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Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome.

ABSTRACT: Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical scores. Vector integration analyses revealed highly polyclonal and multilineage haematopoiesis resulting from the gene-corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes, and no aberrant clonal expansion was observed after 20 to 32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.

SUBMITTER: Aiuti A

PROVIDER: S-EPMC4375961 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome.

Aiuti Alessandro A Biasco Luca L Scaramuzza Samantha S Ferrua Francesca F Cicalese Maria Pia MP Baricordi Cristina C Dionisio Francesca F Calabria Andrea A Giannelli Stefania S Castiello Maria Carmina MC Bosticardo Marita M Evangelio Costanza C Assanelli Andrea A Casiraghi Miriam M Di Nunzio Sara S Callegaro Luciano L Benati Claudia C Rizzardi Paolo P Pellin Danilo D Di Serio Clelia C Schmidt Manfred M Von Kalle Christof C Gardner Jason J Mehta Nalini N Neduva Victor V Dow David J DJ Galy Anne A Miniero Roberto R Finocchi Andrea A Metin Ayse A Banerjee Pinaki P PP Orange Jordan S JS Galimberti Stefania S Valsecchi Maria Grazia MG Biffi Alessandra A Montini Eugenio E Villa Anna A Ciceri Fabio F Roncarolo Maria Grazia MG Naldini Luigi L

Science (New York, N.Y.) 20130711 6148

Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-i ...[more]

PMID: 23845947

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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.

Project description:ImportanceWiskott-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.ObjectiveTo assess the outcomes and safety of autologous HSC gene therapy in Wiskott-Aldrich syndrome.Design, setting, and participantsGene-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.InterventionA single infusion of gene-modified CD34+ cells with an advanced lentiviral vector.Main outcomes and measuresPrimary 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.ResultsSix 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 relevanceThis 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.

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Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome.

Publications

Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome.

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