مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
Engineering Alzheimer’s Disease Models and Therapies Using CRISPR-Cas9 Technology
Engineering Alzheimer’s Disease Models and Therapies Using CRISPR-Cas9 Technology
sadaf safaei,1,*
1. Department of pharmaceutical biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
Introduction: Introduction: In the earlier years, the majority of AD animal models stemmed from the overexpression of human modified genes correlated with the generation of Aβ and tau. These animal models have been extremely helpful in understanding some facets of the pathogenesis of AD, but are limited in scope as most AD mouse models fail to develop (frank) neurodegeneration. Recently, the CRISPR-Cas9 technology advances to constructing new AD models, demonstrating a more precise disease phenotype, clarifying mechanisms of pathogenesis, screening pathogenic genes, and searching for a therapy for this insidious disorder. The most innovative use of CRISPR-Cas9 gene editing technologies used to develop new models and treat AD are game changing.
Methods: Methods: The construction of CRISPR-Cas9 gene editing tools to make changes in AD animal models was the first step. These tools targeted the construction of knock-in mutations in APP and Plcγ2, deletions of tau genes, and rodent APP loci humanization. The first therapeutic strategies targeted mutant allele CRISPR-Cas9 gene editing, APP processing, and transcriptional regulation using dCas9 gene-activator and gene-inhibitors. The aim of the capsule systems was Central Nervous System (CNS) targeting.
Results: Results: The CRISPR-engineered models displayed greater fidelity to human AD pathology, specifically with lower levels of Aβ deposition and changes to tau expression. CRISPR introduced protective APP variants which brought down the amyloid burden. Plcγ2-P522R knock-in mice manifested better functioning microglia and subsequently lower AD risk. Towards a therapeutic goal, CRISPR techniques brought down Aβ production both in vitro and in vivo with a low degree of off-target consequences. dCas9 drove transcriptional control of both BACE-1 and ADAM10 which further lessened the AD-like pathology.
Conclusion: Conclusion: CRISPR-Cas9 techniques provide new modeling opportunities for AD and potential new therapeutic targets. CRISPR techniques provide the means to both slow down and reverse pathways of AD by manipulating protective and causative genetic factors, advancing our understanding of the disease and its mechanisms. The improvement of off-target control and delivery systems will be vital for the technology’s use in the clinical approaches.