Bauer G, Zaia JA, Ito J, Valdez P, Rothschild JC, Li S, Castanotto D, Li H, Yam P, Rossi J, Forman SJ, Kohn DB; International Conference on AIDS.

Int Conf AIDS. 1998; 12: 790 (abstract no. 41241).

Childrens Hospital, Los Angeles, CA 4650, USA.

BACKGROUND: Hematopoietic stem cells may be a useful target for the introduction of genes which inhibit HIV-1 replication since they produce essentially all the cells involved in HIV-1 infection and pathogenesis. A number of genes designed to inhibit HIV-1 replication were evaluated in different Retroviral vector configurations, which led to the identification of several vector constructs as being strongly and consistently inhibitory to HIV-1 replication in in vitro assays using transduced human CD34+ hematopoietic progenitor cells. Two anti HIV-vector constructs, a double hammerhead ribozyme and an RRE-decoy have now been evaluated in phase-1 clinical trials to determine 1) the safety and feasibility of isolating and transducing stem cells from HIV-1 (+) donors, 2) the ability of the transduced cells to engraft and produce gene containing mature hematopoietic and lymphoid cells, and 3) whether expression of a gene which inhibits HIV-1 replication can confer a selective survival advantage to HIV-1 target cells in vivo. METHODS: In separate clinical trials, CD34+ cells were obtained from G-CSF mobilized peripheral blood of HIV-1 infected adults, and from bone marrow of HIV-1 infected children. In the adult study, CD34+ cells were transduced with a vector containing the double hammerhead ribozyme, CD34+ cells from children were transduced with the RRE decoy vector. RESULTS: Preliminary results show high transduction frequency into CD34+ cells (approx. 40 to 80% measured by G418 resistance and neo-DNA PCR), and safety of the procedure with no adverse events seen in patients after reinfusion of autologous stem cells. In two out of three patients having reached the six month time point after infusion, gene containing cells can be detected in bone marrow or peripheral blood. Long term studies to evaluate the production and selective survival of anti HIV-gene containing lymphoid cells are currently being conducted. CONCLUSIONS: High transduction efficiencies into CD34+ cells obtained from HIV-1 infected individuals in a clinical setting can be achieved routinely, and it is feasible and safe to proceed to phase-2 clinical trials of stem cell gene therapy for AIDS.

Publication Types:

• Meeting Abstracts

Keywords:

• Acquired Immunodeficiency Syndrome
• Adult
• Antigens, CD34
• Child
• Clinical Trials as Topic
• Granulocyte Colony-Stimulating Factor
• HIV Infections
• HIV-1
• Hematopoietic Stem Cells
• Humans
• In Vitro
• RNA, Catalytic
• hammerhead ribozyme
• immunology

Other ID:

• 98402857

UI: 102230889

From Meeting Abstracts