Sangamo BioSciences, Inc. has announced that its collaborators at the University of Pennsylvania have opened a Phase 1 clinical trial to evaluate SB-728-T for the treatment of HIV/AIDS.
Based on Sangamo's zinc finger DNA-binding protein nuclease (ZFN) technology, SB-728-T has been shown in an animal model of HIV infection to lead to an increase in CD4+ T-cell counts, a reduction in viral load and expansion of CCR5-modified T-cells, suggesting resistance to HIV.
"This is the first time that we have had the ability to make a patient's T-cells permanently resistant to infection by CCR5-specific strains of HIV and we are very excited to begin a clinical trial of this novel ZFN-based therapy," said Carl June, M.D., Director of Translational Research at the Abramson Family Cancer Research Institute at the University of Pennsylvania School of Medicine. "The ability to protect immune cells from infection with HIV and the expansion of CCR5-modified T-cells has the potential to provide long-term control of both the virus itself and eventually the opportunistic infections characteristic of AIDS."
CCR5 is a co-receptor that enables HIV to enter and infect cells of the immune system. About ten years ago, it was observed that individuals carrying a natural mutation of their CCR5 gene, CCR5-delta32, were highly resistant to infection by HIV. These individuals, lacking a functional CCR5 (approximately 1-2% of the general population), are immunologically "normal". A variety of small molecule and antibody antagonists of CCR5 binding have been tested and developed as potential therapeutic agents for the treatment of HIV infection. In addition, there is a recent report of a patient who had both HIV infection and leukemia and received a bone marrow transplant from a donor carrying the CCR5 mutation. After the successful bone marrow transplant, HIV treatment was discontinued and the virus could not be found in the circulating blood several months after the procedure. Sangamo's ZFNs are designed to modify the DNA sequence encoding CCR5. This modification can occur directly in T-cells with only a brief exposure to the ZFNs. Once the modification is made to the T-cell's CCR5 gene it is permanently disrupted.
"Our ZFN approach is very well-validated by naturally occurring mutations in man and the recent bone marrow transplant report," commented Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "However, allogeneic bone marrow transplantation (bone marrow taken from a different person) is not widely applicable as a therapeutic approach for HIV as it is a risky procedure requiring irradiation and ablation of the immune system and matched donors who also carry the CCR5-delta32 mutation are likely to be rare. Small molecule or antibody antagonists require the constant presence of a high concentration of drug in order to block therapeutically relevant numbers of the CCR5 protein.
In contrast, we believe that our ZFN technology provides an approach that circumvents the dosing and potential toxicity issues of a systemic therapy and provides a simpler approach than a transplant. We specifically modify the patient's own CD4+ T-cells, the principal target of HIV infection, with a one-time exposure of the cells to CCR5-specific ZFNs. This generates a population of T-cells that lack the CCR5 receptor, are resistant to HIV and can be infused back into the patient to provide a reservoir of HIV-resistant functional immune cells and, more importantly, may expand and provide an HIV immune response."
"Our ZFP technology functions at the DNA level and, as this application demonstrates, enables us to address highly validated therapeutic targets that have proven difficult to drug at the protein and RNA levels," commented Edward Lanphier, Sangamo's president and CEO. "ZFPs can be engineered to regulate or modify any gene, in any cell type, which provides numerous opportunities for its therapeutic applications. This trial is another important step in establishing our ZFP technology as a major new therapeutic product development platform."
About the SB-728-T Clinical Trial
The study is an open-label Phase 1 clinical trial of the safety and tolerability of a single infusion of autologous (a patient's own) CD4+ T cells genetically modified at the CCR5 gene by CCR5-specific ZFNs (SB-728-T). A total of twelve subjects with HIV will be enrolled in this trial in two treatment cohorts. The first cohort to be treated comprises six subjects who have failed two or more HAART (Highly Active Antiretroviral Therapy) regimen. The first three subjects in this cohort will be treated sequentially and monitored for the first 21-days post treatment before an additional subject is treated. After this period of evaluation and monitoring has passed successfully, the next three subjects will be treated. The second cohort comprises six subjects who are responsive to their current therapy regimen who will be treated with CCR5-modified T-cells and undergo a structured therapy interruption (STI) or therapy "break". The primary objective of the study is to evaluate the safety and tolerability of SB-728-T. In addition to safety monitoring, data will be collected on the expansion and persistence of ZFN-modified cells, CD4+ cell counts and viral load. Individuals interested in participating in this trial should visit http://www.clinicaltrials.gov/ or contact Larisa Zifchak, R.N. at 215-349-8091 ( larisa.zifchak@uphs.upenn.edu), Joe Quinn at 215-349-8091 ( joseph.quinn@uphs.upenn.edu) or Pablo Tebas, M.D. at 215-349-8091.
Preclinical Data