Applications of CRISPR-Cas9 in Alzheimer’s Disease and Related Disorders

Abstract

Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease represent some of the most prevalent neurodegenerative disorders afflicting millions of people worldwide. Unfortunately, there is a lack of efficacious treatments to cure or stop the progression of these disorders. While the causes of such a lack of therapies can be attributed to various reasons, the disappointing results of recent clinical trials suggest the need for novel and innovative approaches. Since its discovery, there has been a growing excitement around the potential for CRISPR-Cas9 mediated gene editing to identify novel mechanistic insights into disease pathogenesis and to mediate accurate gene therapy. To this end, the literature is rich with experiments aimed at generating novel models of these disorders and offering proof-of-concept studies in preclinical animal models validating the great potential and versatility of this gene-editing system. In this review, we provide an overview of how the CRISPR-Cas9 systems have been used in these neurodegenerative disorders.

Screening Techniques for Drug Discovery in Alzheimer’s Disease

“…78 Several interesting reviews have been published on this topic related to AD recently. 19,20,22,79 One to highlight is the work by Inoue et al where they have increased the expression of APP and/or BACE1 using CRISPR gene activation to reveal the hidden defect in γsecretase in fibroblasts of FAD which results in the increased level of Aβ42. 80…”

“…CRISPR technology has generated a broad precision mammalian genome regulatory toolbox, enabling gene knockout, insertion, activation, and suppression . Several interesting reviews have been published on this topic related to AD recently. ,,, One to highlight is the work by Inoue et al where they have increased the expression of APP and/or BACE1 using CRISPR gene activation to reveal the hidden defect in γ-secretase in fibroblasts of FAD which results in the increased level of Aβ42 …”

“…The “hits” allow further modification and development of drugs. Recently, techniques such as artificial intelligent (AI), deep learning, and CRISPR have also been used to identify potential drugs for AD. − This review aims to provide a brief description and highlight the recent development of drug screening methodology used for the three main mechanisms of AD in the past decade (Table ).…”

Genetic Targets and Applications of Iron Chelators for Neurodegeneration with Brain Iron Accumulation

“…AAVs have been used as a delivery system for CRISPR genome editing, along with Cas9 ribonucleoprotein, due to their versatility and adaptability to many different types of host cells . CRISPR-Cas9 genome editing has been used to treat AD, PD, ALS and other neurodegenerative diseases and were shown to be successful in either reducing or reversing the mutation expression of disease pathologies . Challenges that arise with this form of therapy lie in target delivery, and current animal models do not illustrate the exact motor or cognitive features of the human disease .…”

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease

“…22 In this frame, a central role for the nuclear factor erythroid 2related factor 2 (NRF2) has been unveiled. 23,24 This protein is an important regulator of cellular antioxidant response, and upon the increase of ROS production, it translocates into the nucleus, where it induces the transcription of genes involved in the antioxidant response. Specifically, it induces the expression of heme oxygenase-1 (HO-1), quinone oxidoreductase-1 (NQO-1), and superoxide dismutase (SOD), 25,26 but it also reduces the activity and expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), increasing the production of amyloid-β (Aβ).…”