Evidence for Long-term Efficacy and Safety of Gene Therapy for Wiskott–Aldrich Syndrome in Preclinical Models

San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy.
Molecular Therapy (Impact Factor: 6.23). 04/2009; 17(6):1073-82. DOI: 10.1038/mt.2009.31
Source: PubMed


Wiskott-Aldrich Syndrome (WAS) is a life-threatening X-linked disease characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancies. Gene therapy could represent a therapeutic option for patients lacking a suitable bone marrow (BM) donor. In this study, we analyzed the long-term outcome of WAS gene therapy mediated by a clinically compatible lentiviral vector (LV) in a large cohort of was(null) mice. We demonstrated stable and full donor engraftment and Wiskott-Aldrich Syndrome protein (WASP) expression in various hematopoietic lineages, up to 12 months after gene therapy. Importantly, we observed a selective advantage for T and B lymphocytes expressing transgenic WASP. T-cell receptor (TCR)-driven T-cell activation, as well as B-cell's ability to migrate in response to CXCL13, was fully restored. Safety was evaluated throughout the long-term follow-up of primary and secondary recipients of WAS gene therapy. WAS gene therapy did not affect the lifespan of treated animals. Both hematopoietic and nonhematopoietic tumors arose, but we excluded the association with gene therapy in all cases. Demonstration of long-term efficacy and safety of WAS gene therapy mediated by a clinically applicable LV is a key step toward the implementation of a gene therapy clinical trial for WAS.

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    • "A similar selective advantage of modified cells has been observed for a gene therapy of another pathology of hematopoı¨esis, the Wiksott–Aldrich syndrome (WAS) (Marangoni et al. 2009). 3 This hypothesis amounts to positing that the limiting factor is the enzyme concentration in a large compartment, on which enzyme use by A cells has little effect. "
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    ABSTRACT: In this article, we apply the perspective of intraorganismal ecology by investigating a family of ecological models suitable to describe a gene therapy for a particular metabolic disorder, the adenosine deaminase deficiency. The gene therapy is modeled as the prospective ecological invasion of an organ (here, bone marrow) by genetically modified stem cells, which then operate niche construction in the cellular environment by releasing an enzyme they synthesize. We show that depending on the order chosen for the model (a choice that cannot be made on a priori assumptions), different kinds of dynamics are expected, possibly leading to different therapeutic strategies. This drives us to discuss several features of the extension of ecology to intraorganismal ecology.
    Biological Theory 12/2014; DOI:10.1007/s13752-014-0190-y
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    • "Preclinical data in the murine model indicate that the LV-mediated GT approach is effective in restoring immune cell functionality (Blundell et al., 2008; Marangoni et al., 2009; Bosticardo et al., 2011; Catucci et al., 2011). GT treated Was −/− mice did not show any adverse events or tumors even in long-term follow up studies (Marangoni et al., 2009). Finally, we and others demonstrated the efficacy of LV-mediated GT in CD34 + cells obtained from WAS patients (Charrier et al., 2007; Scaramuzza et al., 2012). "
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    ABSTRACT: Wiskott-Aldrich Syndrome (WAS) is a severe X-linked Primary Immunodeficiency that affects 1-10 out of 1 million male individuals. WAS is caused by mutations in the WAS Protein (WASP) expressing gene that leads to the absent or reduced expression of the protein. WASP is a cytoplasmic protein that regulates the formation of actin filaments in hematopoietic cells. WASP deficiency causes many immune cell defects both in humans and in the WAS murine model, the Was(-/-) mouse. Both cellular and humoral immune defects in WAS patients contribute to the onset of severe clinical manifestations, in particular microthrombocytopenia, eczema, recurrent infections, and a high susceptibility to develop autoimmunity and malignancies. Autoimmune diseases affect from 22 to 72% of WAS patients and the most common manifestation is autoimmune hemolytic anemia, followed by vasculitis, arthritis, neutropenia, inflammatory bowel disease, and IgA nephropathy. Many groups have widely explored immune cell functionality in WAS partially explaining how cellular defects may lead to pathology. However, the mechanisms underlying the occurrence of autoimmune manifestations have not been clearly described yet. In the present review, we report the most recent progresses in the study of immune cell function in WAS that have started to unveil the mechanisms contributing to autoimmune complications in WAS patients.
    Frontiers in Immunology 07/2012; 3:209. DOI:10.3389/fimmu.2012.00209
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    • "We have developed an HSC gene therapy approach based on lentiviral-mediated gene transfer of WAS complementary DNA under the control of a 1.6 kb fragment of the endogenous WAS promoter. We previously showed that transplantation of gene corrected WAS-deficient murine HSC in non-lethally irradiated Was−/− mice resulted in long-term multilineage engraftment of WASp-expressing cells and functional correction of lymphocyte and dendritic cells with a lack of observable toxicity over a short- and long-term period.22,23 Moreover, the vector was able to restore in vitro expression of WASp in CD34+ cells and mature cells from WAS patients.24,25 "
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    ABSTRACT: Gene therapy with ex vivo-transduced hematopoietic stem/progenitor cells may represent a valid therapeutic option for monogenic immunohematological disorders such as Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency associated with thrombocytopenia. We evaluated the preclinical safety and efficacy of human CD34(+) cells transduced with lentiviral vectors (LV) encoding WAS protein (WASp). We first set up and validated a transduction protocol for CD34(+) cells derived from bone marrow (BM) or mobilized peripheral blood (MPB) using a clinical grade, highly purified LV. Robust transduction of progenitor cells was obtained in normal donors and WAS patients' cells, without evidence of toxicity. To study biodistribution of human cells and exclude vector release in vivo, LV-transduced CD34(+) cells were transplanted in immunodeficient mice, showing a normal engraftment and differentiation ability towards transduced lymphoid and myeloid cells in hematopoietic tissues. Vector mobilization to host cells and transmission to germline cells of the LV were excluded by different molecular assays. Analysis of vector integrations showed polyclonal integration patterns in vitro and in human engrafted cells in vivo. In summary, this work establishes the preclinical safety and efficacy of human CD34(+) cells gene therapy for the treatment of WAS.
    Molecular Therapy 02/2012; 21(1). DOI:10.1038/mt.2012.23 · 6.23 Impact Factor
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