This R34 application was submitted to support the complete planning, design and documentation for a Phase I clinical trial of gene transfer for pediatric patients infected with HIV-1. The clinical trial will use a lentiviral vector to carry and express a dominant-negative HIV-1 rev gene (huM10) in hematopoietic stem cells (HSC) from the bone marrow of children with HIV-1 infection. A moderate dosage of busulfan will be administered prior to re-infusion of the gene-modified CD34+ cells to """"""""make space"""""""" and increase the engraftment and contribution of the gene-modified HSC. This trial will be a unique effort to advance the potential for applying gene therapy as a novel therapeutic approach to HIV-1 infection. The R34 will have three Specific Aims: 1) to complete development of the clinical trial protocol, informed consent and other necessary documents and plans needed for regulatory review, 2) to submit the protocol for necessary regulatory reviews and 3) to develop the clinical trial infrastructure and acquire study agents (vector, cytokines, other). The group of clinical and laboratory investigators for gene therapy using hematopoietic stem cells at Children's Hospital Los Angeles is an experienced and capable team. Support by the R34 mechanism will also be valuable in providing the expertise of the DAIDS, NIAID in development of the protocol. The purpose of this application will be to use this planning period to advance the status of this trial proposal to support the submission of a Clinical Trials Implementation (U01) Cooperative Agreement by September 2006. ? ? Potential impact on public health: There are at least 1 million people with HIV-1 infection in North America and between 2.8-3.5 million people world-wide who died from HIV-1 infection in 2004 (UNAIDS/WHO, 2004). There remains a significant portion of patients for whom these HAART regimens are not successful, with break-through of resistant virus or intolerable side-effects from the medications. New, complementary approaches are needed to provide effective therapies for these patients. Gene therapy, by introducing genes that confer resistance to HIV-1 in the susceptible cells of patients (""""""""intracellular immunization""""""""), may provide a novel therapeutic approach to HIV-1 infection by producing a repertoire of T lymphocytes that are relatively protected from HIV-1 induced cytopathicity. ? ? ?
