CRISPR-Cas9: A Promising Genome Editing Therapeutic Tool for Alzheimer’s Disease—A Narrative Review

Abstract

Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disorder characterized by cognitive deficiency and development of amyloid-b (Ab) plaques and neurofibrillary tangles, comprising hyperphosphorylated tau. The number of patients with AD is alarmingly increasing worldwide; currently, at least 50 million people are thought to be living with AD. The mutations or alterations in amyloid-b precursor protein (APP), presenilin-1 (PSEN1), or presenilin-2 (PSEN2) genes are known to be associated with the pathophysiology of AD. Effective medication for AD is still elusive and many gene-targeted clinical trials have failed to meet the expected efficiency standards. The genome editing tool clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 has been emerging as a powerful technology to correct anomalous genetic functions and is now widely applied to the study of AD. This simple yet powerful tool for editing genes showed the huge potential to correct the unwanted mutations in AD-associated genes such as APP, PSEN1, and PSEN2. So, it has opened a new door for the development of empirical AD models, diagnostic approaches, and therapeutic lines in studying the complexity of the nervous system ranging from different cell types (in vitro) to animals (in vivo). This review was undertaken to study the related mechanisms and likely applications of CRISPR-Cas9 as an effective therapeutic tool in treating AD.

Epigenetics of Alzheimer’s Disease

“…Contemporary methods of gene editing include the use of programmable DNA binding proteins such as such zinc finger proteins (ZFP), transcription activator-like effectors (TALE), and RNA-guided clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) [ 263 ]. The latest genome editing technology, CRISPR/Cas9, showed several advantages over ZFP and TALE, and demonstrated promising potential in the treatment of several neurological disorders, including AD [ 264 , 265 , 266 ]. The CRISPR/Cas9 system, in which Cas9 endonuclease is able to target specific DNA sequences with the help of guide RNAs (gRNAs) [ 267 ], can be used to target and correct any specific gene sequences, including AD genetic risk factors.…”

Exploring nano-enabled CRISPR-Cas-powered strategies for efficient diagnostics and treatment of infectious diseases

“…This method obtained genetic manipulation in 6 percent of hepatocytes with a 24.1-percent indel rate calculated by high-throughput sequencing of the desired target in total liver genomic DNA after adjusting the length of time of Lipid NP and Adeno-Associated Virus (AAV) administration to increase the traversal between peak Cas9 and sgRNA expression [186]. CRISPR/Cas9 nano complexes consisting of R7L10 peptides with Cas9-sgRNA ribonucleoprotein were shown to have the lowest off-target efficacy in adult mouse brains [187]. A single administration of CRISPR-Cas9 delivered by liver-targeting lipid nanoparticles (LNP), resulted in a 60% downregulation of the target gene (ATTR) and a 70-80% corresponding decrease in serum concentration of the dysfunctional transthyretin protein in a preclinical mouse model of transthyretin amyloidosis [188,189].…”

Personalizing the Care and Treatment of Alzheimer’s Disease: An Overview

“…Starting of treatments late during the course of AD progress, inappropriate drug doses, invalid target selection, and predominantly an insufficient knowledge of the diverse pathophysiology of AD are the reasons for failures of disease-modifying treatments for AD. 56 It has been proposed that some promising drugs that failed to show clinical improvement in subjects with MCI or moderate stage of AD were administered too late in the disease course. 57 In addition, so far most of the clinical trials have neglected the underlying clinical and molecular heterogeneity of AD and considered AD as a homogeneous disease, which could be one of the main reasons for their failure to identify an AD effective therapy.…”