Haplotype editing with CRISPR/Cas9 as a therapeutic approach for dominant-negative missense mutations in NEFL.

ABSTRACT: Inactivation of disease alleles by allele-specific editing is a promising approach to treat dominant-negative genetic disorders, provided the causative gene is haplo-sufficient. We previously edited a dominant NEFL missense mutation with inactivating frameshifts and rescued disease-relevant phenotypes in induced pluripotent stem cell (iPSC)-derived motor neurons. However, a multitude of different NEFL missense mutations cause disease. Here, we addressed this challenge by targeting common single-nucleotide polymorphisms in cis with NEFL disease mutations for gene excision. We validated this haplotype editing approach for two different missense mutations and demonstrated its therapeutic potential in iPSC-motor neurons. Surprisingly, our analysis revealed that gene invers

SUBMITTER: Dua PH 

PROVIDER: S-EPMC11702708 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature