Curing Hemoglobin H-Constant Spring through Base Editing of Autologous CD34+ Hematopoietic Stem and Progenitor Cells

作者：Li Wang, Huiyan Xu, Junbin Liang, Yaoyun Li, Lin Cheng, Ying Luo, Liancheng Huang, Lihong Zeng, Rongrong Luo, Bin Xiao, Meiping Liu, Liping Huang, Zhen‐Dong Xiao, Xinhua Zhang, Junjiu Huang · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-382 · 被引用次数：1 · 研究领域：Hemoglobinopathies and Related Disorders、CRISPR and Genetic Engineering、Hematopoietic Stem Cell Transplantation

Abstract Background: Hemoglobin H Constant Spring (HbH-CS) (–/αCSα) is the most common non-deletional α-thalassemia that can lead to severe health problems. The clinical severity of HbH-CS is widely variable and a considerable proportion of patients with HbH-CS need regular or irregular transfusions to support a normal growth, development, and quality of life. Currently, there is no cure for this type of disease worldwide. Because patients with HbH-CS have only a single base mutation in the Hemoglobin Subunit Alpha 2 (HBA2: c.427T>C) compared to that of asymptomatic carriers (–/αα), we speculate that correction of the mutation by base editing may provide a potential cure for this type of disease. Aims: To correct the CS mutation of HBA2 gene and increase the expression of the normal α-globin chain in erythrocytes, we used ex vivo Cytosine Base Editor (CBE)–based gene editing to modify HBA2 gene in hematopoietic stem and progenitor cells (HSPCs), producing RM-004. NCT06107400 is an investigator initiated, first-in-human study evaluating edited autologous patient cells (RM-004) in transfusion-dependent HbH-CS patients. Here, we present the initial results from the first patient treated with RM-004. Methods: Patients (12–35 years of age) with HbH-CS receiving packed red blood cells (pRBC) transfusions of ≥100 mL/kg/year or ≥10 units/year in the previous 2 years were eligible. Peripheral CD34+ HSPCs were collected by apheresis after mobilization with G-CSF and plerixafor. ...