Journal Article

Lentiviral gene therapy for X-linked chronic granulomatous disease

Rivat, Christine, Everett, John K., Grez, Manuel, Armant, Myriam, Darwish, Jinan, Biasco, Luca, De Ravin, Suk See, Booth, Claire, Buckland, Karen F., Choi, Uimook, Honnet, Geraldine, Santilli, Giorgia, Kohn, Donald B., Gilmour, Kimberly, Bushman, Frederic D., Williams, David A., Dip, Jinhua Xu-Bayford, Wang, Leo D., Pai, Sung-Yun, Gregg, John, Morris, Emma C., Paprotka, Tobias, Newburger, Peter E., Kuhns, Douglas B., Gaspar, H. Bobby, Galy, Anne, Kang, Elizabeth M., Snell, Katie, Malech, Harry L., Izotova, Natalia, Raymond, Hayley E., Kuo, Caroline Y., Shaw, Kit L., Terrazas, Dayna, Thrasher, Adrian J., Dorsey, Morna J., Leon-Rico, Diego, Bauser, Christopher A.

2020

Overview

Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytic cells 1 , 2 . We report the initial results of nine severely affected X-linked CGD (X-CGD) patients who received ex vivo autologous CD34 + hematopoietic stem and progenitor cell-based lentiviral gene therapy following myeloablative conditioning in first-in-human studies (trial registry nos. NCT02234934 and NCT01855685). The primary objectives were to assess the safety and evaluate the efficacy and stability of biochemical and functional reconstitution in the progeny of engrafted cells at 12 months. The secondary objectives included the evaluation of augmented immunity against bacterial and fungal infection, as well as assessment of hematopoietic stem cell transduction and engraftment. Two enrolled patients died within 3 months of treatment from pre-existing comorbidities. At 12 months, six of the seven surviving patients demonstrated stable vector copy numbers (0.4–1.8 copies per neutrophil) and the persistence of 16–46% oxidase-positive neutrophils. There was no molecular evidence of either clonal dysregulation or transgene silencing. Surviving patients have had no new CGD-related infections, and six have been able to discontinue CGD-related antibiotic prophylaxis. The primary objective was met in six of the nine patients at 12 months follow-up, suggesting that autologous gene therapy is a promising approach for CGD patients. Initial results from phase I/II lentiviral gene therapy trials provide early evidence supporting its safety and efficacy in treating patients with X-linked chronic granulomatous disease.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/2489/201/2110 / 692/699/249/2512 / Adolescent / Antibiotics / Antigens, CD34 - genetics / Autografts / Biomedical and Life Sciences / Biomedicine / Cancer Research / Care and treatment / CD34 antigen / Child / Child, Preschool / Chromosomes, Human, X / Chronic granulomatous disease / Clinical trials / Comorbidity / Crohn's disease / Disease prevention / Evaluation / Gene Silencing / Gene therapy / Genes, Regulator / Genetic aspects / Genetic disorders / Genetic Therapy - methods / Genetic Vectors / Granulomatous Disease, Chronic - genetics / Granulomatous Disease, Chronic - therapy / Health aspects / Hematopoietic stem cells / Hematopoietic Stem Cells - cytology / Humans / Infectious Diseases / Lentivirus / Lentivirus - genetics / Letter / Leukocytes (neutrophilic) / Life Sciences / Male / Metabolic Diseases / Molecular Medicine / NADPH Oxidases - genetics / Neurosciences / Neutrophils - metabolism / Patient outcomes / Patient Safety / Phagocytes / Progenitor cells / Progeny / Promoter Regions, Genetic / Safety / Stability analysis / Stem cells / Transplantation Conditioning / Treatment Outcome / United Kingdom / United States / Young Adult