Journal
NATURE MEDICINE
Volume 27, Issue 4, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41591-021-01284-y
Keywords
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Funding
- Doris Duke Charitable Trust [22399]
- NIH NHLBI [T32-HL120824, R01-HL135607]
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The study presents a novel genome editing strategy that can restore the balance of beta-globin:alpha-globin in human hematopoietic stem cells from patients with beta-thalassemia, leading to the functional restoration of adult hemoglobin tetramers in patient-derived red blood cells.
beta-Thalassemia pathology is due not only to loss of beta-globin (HBB), but also to erythrotoxic accumulation and aggregation of the beta-globin-binding partner, alpha-globin (HBA1/2). Here we describe a Cas9/AAV6-mediated genome editing strategy that can replace the entire HBA1 gene with a full-length HBB transgene in beta-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize beta-globin:alpha-globin messenger RNA and protein ratios and restore functional adult hemoglobin tetramers in patient-derived red blood cells. Edited HSPCs were capable of long-term and bilineage hematopoietic reconstitution in mice, establishing proof of concept for replacement of HBA1 with HBB as a novel therapeutic strategy for curing beta-thalassemia. A new genome editing strategy can normalize the beta-globin:alpha-globin balance in human hematopoietic stem cells from patients with beta-thalassemia and restore functional adult hemoglobin tetramers in patient-derived red blood cells.
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