ABSTRACT
Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes o f Health, 49 Convent Dr., Bid. 49, Rm. 3A20 Bethesda, Maryland 20892-4442, USA
Table of Contents 1. Introduction 2. Gene therapy trials for adenosine deaminase (ADA) deficiency
a) ADA deficiency b) First clinical trial: T lymphocyte-directed gene transfer c) Second clinical trial: T lymphocyte-and bone marrow hematopoietic stem cell
(HSC)-directed gene transfer d) Clinical trial with transduced autologous umbilical cord blood CD34+ cells e) Other early pilot clinical trial directed at bone marrow HSCs f) Perspectives
3. Gene therapy trials for chronic granulomatous disease (CGD) 4. Gene therapy trial for leukocyte adhesion deficiency type 1 (LAD-1) 5. Gene therapy trials for X-linked severe combined immunodeficiency (X-SCID)
a) Pre-clinical studies b) First successful trial c) Adverse events d) Second successful trial
6. Gene therapy trial for Janus kinase 3 (JAK3) deficiency 7. Conclusions 8. References 9. Summary
* E-mail: fabio@nhgri.nih.gov
Several primary immunodeficiency diseases (IDs) share a number of advantageous characteristics that have made them very attractive candidate diseases for gene therapy since the very early days of this novel branch of medicine. First, IDs are often curable by allogeneic bone marrow transplantation (BMT), which translates into the theoretical possibility that they should also be treatable by gene therapy procedures combining ex vivo manipulation and reinfusion of autologous, gene-corrected hematopoietic stem cells. Second, the target cells for genetic manipulation resides in the bone marrow, an environment readily accessible and amenable to ex vivo gene transfer procedures, which to date offer the best chance for successful treatment. In addition, while currently available technology does not allow reproducing the physiological control mechanisms that are critical for the proper and coordinated expression of genes responsible for hematological diseases such as hemoglobinopathies, the regulation of genes responsible for many IDs (i.e. ADA deficiency, X-SCID, CGD) is relatively simple and current gene transfer vectors are more than adequate to provide expression of the gene of interest at levels compatible with clinical benefit. Finally, for several IDs it can be expected that gene-corrected progenitors and mature cells will have a selective survival advantage over the unmodified affected cell populations, which translates in the very advantageous possibility that even low gene transfer efficiency may have therapeutic effects.
