Gene Therapy Approaches for Primary Immunodeficiencies

Human Genome Research

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Abstract

Primary immunodeficiency diseases represent an unique model to study the development on the human immune system. For several of these diseases, the only currently available therapy is allogeneic bone marrow transplantation, which may result in incomplete reconstitution of immunity and may be associated with severe graft versus host reactions. Genetic correction of autologous hematopoietic stem cells would thus represent a beneficial alternative form of treatment for those immunodeficiencies of known genetic origin. Once proven feasible for inherited immunodeficiencies, it is expected that similar genetic manipulations of hematopoietic stem cells can be applied to the prevention and/or treatment of secondary forms of immunodeficiency such as that caused by HIV-1 infection. We have developed pre-clinical models of gene therapy for two immunodeficiencies called X-linked severe combined immunodeficiency (X-SCID) and Wiskott-Aldrich syndrome. In these experiments, vectors based on retroviruses are being used to correct the responsible genetic aberration and to express the missing or mutated protein in cells obtained from affected patients. Animal models are available for both immunodeficiencies, which allows experiments of genetic correction of bone marrow hematopoietic progenitors. These experiments are performed to verify in vivo safety and efficacy of the gene therapy approaches. A clinical gene therapy trial in ongoing under this project to attempt the cure of another immunodeficiency called adenosine deaminase deficiency. In this trial, CD34+ hematopoietic progenitor cells are collected from affected patients, corrective gene transfer is performed in vitro, and the cells are returned to the patients. Immunologic follow-up will reveal if this procedure can restore the immune responses of treated patients.