Long term rescue of Alzheimer's deficits <i>in vivo</i> by one-time gene-editing of <i>App</i> C-terminus.

ABSTRACT: Gene-editing technologies promise to create a new class of therapeutics that can achieve permanent correction with a single intervention. Besides eliminating mutant alleles in familial disease, gene-editing can also be used to favorably manipulate upstream pathophysiologic events and alter disease-course in wider patient populations, but few such feasible therapeutic avenues have been reported. Here we use CRISPR-Cas9 to edit the last exon of amyloid precursor protein (App), relevant for Alzheimer's disease (AD). Our strategy effectively eliminates an endocytic (YENPTY) motif at APP C-terminus, while preserving the N-terminus and compensatory APP-homologues. This manipulation favorably alters events along the amyloid-pathway - inhibiting toxic APP-β-cleavage fragments (including Aβ)

SUBMITTER: Aulston BD 

PROVIDER: S-EPMC11185791 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature