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A New Dawn for Hemophilia A? Lentiviral Gene Therapy Using Autologous Stem Cells
The hemophilia treatment landscape is evolving with the approval of adeno-associated virus (AAV) vector-based gene therapies, but limitations underscore the need for better strategies. In a phase 1 trial conducted in India, investigators evaluated a novel gene therapy for severe hemophilia A in five participants aged 22 to 41 who received on-demand treatment and had an annualized bleeding rate (ABR) of at least 20 events. Investigators used autologous hematopoietic stem cells (HSCs) transduced with CD68-LV-ET3, a lentiviral vector containing a novel F8 transgene and a myeloid-directed CD68 promoter. Participants underwent myeloablative conditioning with treosulfan instead of busulfan. Therapy was administered with or without a transduction enhancer.
All participants had stable factor VIII expression, with activity levels correlating to vector copy numbers in peripheral blood. Median factor VIII levels were higher in the three patients who received a transduction enhancer (19.3, 37.1, and 39.9 IU/dL) than in the two who did not (5.2 and 1.7 IU/dL). The ABR dropped to zero for all participants over a cumulative follow-up of 81 months (median, 14 months). Notably, four participants retained normal sperm counts posttreatment.
Comment
This HSC-based gene therapy approach for hemophilia A addresses key limitations of AAV-based gene therapy. It offers lifelong factor VIII expression and broader eligibility, including for children and adults regardless of preexisting anti-AAV antibodies. The ET3 transgene provides significantly higher (10–100 times) efficiency, while the CD68 promoter targets expression to monocytes and macrophages, potentially enhancing joint hemostasis. Additionally, using treosulfan for conditioning may reduce risks of severe mucositis and infertility compared with traditional regimens. If successful in larger trials, this approach could potentially free patients from chronic factor VIII administration, significantly improving quality of life. Nevertheless, long-term follow-up remains crucial to assess safety, especially insertional mutagenesis risks.
Citation(s)
Author:
Srivastava A et al.
Title:
Lentiviral gene therapy with CD34+ hematopoietic cells for hemophilia A.
Source:
N Engl J Med
2024
Dec
9; [e-pub].
(Abstract/FREE Full Text)
Empfohlen von
Anjali A. Sharathkumar, MBBS, MD, MS