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4959 First-in-Human Study of Autologous HBA2-Edited CD34+ Hematopoietic Stem and Progenitor Cells in Alpha-Thalassemia with Constant Spring Mutation

Program: Oral and Poster Abstracts
Session: 801. Gene Therapies: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical trials, Translational Research, Clinical Research, Thalassemia, Hemoglobinopathies, Diseases, Gene Therapy, Treatment Considerations, Biological therapies, Young adult , Technology and Procedures, Gene editing, Human
Monday, December 9, 2024, 6:00 PM-8:00 PM

Li Wang, MD1*, Hui Xu, PhD2, Junbin Liang2*, Yaoyun Li3*, Lin Cheng2*, Ying Luo2*, Liancheng Huang2*, Lei Shi2*, Lihong Zeng4*, Rongrong Luo3*, Bin Xiao3*, Meiping Liu3*, Liping Huang3*, Zhendong Xiao5*, Xinhua Zhang, MD1* and Junjiu Huang, PhD6*

1923rd Hospital of the People's Liberation Army, Nanning, Guangxi, China
2Reforgene Medicine, Guangzhou, China
3Department of Pediatrics, 923rd Hospital of the People's Liberation Army, Nanning, China
4Department of Blood Transfusion, 923rd Hospital of the People's Liberation Army, Nanning, China
5Biotherapy Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
6School of Life Sciences, Sun Yat-sen University, Guangzhou, China

Background:

Hemoglobin H Constant Spring (HbH-CS) (--/αCSα) is the most common non-deletion α-thalassemia that can lead to severe health problems. The clinical manifestations of HbH-CS patients are widely variable and a considerable proportion of patients with HbH-CS need regular or irregular transfusions to support normal growth, development and life. Currently, there is no specific therapy for transfusion dependent α-thalassemia, and allogeneic hematopoietic stem cell transplantation is the only available curative option. Because patients with HbH-CS has 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 repairing of the mutation by base editing may provide a potential cure for this type of disease.

Aims:

To repair the CS mutation of HBA2 gene and increase the expression of 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 of edited patient cells (RM-004) in transfusion-dependent HbH-CS. Here, we present the initial results from the first patient treated with RM-004.

Methods:

Patients (12–35 y of age) with HbH-CS receiving packed red blood cell (pRBC) transfusions of ≥100 mL/kg/y or ≥10 units/y in the previous 2 y were eligible. Peripheral CD34+ HSPCs were collected by apheresis after mobilization with G-CSF and plerixafor. CD34+ cells were edited with CBEs using a guide RNA specific for the CS mutation. Prior to RM-004 infusion, patient received myeloablative conditioning with busulfan form day-7 to day-3. Patient were monitored for stem cell engraftment/hematopoietic recovery, adverse events (AEs), Hb production, HbA/HbH/Hb-CS expression and packed red blood cell (pRBC) transfusion requirements.

Results:

The first subject was a 14-y female patient with HbH-CS, who received an annualized 29 units/y pRBC transfusions before enrollment. She received a single dose of RM-004 cells, achieved neutrophil and platelet engraftment on Day14 and Day20 post-RM-004 infusion, respectively. She received the last pRBC transfusion on Day13 after RM-004 treatment, and has been transfusion-free over 3 months. The total Hb stably over 9 g/dL since Day26 and maintained between 10~11 g/dL currently. The proportion of HbH and Hb-CS were 3.8% and 1.1% respectively before enrollment (with regular transfusions), both dropped to 0.3% at 3-month after RM-004 infusion; the proportion of HbA1 has increased to 97.2%. The safety profile was generally consistent with busulfan myeloablation and autologous hematopoietic stem cell transplantation. No serious adverse event reported.

Conclusion:

The first patient treated with RM-004 demonstrated successful engraftment and clinical meaningful increase in Hb level. Although the follow-up time is relatively short, available data have shown that the patient has entered a transfusion-independence state. This is the first-ever clinical report of patients with α-thalassemia treated successfully with gene editing and indicates that RM-004 is a promising approach for the treatment of HbH-CS. Data will be updated for the presentation.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH