Journal
BLOOD
Volume 133, Issue 21, Pages 2255-2262Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2019-01-895094
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Funding
- National Institutes of Health, National Human Genome Research Institute [R00HG008399]
- National Institutes of Health, National Institute of Allergy and Infectious Diseases [R01AI117839]
- National Institutes of Health, National Institute of General Medical Sciences [1R01GM115911]
- National Institutes of Health, National Heart, Lung, and Blood Institute [DP2OD022716, P01HL032262]
- Doris Duke Charitable Foundation
- Burroughs Wellcome Fund
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The thalassemias are compelling targets for therapeutic genome editing in part because monoallelic correction of a subset of hematopoietic stem cells (HSCs) would be sufficient for enduring disease amelioration. A primary challenge is the development of efficient repair strategies that are effective in HSCs. Here, we demonstrate that allelic disruption of aberrant splice sites, one of the major classes of thalassemia mutations, is a robust approach to restore gene function. We target the IVS1-110G> A mutation using Cas9 ribonucleoprotein (RNP) and the IVS2-654C> T mutation by Cas12a/Cpf1 RNP in primary CD34(+) hematopoietic stem and progenitor cells (HSPCs) from beta-thalassemia patients. Each of these nuclease complexes achieves high efficiency and penetrance of therapeutic edits. Erythroid progeny of edited patient HSPCs show reversal of aberrant splicing and restoration of beta-globin expression. This strategy could enable correction of a substantial fraction of transfusion-dependent beta-thalassemia genotypes with currently available geneediting technology.
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