CRISPR/Cas therapeutic strategies for autosomal dominant disorders

• Published in: The Journal of clinical investigation Vol. 132; no. 9; pp. 1 - 11
• Main Authors: Caruso, Salvatore Marco, Quinn, Peter M.J., da Costa, Bruna Lopes, Tsang, Stephen H.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.05.2022
• Subjects: Alleles; Biomedical research; Care and treatment; Cell cycle; Clinical trials; Cornea; CRISPR; CRISPR-Cas Systems; Design; Efficiency; Fibroblasts; Gene polymorphism; Gene therapy; Genetic disorders; Genomes; Homology; Mutation; Review; Single-nucleotide polymorphism; Therapeutics, Experimental; United States
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI158287

Autosomal dominant disorders present unique challenges, as therapeutics must often distinguish between healthy and diseased alleles while maintaining high efficiency, specificity, and safety. For this task, CRISPR/Cas remains particularly promising. Various CRISPR/Cas systems, like homology-directed repair, base editors, and prime editors, have been demonstrated to selectively edit mutant alleles either by incorporating these mutations into sgRNA sequences (near the protospacer-adjacent motif ["near the PAM"]) or by targeting a novel PAM generated by the mutation ("in the PAM"). However, these probability-based designs are not always assured, necessitating generalized, mutation-agnostic strategies like ablate-and-replace and single-nucleotide polymorphism editing. Here, we detail recent advancements in CRISPR therapeutics to treat a wide range of autosomal dominant disorders and discuss how they are altering the landscape for future therapies.