RNA-Targeting Therapeutics via CRISPR-Cas13: Mechanisms, Applications, and Future Directions — A Narrative Review

Abstract

Background: Pathogenic RNA transcripts underlie a substantial proportion of human diseases, yet existing RNA-targeting platforms — antisense oligonucleotides and RNA interference — are constrained by mechanistic inflexibility, saturation of endogenous machinery, and inability to perform precise transcript editing. CRISPR-Cas13, a family of RNA-guided RNA endonucleases, has emerged as a programmable, reversible alternative capable of targeted transcript knockdown, precise base editing, and splicing modulation without altering genomic DNA. Objective: This narrative review synthesises current evidence on the mechanisms, therapeutic applications, delivery platforms, safety considerations, and ethical dimensions of the CRISPR-Cas13 system, with the objective of providing a structured, evidence-grounded account of its translational trajectory as of 2024. Methods: A structured literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, and Embase, covering January 2016 through October 2024. Search terms combined Cas13 subtype nomenclature with therapeutic and disease-specific keywords. Articles were screened for relevance to Cas13 mechanisms, applications, or translational barriers; English-language peer-reviewed publications and pre-reviewed preprints with corroborating evidence were eligible. The review was organised thematically across eight conceptual domains and reported in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA). Results: Across nine therapeutic application areas, CRISPR-Cas13 — primarily Cas13d (CasRx) — has demonstrated robust preclinical efficacy, including phenotypic rescue in Huntington's disease rodent models, potent antiviral activity against SARS-CoV-2 and HIV-1, and selective oncogenic mRNA knockdown in xenograft cancer models. Catalytically dead Cas13 fused to adenosine deaminase (dCas13-ADAR) enables A-to-I RNA base editing with measurable codon correction in patient-derived cell lines. Lipid nanoparticles and AAV vectors represent the dominant delivery modalities; collateral RNase activity, immunogenicity, and transient effect duration remain the principal translational barriers. Conclusion: CRISPR-Cas13 constitutes a promising and mechanistically distinct RNA-targeting platform with broad therapeutic reach. Realisation of its clinical potential depends on engineering of collateral-minimised Cas13 variants, development of tissue-specific delivery architectures, and initiation of first-in-human trials in monogenic disorders where reversibility of effect offers a meaningful safety advantage over permanent DNA editing.