Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott–Aldrich syndrome
Alessandra Magnani, Michaëla Semeraro, Frédéric Adam, Claire Booth, Loı̈c Dupré, Emma Morris, Aurélie Gabrion, Cécile Roudaut, Delphine Borgel, Antoine Toubert, Emmanuel Clave, Chrystelle Abdo, Guy Gorochov, Rachel Petermann, Mélanie Guiot, Makoto Miyara, Despina Moshous, Elisa Magrin, Adeline Denis, Felipe Suárez, Chantal Lagresle‐Peyrou, Ansley M. Roche, J.K. Everett, Amélie Trinquand, M. Guisset, Jinhua Bayford, S. Hacein-Bey-Abina, Alexandre Kauskot, Reem Elfeky, Christine Rivat, S. Abbas, H. Bobby Gaspar, Elizabeth Macintyre, Capucine Pïcard, Frederic D. Bushman, Anne Galy, Alain Fischer, Emmanuelle Six, Adrian J. Thrasher, Marina Cavazzana
Abstract
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.