extra‑mitochondrial FXN‑E isoform, discuss delivery and safety challenges across modalities, and highlight biomarker frameworks integrating isoform‑resolved FXN protein measurements and chromatin readouts.

Epigenetic reactivation in Friedreich’s ataxia from benzamides to gene‑targeted chimeras