Mutation-Agnostic Base Editing of the Progerin Farnesylation Site Rescues Hutchinson-Gilford Progeria Syndrome Phenotypes in Neuromuscular Organoids

ABSTRACT: Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, fatal premature aging disorder caused by a de novo mutation in the LMNA gene that leads to the production of progerin, a farnesylated, pathogenic form of lamin A. Treatment with farnesyltransferase inhibitors achieves significant yet limited life extension, highlighting progerin farnesylation as a key pathogenic driver of HGPS. In this study, rather than correcting the single pathogenic point mutation, we introduce Farnesylation Amino acid Targeted Editing (FATE), a novel, mutation-agnostic precision genome editing strategy that selectively disrupts the farnesylation site of LMNA. Next-generation sequencing confirmed that FATE exclusively edits the LMNA locus without inducing off-target mutations or affecting other genes encoding farnesylated proteins. Using neuromuscular organoids (NMOs) derived from two isogenic pairs of human pluripotent stem cells (hPSCs) carrying the HGPS mutation (HGPS-hPSCs), we found perinuclear progerin accumulation exclusive to the muscular compartment to be associated with defective formation of DNA damage foci and loss of perinuclear heterochromatin. Notably, applying FATE to HGPS-hPSCs successfully abolished these muscle-specific pathologies in subsequently-derived NMOs. Direct delivery of FATE mRNA into HGPS-NMOs likewise effectively inhibited perinuclear accumulation of progerin and rescued the formation of DNA damage repair foci. These findings demonstrate FATE as a broadly applicable, mutation-agnostic editing approach that targets a fundamental pathogenic mechanism in HGPS and therefore has feasible utility in clinical application.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305237 | GEO | 2026/07/13

REPOSITORIES: GEO