CREATING PERMANENT T-CELL RESISTANCE AGAINST HIV?
SANGAMO BIOSCIENCES (SGMO)
We are impressed by Sangamo BioSciences’ (SGMO) approach to HIV treatment and by the data presented about its zinc finger DNA-binding protein (ZFP) Therapeutic™ for HIV/AIDS. The data demonstrate that ZFN-modified human T-cells are protected from HIV infection.
It is like immunizing the T cells against HIV, giving them a selective survival advantage. Sangamo expects to initiate a Phase 1 clinical trial to test this HIV ZFP Therapeutic after it has confirmed its success on mice. The firm chose to work with Dr. Carl June, Director of Translational Research at the Abramson Family Cancer Research Institute and collaborators at the University of Pennsylvania.
Sangamo’s ZFP nuclease (ZFN™) technology enables human T-cells to resist HIV infection by permanently modifying the DNA sequence encoding CCR5, an essential co-receptor for the entry of HIV into immune cells. Individuals who carry a natural mutation of the CCR5 gene (CCR5-delta32), which confers resistance to HIV infection.
HIV infection kills or impairs cells of the immune system, progressively destroying the body’s ability to fight infections resulting in AIDS (Acquired Immune Deficiency Syndrome). Individuals diagnosed with AIDS are susceptible to life-threatening diseases or opportunistic infections, which are caused by microbes that usually do not cause illness in people with healthy immune systems. Sangamo’s initial approach is to modify the CCR5 gene in T-cells to provide patients with a reservoir of ZFN-modified HIV-resistant immune cells that can fight opportunistic infections and the virus itself.
Telling the story that led to his collaboration with Sangamo, Dr. Carl June said, “Scientists from Sangamo Biosciences approached me with an extraordinary proposition. They told me that they had the means to create CD4+ T-cells with permanent modification of the CCR5 gene and a robust resistance to HIV infection. This exciting collaboration, involving my colleagues at the University of Pennsylvania and the team of scientists at Sangamo has rapidly progressed from that idea to data demonstrating that ZFN modified cells are HIV resistant and have a selective survival advantage when reintroduced into an animal. This is consistent with our aim of reconstituting a functional HIV-resistant immune system in patients infected with the virus.”
Dale Ando, M.D., Sangamo’s vice president of therapeutic development and chief medical officer said “This is the first presentation of in vivo data from our program to develop a ZFP Therapeutic for the treatment of HIV, and it is significant that these animal data confirm our earlier observations in isolated cells. Previously, we had shown that ZFN-modified primary human T-cells are resistant to HIV infection not only surviving continuous exposure to HIV but selectively expanding in cell culture to the point that they represented the vast majority of cells in the population at the end of the experiment. In these more recent data we show that that observation holds true when these HIV-resistant cells are tested in a mouse model of HIV infection and demonstrate that after ZFN-modification the cells are stable and have a selective advantage in the presence of HIV.”
In the experiments, human T-cells were isolated and treated with ZFNs specific for CCR5. The modified cells were infused into a mouse model, the NOG mouse, with or without a source of HIV. The NOG mouse lacks an immune system and thus does not reject the human cells. After 33 days, the mice were sacrificed and their blood analyzed for the presence of ZFN-modified cells. Researchers determined that ZFN-modified cells engrafted normally in the mouse and that the proportion of modified cells present at the end of the experiment was statistically significantly higher in mice in the presence of HIV infection (p=0.008). These data suggest that, in the presence of HIV, the ZFN-modified cells have a selective advantage and evade HIV infection and destruction.
Based on these animal data, which Sangamo’s scientists and collaborators believe are very encouraging, the firm decided to initiate a Phase 1 clinical trial in HIV/AIDS with this ZFP Therapeutic in the second half of 2007. By administering ZFNs to patients’ T-cells, the goal is to provide HIV-infected individuals with a reservoir of healthy and uninfectable immune cells that would be available to combat opportunistic infections and HIV itself. The firm believes that using ZFNs to permanently modify the CCR5 gene in T-cells and thus directly block HIV from entering cells may have a number of advantages over the systemic effects of CCR5 antagonists in development.
The data were presented on June 1, 2007 at the 10th Annual Meeting of the American Society of Gene Therapy (ASGT), which was held in Seattle, Washington. In addition to Dr. Holmes’ presentation, Sangamo scientists and collaborators presented data in six oral presentations and three posters describing preclinical data from Sangamo’s ZFP Therapeutic programs. These included programs in pain, nerve crush and spinal cord injury, macular degeneration and glioblastoma. In addition, Sangamo sponsored a Symposium chaired by Donald Kohn, M.D., Director, Gene, Immune and Stem Cell Therapy Program at Children’s Hospital Los Angeles.