Lentiviral gene therapy with reduced-intensity conditioning for sickle cell disease: a phase 1/2 trial

• Published in: Nature medicine Vol. 31; no. 7; pp. 2204 - 2212
• Main Authors: Grimley, Michael, Davies, Stella M., Shrestha, Archana, Shova, Amy, Asnani, Monika, Kent, Michael, Sayani, Farzana, Quinn, Charles T., Niss, Omar, Lutzko, Carolyn, Mehta, Parinda A., Khandelwal, Pooja, Little, Courtney, Chandra, Sharat, Felker, Sydney, Chi, Mengna, Kalfa, Theodosia A., Knight-Madden, Jennifer, Arumugam, Paritha I., Ramos, Kristie N., Witting, Scott, Latham, Teresa, Bushman, Frederic D., Malik, Punam
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2025; Nature Publishing Group
• Subjects: 692/308/2171; 692/308/575; 692/699/1541/13; Adolescent; Adult; Adverse events; Anemia, Sickle Cell - genetics; Anemia, Sickle Cell - therapy; Autografts; Biomedical and Life Sciences; Biomedicine; Body weight; Cancer Research; CD34 antigen; Chemotherapy; Child; Cholecystectomy; Clinical trials; Conditioning; Copy number; Enrollments; Feasibility; Female; Fertility; Fetal Hemoglobin - genetics; Fetuses; Gallstones; gamma-Globins - genetics; Gene therapy; Genetic modification; Genetic Therapy - adverse effects; Genetic Therapy - methods; Genetic Vectors - genetics; Health services; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Hemoglobin; Humans; Infectious Diseases; Lentivirus - genetics; Male; Medical history; Metabolic Diseases; Molecular Medicine; Neurosciences; Neutropenia; Neutrophils; Ovaries; Patients; Pharmacokinetics; Sickle cell disease; Stem cells; Thrombocytopenia; Toxicity; Transplantation Conditioning - methods; Young Adult
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-025-03662-2

Autologous transplantation of gene-modified cells for treatment of sickle cell disease has involved myeloablative conditioning with associated cytopenias and toxicities. We report results of seven patients treated in a first-in-human phase 1/2 study for sickle cell disease using reduced-intensity conditioning transplant of autologous hematopoietic stem cells genetically modified with a lentiviral vector (GbG M ), with 2–7 yr of follow-up. GbG M encodes a modified γ-globin gene that expresses a potent anti-sickling fetal hemoglobin, HbF G16D . The primary study objectives were safety (occurrence of adverse events and duration of neutropenia and thrombocytopenia) and feasibility of treatment. Primary feasibility endpoints of collection of at least 8 × 10 6 CD34 + cells per kg body weight, successful transduction of a minimum of 4 × 10 6 CD34 + cells per kg body weight and the number of subjects with an average vector copy number of >0.01 copies per cell 1 yr after infusion were met. A median of 4 collections (range, 4–8) were needed to achieve the target cell dose, and all products achieved the target vector copy number. There were 503 adverse events in the seven patients throughout the study period, the most common being grade 2–3 vaso-occlusive crisis. Median duration of grade 4 thrombocytopenia was 5 d and of grade 4 neutropenia was 8 d. All seven patients exhibited sustained HbF G16D expression and >80% reduction in severe vaso-occlusive events (secondary endpoints). The clinical trial was terminated after infusion of the seventh patient as the predetermined primary endpoints were met and industry funding was complete. Larger trials are warranted to evaluate the benefits of reduced-intensity conditioning. ClinicalTrials.gov registration number: NCT02186418 . In a first-in-human phase 1/2 study in seven patients with sickle cell disease, autologous hematopoietic stem cell lentiviral gene therapy using reduced-intensity conditioning was considered feasible and safe, achieving >80% reduction in the frequency of vaso-occlusive events.