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Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome.

ABSTRACT: 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.To assess the outcomes and safety of autologous HSC gene therapy in Wiskott-Aldrich syndrome.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.A single infusion of gene-modified CD34+ cells with an advanced lentiviral vector.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.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.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.

SUBMITTER: Hacein-Bey Abina S

PROVIDER: S-EPMC4942841 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome.

Hacein-Bey Abina Salima S Gaspar H Bobby HB Blondeau Johanna J Caccavelli Laure L Charrier Sabine S Buckland Karen K Picard Capucine C Six Emmanuelle E Himoudi Nourredine N Gilmour Kimberly K McNicol Anne-Marie AM Hara Havinder H Xu-Bayford Jinhua J Rivat Christine C Touzot Fabien F Mavilio Fulvio F Lim Annick A Treluyer Jean-Marc JM Héritier Sébastien S Lefrère Francois F Magalon Jeremy J Pengue-Koyi Isabelle I Honnet Géraldine G Blanche Stéphane S Sherman Eric A EA Male Frances F Berry Charles C Malani Nirav N Bushman Frederic D FD Fischer Alain A Thrasher Adrian J AJ Galy Anne A Cavazzana Marina M

JAMA 20150401 15

<h4>Importance</h4>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.<h4>Objective</h4>To assess the outcomes and safety of autologous HSC gene therapy in Wiskott-Aldrich syndrome.<h4>Design, setting, and participants</h4>Gene-corrected autologous HSCs were infused in 7 consecutive patients ...[more]

PMID: 25898053

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Project description:BackgroundWiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and susceptibility to autoimmunity and lymphomas. Hematopoietic stem cell transplantation is the treatment of choice; however, administration of WAS gene-corrected autologous hematopoietic stem cells has been demonstrated as a feasible alternative therapeutic approach.ObjectiveBecause B-cell homeostasis is perturbed in patients with WAS and restoration of immune competence is one of the main therapeutic goals, we have evaluated reconstitution of the B-cell compartment in 4 patients who received autologous hematopoietic stem cells transduced with lentiviral vector after a reduced-intensity conditioning regimen combined with anti-CD20 administration.MethodsWe evaluated B-cell counts, B-cell subset distribution, B cell-activating factor and immunoglobulin levels, and autoantibody production before and after gene therapy (GT). WAS gene transfer in B cells was assessed by measuring vector copy numbers and expression of Wiskott-Aldrich syndrome protein.ResultsAfter lentiviral vector-mediated GT, the number of transduced B cells progressively increased in the peripheral blood of all patients. Lentiviral vector-transduced progenitor cells were able to repopulate the B-cell compartment with a normal distribution of B-cell subsets both in bone marrow and the periphery, showing a WAS protein expression profile similar to that of healthy donors. In addition, after GT, we observed a normalized frequency of autoimmune-associated CD19(+)CD21(-)CD35(-) and CD21(low) B cells and a reduction in B cell-activating factor levels. Immunoglobulin serum levels and autoantibody production improved in all treated patients.ConclusionsWe provide evidence that lentiviral vector-mediated GT induces transgene expression in the B-cell compartment, resulting in ameliorated B-cell development and functionality and contributing to immunologic improvement in patients with WAS.

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Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome.

Publications

Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome.

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