Precise Progerin Targeting Using RfxCas13d: A Therapeutic Avenue for Hutchinson-Gilford Progeria Syndrome.

Abstract

Hutchinson-Gilford progeria syndrome (HGPS), an extremely rare progressive genetic disorder, is caused by a point mutation in LMNA that induces progerin production, which disrupts cellular function and triggers premature aging and mortality. Despite extensive efforts, HPGS remains incurable. We successfully implemented a strategy using RfxCas13d to selectively target progerin mRNA at specific junction regions, without unintended cleavage and reduce its expression. This technique discriminated between normal lamin A and progerin, thus providing a safe and targeted therapeutic avenue to treat HGPS. Our approach effectively restored aberrant gene expression and progerin-induced cellular phenotypes, including senescence, mitochondrial dysfunction, and DNA damage in cells with HGPS and LMNAG608G/G608G mice. Notably, LMNAG608G/G608G mice exhibited improved progeroid phenotypes, suggesting a potential therapeutic application of this approach for other diseases resulting from abnormal RNA splicing.