Authors:
Salima Hacein-Bey Abina, PharmD, PhD; H. Bobby Gaspar, MRCP, PhD; Johanna Blondeau, MS; Laure Caccavelli, PhD; Sabine Charrier, PhD; Karen Buckland, PhD; Capucine Picard, MD, PhD; Emmanuelle Six, PhD; Nourredine Himoudi, PhD; Kimberly Gilmour, PhD; Anne-Marie McNicol, PhD; Havinder Hara, MS; Jinhua Xu-Bayford, DipHE; Christine Rivat, PhD; Fabien Touzot, MD, PhD; Fulvio Mavilio, PhD; Annick Lim, MS; Jean-Marc Treluyer, MD, PhD; Sébastien Héritier, MD; Francois Lefrère, MD; Jeremy Magalon, PharmD; Isabelle Pengue-Koyi, PharmD, PhD; Géraldine Honnet, MD; Stéphane Blanche, MD; Eric A. Sherman, BA; Frances Male, BA; Charles Berry, PhD; Nirav Malani, MS; Frederic D. Bushman, PhD; Alain Fischer, MD, PhD; Adrian J. Thrasher, MB, BS, PhD; Anne Galy, PhD; Marina Cavazzana, MD, PhD
Summary:
Importance - 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.
Objective - To assess the outcomes and safety of autologous HSC gene therapy in Wiskott-Aldrich syndrome.
Design, Setting, and Participants - 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.
Intervention - A single infusion of gene-modified CD34+ cells with an advanced lentiviral vector.
Main Outcomes and Measures - 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.
Results - 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.
Conclusions and Relevance - 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.
Source:
The Journal of the American Medical Association; Vol. 313, No. 15, 1550-1563 (04/21/15)