Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome.
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Hacein-Bey Abina Salima, Gaspar H Bobby, Blondeau Johanna, Caccavelli Laure, Charrier Sabine, Buckland Karen, Picard Capucine, Six Emmanuelle, Himoudi Nourredine, Gilmour Kimberly, McNicol Anne-Marie, Hara Havinder, Xu-Bayford Jinhua, Rivat Christine, Touzot Fabien, Mavilio Fulvio, Lim Annick, Treluyer Jean-Marc, Héritier Sébastien, Lefrère Francois, Magalon Jeremy, Pengue-Koyi Isabelle, Honnet Géraldine, Blanche Stéphane, Sherman Eric A, Male Frances, Berry Charles, Malani Nirav, Bushman Frederic D, Fischer Alain, Thrasher Adrian J, Galy Anne, Cavazzana Marina
Аннотация
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.