69 Small‑Molecule–regulated RNA switch achieves therapeutically safe levels of Frataxin in mouse models of Friedreich’s Ataxia.
69 Small‑Molecule–regulated RNA switch achieves therapeutically safe levels of Frataxin in mouse models of Friedreich’s Ataxia. Jon Dempersmier, Mariam Elhawary, Ian McLachlan, Hayley Ulloa, Kai Li, Diane Hamann, Zhiping Weng, Ricardo Mouro Pinto, Travis Wager, Simon Xi, Sam Hasson;
Friedreich’s ataxia (FA) represents a compelling use case for regulated gene therapy. FA is an autosomal recessive disorder caused by repeat expansion–mediated silencing of the FXN gene, resulting in impaired iron–sulfur cluster biogenesis, mitochondrial dysfunction, neurodegeneration, and cardiomyopathy. While constitutive AAV-mediated FXN replacement has shown efficacy in preclinical models, excessive Frataxin expression has been associated with cardiotoxicity, highlighting the need for controlled dosing.
This system consists of DNA-encoded regulatory elements, termed RSwitches, which are selectively modulated by matched synthetic small molecules, or RDrugs, in a dose-dependent manner.
RDrugs direct specific pre-mRNA splicing events required for productive transgene expression, enabling temporal control on the order of hours and quantitative control of protein output almost five orders of magnitude from AAV vectors.
