Editor's Note：Thalassemia, an inherited blood disorder, imposes a significant economic and resource burden on patients, families, and society at large. In recent years, advances in medical research have led to a growing range of treatment options for thalassemia, including traditional blood transfusions and iron chelation therapy, drugs to induce gamma-globin production, hematopoietic stem cell transplantation (HSCT), and emerging approaches like gene and cell therapies, as well as nanomedicine. Among these, gene therapy has garnered particular attention as a potential cure, offering renewed hope to patients worldwide.

From January 3–5, 2025, the 5th Annual Meeting of Chinese Alliance for Societies of Hematology (2025 CASH) was held in Tianjin, where Dr. Yongrong Lai from The First Affiliated Hospital of Guangxi Medical University delivered a compelling presentation titled Advances in Gene Therapy for Thalassemia. His report provided a detailed overview of the latest progress and future prospects of gene therapy in thalassemia treatment.

Overview of Thalassemia Treatment Strategies

Thalassemia treatment encompasses a variety of approaches. Traditional treatments, such as regular blood transfusions and iron chelation therapy, have long been pivotal in alleviating symptoms and sustaining life. However, they cannot cure the disease. Moreover, chronic transfusions may lead to complications such as iron overload, necessitating iron chelation therapy to minimize damage to vital organs.

Drug therapies aimed at inducing gamma-globin production offer a promising alternative. Medications such as hydroxyurea, erythropoietin (EPO), demethylating agents like 5-azacytidine, short-chain fatty acid derivatives (e.g., arginine butyrate), and thalidomide work by stimulating fetal hemoglobin (HbF) production to improve anemia symptoms. However, the efficacy and safety of these drugs require further study and validation.

For curative treatment, HSCT remains the only available option. Yet, challenges such as donor availability, HLA matching, graft-versus-host disease (GVHD), and immune rejection limit its accessibility and applicability to all patients.

Emerging approaches such as gene and cell therapies, as well as nanomedicine, represent significant breakthroughs in thalassemia treatment. Gene therapy, in particular, has made remarkable strides. Methods include gene replacement and gene editing. Gene replacement, exemplified by Beti-cel (betibeglogene autotemcel), involves adding functional beta or gamma-globin genes into defective cells via lentiviral vectors, enabling normal protein expression. Gene editing, using tools like CRISPR/Cas9 or zinc finger nucleases (ZFNs), allows for gene mutation repair, abnormal gene deletion, disruption of the BCL11A gene, or insertion of healthy genes to correct sequences or activate HBG gene expression for therapeutic purposes.

Advances in Gene Therapy for Thalassemia

Substantial progress has been made globally in gene therapy for thalassemia. Two products, Zynteglo and Casgevy, have already received regulatory approval in the EU and the United States. In China, several products are in development or undergoing clinical trials, driving the field forward. At the First Affiliated Hospital of Guangxi Medical University, Dr. Yongrong Lai and his team have been actively contributing to this progress, conducting 14 clinical studies on gene therapy for thalassemia.

To date, they have successfully treated 32 thalassemia patients using gene therapy, accumulating extensive experience. At the 2024 ASH Annual Meeting, their team presented seven studies, including one oral presentation and six poster sessions. Below are highlights from three key studies.

Study 1: Efficacy and Safety of BRL-101 for Transfusion-Dependent Beta-Thalassemia

This study evaluated BRL-101 in 15 patients with transfusion-dependent beta-thalassemia (TDT), with a median age of 11.5 years. Results demonstrated that a single dose of BRL-101 led to early and sustained increases in HbF and hemoglobin (Hb) levels over 4.3 years. The longer the follow-up, the greater the Hb increase, with maximum levels exceeding 140 g/L. All patients became transfusion-independent following BRL-101 treatment, and Hb and HbF levels stabilized rapidly.

In terms of safety, adverse events observed post-treatment were consistent with known toxicities of conditioning regimens and autologous transplantation.

Study 2: Long-Term Follow-Up of RM-001 for TDT

RM-001 is a novel non-viral gene therapy that employs ex vivo CRISPR-Cas9 editing to target the BCL11A binding site in the HBG1/2 promoter of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs), reactivating HbF production.

As of July 24, 2024, 19 patients had received RM-001, with a median follow-up of 14.5 months (range: 7–32.6 months). All patients (100%) achieved transfusion independence for at least six months, with a median time to cessation of transfusions of 22 days (range: 10–95 days). Median time to stable Hb ≥9 g/dL was 31 days (range: 14–127 days). At three months, the average total Hb and HbF levels were 10.8 g/dL and 9.2 g/dL, respectively.

No serious adverse events (SAEs) related to the product were reported, highlighting the promising potential of RM-001 as a single-dose cure for TDT.

Study 3: Efficacy of CS-101 in TDT

CS-101, the first clinical trial involving base editing for beta-thalassemia, focuses on a single-gene editing approach. By July 22, 2024, six participants had undergone CS-101 treatment, with an average follow-up of 4.9 months. All participants achieved successful neutrophil and platelet engraftment after edited stem cell infusion, with an average transfusion-free period of 4.3 months.

Significant increases in total Hb and HbF levels were observed early in treatment, demonstrating rapid and durable benefits. Editing efficiency remained stable throughout, positioning CS-101 as a potential best-in-class gene editing therapy for TDT.

Conclusion

In summary, gene therapies such as BRL-101, RM-001, and CS-101 have demonstrated encouraging advancements in thalassemia treatment. As technology continues to evolve and research deepens, the field of gene therapy is poised for unprecedented growth, offering hope for a definitive cure.

With more safe and effective gene therapies emerging, patients with thalassemia may soon be able to break free from the burdens of the disease and embrace healthier, brighter futures. The broader application of these research findings holds the potential to benefit even more patients and propel advancements in thalassemia treatment.

About Dr. Yongrong Lai

• Medical Doctor, PhD Supervisor
• Former Director of Hematology, First Affiliated Hospital of Guangxi Medical University
• National Executive Member, Hematology Branch of the Chinese Medical Association
• National Executive Member, Hematology Physician Branch of the Chinese Medical Doctor Association
• Chairperson, Guangxi Hematology Society
• Recipient of six Guangxi Science and Technology Progress Awards (two First Prizes, one Second Prize, three Third Prizes)
• Author of over 100 research publications