GENOME EDITING ENGINEERING STRATEGIES FOR CORRECTING REPEAT EXPANSION NEUROLOGICAL DISORDERS

Abstract

Background: Repeat expansion neurological disorders such as Huntington’s disease, Fragile X syndrome, and myotonic dystrophy are inherited neurodegenerative diseases caused by unstable nucleotide repeat expansions that alter gene expression and neuronal function. Current therapeutic strategies provide mainly symptomatic management and do not address the underlying genetic defects, and there is a significant unmet clinical need.
Objective: Assess genome editing engineering approaches for correcting pathogenic repeat expansions in neurological disorders and compare the therapeutic potential of emerging precision-editing technologies.

Methodology:  We performed a systematic review of the literature in PubMed, Scopus and Web of Science databases. Comparative analyses of CRISPR-Cas9, base editing and prime editing systems were performed as well as evaluation of viral and nanoparticle-based delivery methods and assessment of preclinical neuronal studies.
Findings:  CRISPR-Cas9-mediated repeat excision resulted in ~72% reduction of mutant alleles in models of Huntington’s disease. Base editing resulted in a nearly 45% reduction in off-target mutations while prime editing showed more than 85% correction precision in neuronal cell systems. However, limited blood-brain barrier penetration and delivery efficiency were major translational barriers.

Conclusion: Genome editing technologies have a promising therapeutic potential for repeat expansion neurological disorders. Long-term safety evaluation, delivery engineering, and editing precision continue to improve and may facilitate the development of clinically effective curative therapies.