Inherited disorders of immunity are unique models that allow studying the role of specific genes and molecules in the development on the human immune system. Many of these diseases are currently only curable with allogeneic bone marrow transplantation, an intensive form of therapy with potential serious complications and that often results in only incomplete reconstitution of immunity. For those forms of immunodeficiency caused by a known genetic defect, gene therapy could therefore represent a valid alternative approach. Once proven feasible for inherited immunodeficiencies, it is likely that similar gene-based approach targeting the hematopoietic stem cell can be applied to the prevention andor treatment of secondary forms of immunodeficiency such as that caused by HIV-1 infection. In clinical trials for a form of inherited immunodeficiency due to genetic defects of the adenosine deaminase gene using gene transfer into peripheral blood lymphocytes, we have observed a long-term persistance and expression of the transferred gene for over 15 years. In another gene therapy clinical trial for adenosine deaminase deficiency we attempted the correction of hematopoietic stem cells in four patients. After three years of follow-up, the patients did not show any adverse event, but the level of gene marking was too low to obtain clinical benefit. We have amended our protocol to improve the efficacy of the procedure and treated two patients in 2007 and 1 in 2009 with encouraging preliminary results of restoration of immunity. A third iteration of the protocol was implemented in late 2009 and has enrolled 1 patient. We have also developed pre-clinical models of gene therapy for another immunodeficiency called Wiskott-Aldrich syndrome (WAS). In these experiments, we have shown that vectors based on retroviruses can be used to correct the responsible genetic defect and to express the missing or mutated protein in cells obtained from affected patients. We have also shown that gene transfer vectors based on the Foamy Virus can correct the defects in mouse models of the disease. At the same time, we are attempting a better characterizion of the immune defects seen in WAS in order to establish if they will be able to be corrected by gene therapy. To this aim, we are studying the function of regulatory T cells and the developmental stages of B lymphocytes in patients with WAS. We have demonstrated functional defects in both natural occurring and inducible regulatory T cell populations carrying WAS mutations. These studies will provide mechanistic information into the basis of the immunodeficiency and tendency to autoimmunity that affects these patients.

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National Human Genome Research Institute
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Ikawa, Yasuhiro; Hess, Richard; Dorward, Heidi et al. (2015) In vitro functional correction of Hermansky-Pudlak Syndrome type-1 by lentiviral-mediated gene transfer. Mol Genet Metab 114:62-5
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