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

Autor:	Aulston BD; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA., Gimse K; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, 53715, USA; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA., Bazick HO; Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Kramar EA; Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine 92697-2695, USA., Pizzo DP; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA., Parra-Rivas LA; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA., Sun J; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.; Present address: Department of Geriatrics and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China., Branes-Guerrero K; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.; Present address: Eli Lilly Pharmaceuticals, Indianapolis, IN, USA., Checka N; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA., Bagheri N; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA., Satyadev N; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.; Present address: Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA., Carlson-Stevermer J; Synthego Corporation, 3696 Haven Ave Suite A, Redwood City, CA 94063.; Present address: Serotiny Inc., 329 Oyster Point Boulevard, 3rd Floor, South San Francisco, CA 94080., Saito T; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.; Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan., Saido TC; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan., Audhya A; Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., Wood MA; Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine 92697-2695, USA., Zylka MJ; Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Saha K; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, 53715, USA; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA., Roy S; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.; Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 09. Date of Electronic Publication: 2024 Jun 09.
DOI:	10.1101/2024.06.08.598099
Abstrakt:	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 germline App -editing; underlining overall efficacy and safety. Pathologic alterations in the glial-transcriptome of App -KI mice, as seen by single nuclei RNA-sequencing (sNuc-Seq), are also normalized by App C-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. Competing Interests: Competing interest declaration: S.R. is the scientific co-founder and owns equity in CRISPRAlz.
Databáze:	MEDLINE
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