Gene replacement of α-globin with ß-globin restores hemoglobin balance in ß-thalassemia-derived hematopoietic stem and progenitor cells.
Nat Med
; 27(4): 677-687, 2021 04.
Article
em En
| MEDLINE
| ID: mdl-33737751
ABSTRACT
ß-Thalassemia pathology is due not only to loss of ß-globin (HBB), but also to erythrotoxic accumulation and aggregation of the ß-globin-binding partner, α-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 ß-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize ß-globinα-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 ß-thalassemia.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Hemoglobinas
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Células-Tronco Hematopoéticas
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Terapia Genética
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Talassemia beta
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Alfa-Globinas
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Globinas beta
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article