Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott–Aldrich syndrome

• Published in: Nature Medicine Vol. 28; no. 1; pp. 71 - 80
• Main Authors: Magnani, A., Semeraro, M., Adam, F., Booth, C., Dupré, L., Morris, E. C., Gabrion, A., Roudaut, C., Borgel, D., Toubert, A., Clave, E., Abdo, C., Gorochov, G., Petermann, R., Guiot, M., Miyara, M., Moshous, D., Magrin, E., Denis, A., Suarez, F., Lagresle, C., Roche, A. M., Everett, J., Trinquand, A., Guisset, M., Bayford, J. Xu, Hacein-Bey-Abina, S., Kauskot, A., Elfeky, R., Rivat, C., Abbas, S., Gaspar, H. B., Macintyre, E., Picard, C., Bushman, F. D., Galy, A., Fischer, A., Six, E., Thrasher, A. J., Cavazzana, M.
• Format: Journal Article Magazine Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2022; Nature Publishing Group
• Subjects: 692/699/249/2512; 692/700/565/201/2110; Adolescent; Adult; Adverse events; Antigens; Autoimmune diseases; Autoimmunity; Biomedical and Life Sciences; Biomedicine; Biosafety; Biotechnology; Bleeding; Cancer Research; Child; Child, Preschool; Clinical trials; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Eczema; Gene therapy; Genetic Therapy - methods; Genetic Vectors; Health services; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Histocompatibility antigen HLA; Human health and pathology; Humans; Immunology; Infant; Infectious Diseases; Lentivirus - genetics; Leukocytes; Life Sciences; Lymphocytes; Lymphocytes T; Metabolic Diseases; Molecular Medicine; Monitoring; Neurosciences; Patients; Pediatrics; Platelets; Progenitor cells; Safety; Skin diseases; Stems; Subpopulations; Telemedicine; Thrombocytopenia; Treatment Outcome; Wiskott-Aldrich Syndrome - genetics; Wiskott-Aldrich Syndrome - immunology; Wiskott-Aldrich Syndrome - therapy; Young Adult
• ISSN: 1078-8956; 1546-170X; 1744-7933
• DOI: 10.1038/s41591-021-01641-x

Patients with Wiskott–Aldrich syndrome (WAS) lacking a human leukocyte antigen-matched donor may benefit from gene therapy through the provision of gene-corrected, autologous hematopoietic stem/progenitor cells. Here, we present comprehensive, long-term follow-up results (median follow-up, 7.6 years) (phase I/II trial no. NCT02333760 ) for eight patients with WAS having undergone phase I/II lentiviral vector-based gene therapy trials (nos. NCT01347346 and NCT01347242 ), with a focus on thrombocytopenia and autoimmunity. Primary outcomes of the long-term study were to establish clinical and biological safety, efficacy and tolerability by evaluating the incidence and type of serious adverse events and clinical status and biological parameters including lentiviral genomic integration sites in different cell subpopulations from 3 years to 15 years after gene therapy. Secondary outcomes included monitoring the need for additional treatment and T cell repertoire diversity. An interim analysis shows that the study meets the primary outcome criteria tested given that the gene-corrected cells engrafted stably, and no serious treatment-associated adverse events occurred. Overall, severe infections and eczema resolved. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. The results suggest that lentiviral gene therapy provides sustained clinical benefits for patients with WAS. Long-term monitoring of patients with Wiskott–Aldrich syndrome following lentiviral gene therapy shows a safe profile and a reduction in the frequency of autoimmune manifestations and bleeding events, despite incomplete platelet reconstitution.