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Genetic diversity

Accounting for diversity in the design of CRISPR-based therapeutic genome editing

Nature Genetics volume 55, pages 6–7 (2023)Cite this article

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CRISPR cell and gene therapy have been designed largely with respect to a single reference human genome. A new study reveals how human genetic diversity could lead to off-target effects and presents a new tool to identify these risks.

Just as the benefits from a single treatment of CRISPR genome editors can be life-changing and durable1, the risks could be significant and irreversible. Adverse events in early stage trials of CRISPR are starting to be reported, including the recent tragic death2 of a patient with muscular dystrophy dosed with a CRISPR activation editor. While it is too early to determine whether the cause of death was related to genome editing, the genome editing community along with clinicians and patients eagerly awaits the development of new tools to measure the benefits and risks of genome editing strategies. Two particularly vexing questions in the field are whether trial participants should be genotyped before enrollment in these studies and how the resulting sequence data should be interpreted to ensure safety and efficacy. Now, a decade after the first reports of CRISPR-based genome editing, a new study by Cancellieri et al.3 in this issue of Nature Genetics reports on the development of a new tool to quantify the potential of human genetic diversity to alter genome editing outcomes.

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Fig. 1: Assaying human genetic diversity can advance the design of human therapeutics involving genome editing.

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Acknowledgements

K.S. has received funding from the US National Science Foundation, grant nos. EEC-1648035 and AWD-101645-G3/RJ375-G3, and the US National Institutes for Health, grant nos. R35GM119644, U01EY032333 and UH3NS111688.

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  1. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA

    Krishanu Saha

  2. McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI, USA

    Krishanu Saha

  3. Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA

    Krishanu Saha

  4. Department of Medical History & Bioethics, University of Wisconsin-Madison, Madison, WI, USA

    Krishanu Saha

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  1. Krishanu Saha
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Correspondence to Krishanu Saha.

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Competing interests

K.S. receives sponsored research support from Spotlight Therapeutics and Synthego and is an advisor to Notch Therapeutics and Andson Biotech.

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Saha, K. Accounting for diversity in the design of CRISPR-based therapeutic genome editing. Nat Genet 55, 6–7 (2023). https://doi.org/10.1038/s41588-022-01272-z

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