CRISPR-Cas13 RNA Editing for Huntington's Disease: Selective Targeting of Mutant Huntingtin mRNA and Assessment of Off-Target Neuronal Effects

Abstract

Huntington's disease (HD) represents one of the most devastating neurodegenerative disorders, characterized by progressive motor dysfunction, cognitive decline, and psychiatric manifestations stemming from an expanded CAG repeat in the huntingtin gene. The development of CRISPR-Cas13 technology has opened unprecedented opportunities for precise RNA editing, offering a potential therapeutic avenue that circumvents permanent genomic alterations. This comprehensive review examines the application of CRISPR-Cas13 systems in selectively targeting mutant huntingtin (mHTT) mRNA while preserving wild-type huntingtin expression, which remains essential for neuronal function and survival. We analyze the molecular mechanisms underlying Cas13-mediated RNA cleavage, evaluate strategies for discriminating between wild-type and mutant transcripts, and critically assess the potential off-target effects in neuronal populations. Furthermore, we explore delivery mechanisms, clinical translation challenges, and the comparative advantages of RNA-targeting approaches over DNA-editing strategies in the context of neurodegenerative disease therapy. The evidence synthesized in this review suggests that CRISPR-Cas13 technology holds substantial promise for HD treatment, though significant hurdles related to specificity, delivery efficiency, and long-term safety must be addressed before clinical implementation.