ENGINEERING STRATEGIES FOR PRECISION GENOME EDITING IN RARE INHERITED NEUROLOGICAL DISORDERS

Abstract

Background: The monogenic disorders are mostly rare inherited neurological diseases, which result in progressive neurodegeneration, severe disability and limited treatment options. As genome engineering continues to develop so there can be possibilities of targeting mutations that cause diseases directly in central nervous system.

Objective: This paper contrasts the state-of-the-art-engineering strategies to render safe, efficient and accurate genome editing to cure rare inherited neurological diseases potentially viable.

Methodology:

The analysis of viral and non-viral delivery systems, targeting of the blood-brain barrier and translational preclinical studies were compared with different CRISPR-cas9, base editing and prime editing platforms and reviewed.

Findings: Base and prime editing systems were displayed to be efficient in editing with a rate of 70 to 90 per cent in models of neuronal cells with only a 40 to 60 per cent reduction in off-target mutations compared to the usual CRISPR-Cas9 techniques. In preclinical models, engineered AAV9 and lipid nanoparticle delivery systems achieved targeting of the central nervous system with almost 45 % greater efficacy. The functional rescue of neuronal signaling and the decrease of the toxic protein build-up were observed in the models of Huntington as well as Rett syndrome.

Conclusion: Transformative therapeutic applicability of precision genome engineering to rare neurological disorders is underway. However, longevity genomic safety, immunogenicity minimisation and minimisation delivery delivery systems are yet significant concerns on moving forward to clinical applications.