Gene Therapy Approaches for Primary Immunodeficiencies

Human Genome Research

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Abstract

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 and/or 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 10 years. In another clinical trial attempting the correction of hematopoietic stem cells, four patients were enrolled and received treatment which did not result in clinical benefit. Plans are being made to modify the treatment strategy and improve the efficacy of the procedure. We have also developed pre-clinical models of gene therapy for another immunodeficiency called Wiskott-Aldrich syndrome. 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. In other experiments, in vitro and in vivo pre-clinical studies have been performed to verify safety and feasibility of genetc correction as treatment modality for IL-12R beta1 deficiency, an immunodeficiency that exposes affected patients to salmonella and mycobacteria infections.