CRIPSRi: a promising RNA-guided CRISPR-dCas Technology for Alzheimer’s Disease and Glioma Therapy
DOI:
https://doi.org/10.54097/7x9epm29Keywords:
CRISPR interference, Deactivated Cas protein, Alzheimer’s Disease, Glioma, Gene therapy, Epigenome editing, DNA methylation, NeuroepigeneticAbstract
The escalating prevalence and mortality rates of neurological disorders, such as Alzheimer's disease (AD) and glioma, pose significant healthcare challenges. The exploration of novel therapeutic modalities is in urgent need. Among these, CRISPR interference (CRISPRi) leveraging RNA-guided deactivated Cas proteins for the regulation of gene expression stands out for its potential in neuroepigenetic interventions. This paradigm shift from the canonical CRISPR-Cas9 system, which operates via the introduction of double-strand breaks, to CRISPRi's non-cleaving approach mitigates the risk of off-target mutagenesis, thereby presenting a more refined strategy for modulating gene activity within the intricate milieu of the central nervous system (CNS). This review highlights the shift from CRISPR-Cas9 to CRISPR-dCas technologies, focusing on the application of CRISPR interference in addressing the pathogenesis of AD and glioma. The pathological frameworks is further unpacked by revealing the pivotal roles of genes such as APP, MGMT, and TERT. Through allele-specific epigenome editing, CRISPRi has demonstrated considerable efficacy in the preclinical modulation of gene expression via targeted DNA methylation, consequently degrading the pathological manifestations. Notably, evidence suggests CRISPRi's capacity to effectuate significant downregulation of hotspot genes like APP and MGMT expression and to modulate TERT activity. Despite promising results, challenges such as off-target effects, delivery barriers, particularly across the blood-brain barrier (BBB), and potential immunogenic responses limit clinical translation. Advances in sgRNA design, novel delivery systems, and epigenetic editing tools are discussed as strategies to overcome these hurdles. Thus, CRISPRi can be positioned as one of the most promising instruments in genomic medicine, with the potential to reshape the therapeutic strategies of AD and glioma.
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