What is the status of gene therapy for primary immunodeficiency?

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What is the status of gene therapy for primary immunodeficiency? R. Michael Blaese

Published online: 22 May 2007  Humana Press Inc. 2007

Abstract The efforts to find satisfactory treatments for seriously ill patients with primary immunodeficiency have resulted in the development of important new therapeutic procedures with benefits reaching far beyond the relatively small number of patients affected with these rare disorders. Allogeneic bone marrow transplantation, immunoglobulin and enzyme replacement treatments and more recently gene therapy have all been introduced into clinical medicine as treatments for one or more of the primary immunodeficiency diseases. Beginning in 1990, gene-corrected T cells were first used to treat ADA deficiency SCID. With this demonstration that the gene-transfer procedure could be safely used to introduce functional transgenes into patient cells, clinical trials for a broad range of inherited disorders and cancer were started in the mid 90s. Of all these early clinical experiments, those addressing primary immunodeficiency have also been the most successful. Both ADA and X-SCID have now been cured using gene insertion into autologous bone marrow stem cells. In addition some patients with chronic granulomatous disease (CGD) have shown an unexpectedly high level of functionally corrected granulocytes in their blood following infusion of autologous gene-corrected bone marrow. There remain however a great many significant challenges to be overcome before gene therapy becomes the treatment of choice for these and other disorders. The use of genes as medicines is the most complex therapeutic system ever attempted and it may rake several more decades of work before its real potential as a treatment for both inherited and sporadic disorders if finally realized. Keywords Retroviral vector  Hematopoietic stem cell  TIL (tumor infiltrating lymphocytes)  T lymphocytes  ADA-deficiency SCID  X-SCID  Chronic Granulomatous disease  Primary immunodeficiency disease  Genome editing  PEG-ADA  cDNA

Presented at the First Robert A Good Society Symposium, St. Petersburg, FL 2006. R. M. Blaese (&) Immune Deficiency Foundation, 40 W. Chesapeake Ave, Suite 308, Towson, MD 21204, USA e-mail: [email protected]

Immunol Res (2007) 38:274–284

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There are many reasons why the development of gene therapy has been linked closely with the inherited disorders of immunity. These diseases are often lethal in the first months or years and satisfactory treatment may not be available, particularly if a matched sibling donor is not available to permit the strategies of bone marrow transplantation with the highest likelihood of success. Further, many of these disorders involve defects that are limited to the hematopoietic and lymphoid systems and therefore the use of ex vivo treatment of cells from these systems minimizes the challenge of gene delivery that is found with those genetic disorders that require gene delivery in vivo to reach the affected cells (e.g., muscular dystrophy, cystic fibrosis, etc.). An