Gene Replacement of α-globin with β-globin Restores Hemoglobin Balance in β-thalassemia-derived Hematopoietic Stem and Progenitor Cells

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2021 Mar 19

PMID 33737751

Citations 42

Authors

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 Sheehan

John F Tisdale

Daniel P Dever

Matthew H Porteus

Affiliations

Soon will be listed here.

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.

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