In January 2023, Professor Jianmin Wang from Department of Hematology, Shanghai Changhai Hospital published a commentary on Blood Science. The title of the study is "Big stride in gene therapy for hemophilia B in China". This article reviewed the development of treatment of hemophilia B (HB) in China, and the translational potential of gene therapy in HB.
Hemophilia B (HB) is a rare but severe bleeding disorder characterized by deficient or defective Factor IX (FIX), leading to prolonged bleeding episodes and increased morbidity and mortality. Traditional treatments, such as regular infusions of FIX concentrates, pose challenges due to their high cost, risk of inhibitor development, and the need for lifelong administration. However, recent advances in gene therapy offer a promising alternative for HB management. He mentioned that Xue et al(Safety and activity of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX administered with prophylactic glucocorticoids in patients with haemophilia B: a single-centre, single-arm, phase 1, pilot trial. Lancet Haematol. 2022;9:e504–e513.) explores a landmark study conducted in China, where gene therapy using the BBM-H901 vector demonstrated remarkable efficacy and safety in treating HB. The study’s design, methodology, results, and implications for future research and clinical practice are discussed in detail, highlighting the transformative potential of gene therapy in revolutionizing HB treatment.
The primary endpoint of the study was to evaluate the change in FIX coagulation activity levels following gene therapy with BBM-H901. Secondary endpoints included the incidence of adverse events, the development of FIX inhibitors, and the impact of gene therapy on bleeding frequency and quality of life. Patients were followed for a median duration of 58 weeks, with regular assessments of FIX activity, bleeding episodes, and safety parameters.
The gene therapy vector, BBM-H901, was engineered to target liver cells specifically, leveraging the liver’s natural capacity for FIX production. The vector design incorporated a liver-specific promoter and a CpG-reduced FIX Padua coding sequence, optimizing transgene expression and minimizing immune recognition. The choice of AAV vector serotype and administration route was also carefully considered to maximize liver transduction efficiency and minimize off-target effects.
The results of the study exceeded expectations, demonstrating a profound and sustained increase in FIX coagulation activity levels following gene therapy with BBM-H901. After a median follow-up of 58 weeks, patients experienced a mean FIX activity level of 36.9 ± 20.5 IU/dL, representing a remarkable improvement from baseline. Importantly, no patients developed FIX inhibitors or experienced serious adverse events related to gene therapy, underscoring the safety and tolerability of BBM-H901.
In conclusion, the results of this landmark study demonstrate the transformative potential of gene therapy in the treatment of HB. Gene therapy with BBM-H901 offers a safe, effective, and durable treatment option for patients with severe HB, providing hope for improved outcomes and quality of life. The success of BBM-H901 gene therapy represents a major milestone in the field of HB research and has significant implications for the future of gene therapy in other genetic disorders. Moving forward, further research and clinical trials are needed to validate these findings and expand access to gene therapy for patients with HB worldwide.
Reference
1. Blood Sci . 2023 Jan 13;5(2):138-139.
2. Xue F, Li H, Wu X, et al. Safety and activity of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX administered with prophylactic glucocorticoids in patients with haemophilia B: a single-centre, single-arm, phase 1, pilot trial. Lancet Haematol. 2022;9:e504–e513.
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