| Title: |
In vivo safety and efficacy of a CRISPR‐based gene therapy for Alzheimer’s disease |
| Authors: |
Aulston, Brent D; Branes, Kristen; Checka, Nidhi; Parra‐Rivas, Leonardo A; Roy, Subhojit |
| Source: |
Alzheimer's & Dementia ; volume 19, issue S21 ; ISSN 1552-5260 1552-5279 |
| Publisher Information: |
Wiley |
| Publication Year: |
2023 |
| Collection: |
Wiley Online Library (Open Access Articles via Crossref) |
| Description: |
Background Our lab has developed a gene‐editing strategy to target the extreme C‐terminus (C‐term) of APP (amyloid precursor protein) – a gene with a central and indisputable role in AD. In physiologic states, the APP protein is cleaved by α‐secretases to generate neuroprotective sAPPα; but in AD (both sporadic and familial), the alternative β‐cleavage pathway is active, generating pathologic fragments (including Aβ). Specifically, our approach attenuates pathologic β‐cleavage products by disrupting a pentapeptide “YENPTY” domain at the APP C‐term, and this retains the edited APP (APP‐ΔC) at the cell‐surface, augmenting neuroprotective and neuroregenerative α‐cleavage. Method In order to assess the safety and efficacy of our approach in vivo, we used two different CRISPR‐editing approaches. First, we generated germline edits in Wt and APP knockin (APP NL‐G‐F ) mice by injecting embryos with APP C‐term targeting CRISPRs. We then selected founders to produce stable strains of WT and APP‐KI in which the APP C‐term was genomically deleted (referred to as WtΔC and KI‐ΔC mice respectively). In another set of experiments, we packaged APP C‐term CRISPRs into AAV vectors and systemically injected AAVs into APP‐KI mice. Result WtΔC showed no cognitive deficits or histological abnormalities compared to Wt controls. KI‐ΔC showed a dramatic reduction of amyloid beta plaques and associated neuroinflammatory markers and similar results were observed in AAV‐treated KI mice. Moreover, both germline and somatic APP C‐term editing produced an increase in neuroprotective sAPPα. Conclusion In total, these data demonstrate that our approach is safe and efficacious in vivo and validate the feasibility of our APP C‐terminus editing approach as a therapeutic for AD. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1002/alz.076735 |
| Availability: |
https://doi.org/10.1002/alz.076735 |
| Rights: |
http://onlinelibrary.wiley.com/termsAndConditions#vor |
| Accession Number: |
edsbas.28149BA8 |
| Database: |
BASE |