CRISPR/Cas therapeutic strategies for autosomal dominant disorders
Salvatore Marco Caruso, … , Bruna Lopes da Costa, Stephen H. Tsang
Salvatore Marco Caruso, … , Bruna Lopes da Costa, Stephen H. Tsang
Published May 2, 2022
Citation Information: J Clin Invest. 2022;132(9):e158287. https://doi.org/10.1172/JCI158287.
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Review

CRISPR/Cas therapeutic strategies for autosomal dominant disorders

Abstract

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.

Authors

Salvatore Marco Caruso, Peter M.J. Quinn, Bruna Lopes da Costa, Stephen H. Tsang

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Figure 1

CRISPR/Cas road map for the development of autosomal dominant therapeutics.

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CRISPR/Cas road map for the development of autosomal dominant therapeuti...
Decision-making tree that allows researchers to determine the most appropriate therapeutic editing strategy based on responses to a series of questions. This decision tree is particularly for dividing cells and requires substantial amendments for adaptation to nondividing cells, including the removal of HDR and the inclusion of alternative approaches such as homology-independent targeted insertion (HITI) and precise integration into target chromosome (PITCH). It is also important to note that this tree is not exhaustive and parallel decisions must also be considered, such as off-targeting specificity and vector cargo limitations. Note: When deciding which CRISPR-based technology to use, it is important to evaluate each experimental design individually. Critical considerations include in vivo delivery strategies and delivery capacities, off-targeting rates, and editing efficiencies.