Nature communicationsSep 30, 2026

Base editing that avoids specific mutations fixes progeria symptoms in lab-grown nerve and muscle tissues

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 2, 2026

Abstract

Farnesylation Amino acid Targeted Editing (FATE) achieves efficient base editing and phenotypic rescue in neuromuscular organoids derived from human pluripotent stem cells.

FATE selectively disrupts the LMNA farnesylation motif without impacting other farnesylated proteins.
Muscle-specific progerin accumulation is linked to the sequestering of 53BP1, which impairs DNA damage response.
FATE eliminates perinuclear progerin and restores mobility of 53BP1, leading to the reconstitution of DNA repair foci.
Normalization of heterochromatin architecture is observed following FATE treatment in neuromuscular organoids.
The approach demonstrates a mutation-independent strategy targeting a key mechanism in Hutchinson Gilford progeria syndrome.

Simplified

Hutchinson Gilford progeria syndrome (HGPS) is a fatal premature aging disorder caused by pathogenic farnesylated lamin A variants that disrupt nuclear architecture and DNA repair. Current therapies, including farnesyltransferase inhibitors, provide only modest survival benefits and lack molecular specificity, while mutation-specific genome-editing strategies cannot address atypical laminopathies. Here, we develop Farnesylation Amino acid Targeted Editing (FATE), a mutation-agnostic base-editing platform that selectively disrupts the LMNA farnesylation motif without affecting other farnesylated proteins. Using isogenic human pluripotent stem cell derived neuromuscular organoids (NMOs), we reveal muscle-specific progerin accumulation that sequesters 53BP1 and abolishes DNA damage foci formation. FATE eliminates perinuclear progerin, restores 53BP1 mobility, reconstitutes DNA repair foci, and normalizes heterochromatin architecture. Importantly, transient delivery of FATE mRNA conjugated with lipid nanoparticles to HGPS NMOs achieves efficient base editing and phenotypic rescue. These findings establish FATE as a mutation-independent therapeutic strategy targeting a fundamental pathogenic mechanism in HGPS and provide a proof-of-concept for RNA-based in situ genome editing in progeroid disease.