Outcomes Following Gene Therapy in Patients With Severe Wiskott-Aldrich Syndrome
Authors: Salima Hacein-Bey Abina, H. Bobby Gaspar, Johanna Blondeau, Laure Caccavelli, Sabine Charrier, Karen Buckland, Capucine Picard, Emmanuelle Six, Nourredine Himoudi, Kimberly Gilmour, Anne-Marie McNicol, Havinder Hara, Jinhua Xu-Bayford, Christine Rivat, Fabien Touzot, Fulvio Mavilio, Annick Lim, Jean-Marc Treluyer, Sébastien Héritier, Francois Lefrère, Jeremy Magalon, Isabelle Pengue-Koyi, Géraldine Honnet, Stéphane Blanche, Eric A. Sherman, Frances Male, Charles Berry, Nirav Malani, Frederic D. Bushman, Alain Fischer, Adrian J. Thrasher, Anne Galy, Marina Cavazzana
Journal: JAMA (2015)

<h3>Importance</h3> Wiskott-Aldrich syndrome is a rare primary immunodeficiency associated with severe microthrombocytopenia. Partially HLA antigen–matched allogeneic hematopoietic stem cell (HSC) transplantation is often curative but is associated with significant comorbidity. <h3>Objective</h3> To assess the outcomes and safety of autologous HSC gene therapy in Wiskott-Aldrich syndrome. <h3>Design, Setting, and Participants</h3> Gene-corrected autologous HSCs were infused in 7 consecutive patients with severe Wiskott-Aldrich syndrome lacking HLA antigen–matched related or unrelated HSC donors (age range, 0.8-15.5 years; mean, 7 years) following myeloablative conditioning. Patients were enrolled in France and England and treated between December 2010 and January 2014. Follow-up of patients in this intermediate analysis ranged from 9 to 42 months. <h3>Intervention</h3> A single infusion of gene-modified CD34<sup>+</sup>cells with an advanced lentiviral vector. <h3>Main Outcomes and Measures</h3> Primary outcomes were improvement at 24 months in eczema, frequency and severity of infections, bleeding tendency, and autoimmunity and reduction in disease-related days of hospitalization. Secondary outcomes were improvement in immunological and hematological characteristics and evidence of safety through vector integration analysis. <h3>Results</h3> Six of the 7 patients were alive at the time of last follow-up (mean and median follow-up, 28 months and 27 months, respectively) and showed sustained clinical benefit. One patient died 7 months after treatment of preexisting drug-resistant herpes virus infection. Eczema and susceptibility to infections resolved in all 6 patients. Autoimmunity improved in 5 of 5 patients. No severe bleeding episodes were recorded after treatment, and at last follow-up, all 6 surviving patients were free of blood product support and thrombopoietic agonists. Hospitalization days were reduced from a median of 25 days during the 2 years before treatment to a median of 0 days during the 2 years after treatment. All 6 surviving patients exhibited high-level, stable engraftment of functionally corrected lymphoid cells. The degree of myeloid cell engraftment and of platelet reconstitution correlated with the dose of gene-corrected cells administered. No evidence of vector-related toxicity was observed clinically or by molecular analysis. <h3>Conclusions and Relevance</h3> This study demonstrated the feasibility of the use of gene therapy in patients with Wiskott-Aldrich syndrome. Controlled trials with larger numbers of patients are necessary to assess long-term outcomes and safety.