Precise progerin targeting using RfxCas13d: A therapeutic avenue for Hutchinson-Gilford progeria syndrome

Mol Ther. 2025 Sep 3;33(9):4394-4413. doi: 10.1016/j.ymthe.2025.06.017. Epub 2025 Jun 14.

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.

Keywords: Hutchinson-Gilford progeria syndrome; RfxCas13d; lamin A; mis-splicing; progerin.

MeSH terms

  • Animals
  • DNA Damage
  • Disease Models, Animal
  • Humans
  • Lamin Type A* / genetics
  • Lamin Type A* / metabolism
  • Mice
  • Phenotype
  • Progeria* / genetics
  • Progeria* / metabolism
  • Progeria* / therapy
  • RNA Splicing
  • RNA, Messenger / genetics
  • Regulatory Factor X Transcription Factors / genetics

Substances

  • Lamin Type A
  • RNA, Messenger
  • Regulatory Factor X Transcription Factors
  • prelamin A