Gene Therapy Approaches for Primary Immunodeficiencies

Human Genome Research

Investigators

Linked publications & trials

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. We are carrying out a clinical gene therapy trial to attempt the cure of a form of inherited immunodeficiency due to genetic defects of the adenosine deaminase gene. A strong selective advantage of gene-corrected cells is expected in this disease, which should facilitate the outcome of the procedure. 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. This trial is also comparing two different retroviral vectors with the aim of identifying the optimal vehicle for gene transfer in human hematopoietic stem cells. 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. Work in animal models is now planned to verify in vivo safety and efficacy of the gene therapy approaches.