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.

Mol The. 2025 Jun 14:S1525-0016(25)00468-X.

https://www.sciencedirect.com/science/article/pii/S152500162500468X?via%3Dihub