Long term rescue of Alzheimer’s deficitsin vivoby one-time gene-editing ofAppC-terminus

Author:

Aulston Brent D.ORCID,Gimse Kirstan,Bazick Hannah O.ORCID,Kramar Eniko A.,Pizzo Donald P.ORCID,Parra-Rivas Leonardo A.ORCID,Sun JichaoORCID,Branes-Guerrero KristenORCID,Checka Nidhi,Bagheri Neda,Satyadev NihalORCID,Carlson-Stevermer JaredORCID,Saito Takashi,Saido Takaomi C.ORCID,Audhya AnjonORCID,Wood Marcelo A.ORCID,Zylka Mark J.ORCID,Saha KrishanuORCID,Roy SubhojitORCID

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) and upregulating neuroprotective APP-α-cleavage products. AAV-driven editing ameliorates neuropathologic, electrophysiologic, and behavioral deficits in an AD knockin mouse model. Effects persist for many months, and no abnormalities are seen in WT mice even after germlineApp-editing; underlining overall efficacy and safety. Pathologic alterations in the glial-transcriptome ofApp-KI mice, as seen by single nuclei RNA-sequencing (sNuc-Seq), are also normalized byAppC-terminus editing. Our strategy takes advantage of innate transcriptional rules that render terminal exons insensitive to nonsense-decay, and the upstream manipulation is expected to be effective for all forms of AD. These studies offer a path for a one-time disease-modifying treatment for AD.

Publisher

Cold Spring Harbor Laboratory

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