Gene transfer into primates and prospects for gene therapy in humans

Retroviral vectors infect primate bone marrow cells and express in vivo the transferred genes (the human ADA gene and the bacterial gene for neomycin resistance). The SAX vector appears to express human ADA at normal levels, but the infection efficiency is low (less than 1%) so that the gene product is only detectable in the peripheral blood at low levels. Vector expression disappears after 5 months (except for occasional T cells), presumably due to a failure to infect a renewal stem cell. While the level of ADA expression obtained in primates would not appear to be sufficient to correct outright the disease caused by ADA deficiency, it is possible that T-cell progenitors in the marrow will have a selective advantage. T cells expressing an ADA vector would then able to expand and potentially restore immune function. Unfortunately, this hypothesis will go untested until an animal model for ADA deficiency is found or a human clinical trial is performed. At present, consideration of gene therapy as a treatment for ADA deficiency would only be appropriate if all conventional forms of treatment were unsuccessful. If such a scenario should present itself, the critical question becomes one of safety, to both the patient and those in contact with the patient. We have begun to address the safety issues associated with gene therapy. Five animals exposed to replication-competent retrovirus during bone marrow transplantation show no evidence of helper virus, with a mean follow-up of 18.3 months. Four animals injected with replication-competent helper virus cleared the virus rapidly and, after the initial clearance, have shown no evidence of retroviremia, with a mean follow-up of 5.2 months. Our preliminary findings suggest that murine retorviruses do not cause a productive infection in vivo. These results, combined with the availability of better producer cell lines free of helper virus, are encouraging, and suggest that the risk of clinical disease from murine retrovirus introduced by a gene therapy protocol should be small. Unfortunately, high infection efficiency and long-term vector expression still must be obtained before retroviral-mediated gene transfer can be considered as first-line therapy for ADA deficiency.