• Alok Srivastava, Aby Abraham, Fouzia Aboobacker, Gurbind Singh, Tulasi Geevar, Uday Kulkarni, Sushil Selvarajan, Anu Korula, Rutvi Gautam Dave, Mohana Shankar, Abraham S Singh, Anbu Jeba, Navien Kumaar, Christopher Benjamin, Kavitha M Lakshmi, Vivi Miriam Srivastava, Ramachandran V Shaji, Sukesh C Nair, Harrison C Brown, Gabriela Denning, Pete Lollar, Christopher B Doering, and Trent Spencer.
• From the Department of Hematology, Christian Medical College Vellore, Ranipet Campus, Vellore, India (A.S., A.A., F.A., U.K., S.S., A.K., A.S.S., A.J., N.K., C.B., K.M.L., R.V.S.); Center for Stem Cell Research Unit of inStem, Bengaluru, Christian Medical College Vellore, Vellore, India (A.S., G.S., M.S., R.V.S.); the Department of Immunohematology and Transfusion Medicine, Christian Medical College Vellore, Town Campus, Vellore, India (T.G., R.G.D., S.C.N.); the Department of Cytogenetics, Christian Medical College Vellore, Vellore, India (V.M.S.); Expression Therapeutics, Tucker, GA (H.C.B., G.D., P.L., C.B.D., T.S.); and Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta (P.L., C.B.D., T.S.).
• N. Engl. J. Med. 2024 Dec 9.

BackgroundSevere hemophilia A is managed with factor VIII replacement or hemostatic products that stop or prevent bleeding. Data on gene therapy with hematopoietic stem-cell (HSC)-based expression of factor VIII for the treatment of severe hemophilia A are lacking.MethodsWe conducted a single-center study involving five participants 22 to 41 years of age with severe hemophilia A without factor VIII inhibitors. Autologous HSCs were transduced with CD68-LV-ET3 - a lentiviral vector including a new F8 transgene (ET3) with a myeloid-directed CD68 promoter - either without transduction enhancer (group 1) or with transduction enhancer (group 2). Transduced HSCs were transplanted into recipients after myeloablative conditioning. The treatment was assessed for safety (engraftment and regimen-related toxic effects) and efficacy (factor VIII activity and annualized bleeding rate).ResultsParticipants received CD68-ET3-LV-transduced autologous CD34+ HSCs at doses of 5.0×106 to 6.1×106 per kilogram of body weight. The vector copy numbers in the final drug product were 1.0 and 0.6 copies per cell for the two participants in group 1 and 1.5, 0.6, and 2.2 copies per cell for the three participants in group 2. The duration of severe neutropenia was 7 to 11 days and of severe thrombocytopenia was 1 to 7 days. The median factor VIII activity level, measured with the use of a one-stage assay, after day 28 until the last follow-up visit was 5.2 IU per deciliter (range, 3.0 to 8.7) and 1.7 IU per deciliter (range, 1.0 to 4.0) with a peripheral-blood vector copy number of 0.2 and 0.1 copies per cell, respectively, in the two group 1 participants, and 37.1 IU per deciliter (range, 18.3 to 73.6), 19.3 IU per deciliter (range, 6.6 to 34.5), and 39.9 IU per deciliter (range, 20.6 to 55.1) with a peripheral-blood vector copy number of 4.4, 3.2, and 4.8 copies per cell, respectively, in the three group 2 participants. The annualized bleeding rate was zero for all five participants over a cumulative follow-up of 81 months (median follow-up, 14 months; range, 9 to 27).ConclusionsGene therapy for hemophilia A with the use of lentiviral vector-transduced autologous HSCs resulted in stable factor VIII expression, with factor VIII activity correlating to vector copy number in the peripheral blood. (Funded by the Ministry of Science and Technology, Government of India, and others; ClinicalTrials.gov number, NCT05265767; Clinical Trials Registry-India number, CTRI/2022/03/041304.).Copyright © 2024 Massachusetts Medical Society.

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