Gene replacement of α-globin with β-globin restores hemoglobin balance in β-thalassemia-derived hematopoietic stem and progenitor cells

M Kyle Cromer, Joab Camarena, Renata M Martin, Benjamin J Lesch, Christopher A Vakulskas, Nicole M Bode, Gavin Kurgan, Michael A Collingwood, Garrett R Rettig, Mark A Behlke, Viktor T Lemgart, Yankai Zhang, Ankush Goyal, Feifei Zhao, Ezequiel Ponce, Waracharee Srifa, Rasmus O Bak, Naoya Uchida, Ravindra Majeti, Vivien A SheehanJohn F Tisdale, Daniel P Dever, Matthew H Porteus*

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Abstract

β-Thalassemia pathology is due not only to loss of β-globin (HBB), but also to erythrotoxic accumulation and aggregation of the β-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 β-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize β-globin:α-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 β-thalassemia.

OriginalsprogEngelsk
TidsskriftNature Medicine
Vol/bind27
Nummer4
Sider (fra-til)677-687
Antal sider11
ISSN1078-8956
DOI
StatusUdgivet - apr. 2021

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