Sangamo BioSciences starts trial of CCR5-ZFP therapeutic to treat HIV/AIDS

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 or contact Larisa Zifchak, R.N. at 215-349-8091 ( [email protected]), Joe Quinn at 215-349-8091 ( [email protected]) or Pablo Tebas, M.D. at 215-349-8091.

Preclinical Data

Preclinical data on SB-728-T were published in the journal Nature Biotechnology (Perez E. E. et al., Nat Biotechnol. 2008 Jul; 26(7):808-16.) and presented at the joint meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and the Infectious Diseases Society of America (IDSA) in Washington, DC in October 2008. The results demonstrate that a one-time exposure to CCR5-specific ZFNs resulted in the generation of an HIV-resistant population of human primary T-cells by the permanent genetic modification of the CCR5 gene. These ZFN-modified CD4 T-cells expanded stably in HIV-infected cultures for several weeks and appeared to behave identically to untreated T-cells except that they were resistant to infection by HIV. ZFN treated primary CD4 T-cells and transformed CD4 cell lines resisted infection with R5-tropic HIV (virus that uses the CCR5 co-receptor to enter cells), resulting in enrichment of ZFN-generated CCR5-disrupted cells in the population upon long-term exposure to virus (>50 days). Importantly, in the presence of HIV, ZFN-modified CD4 T-cells also preferentially expanded in a mouse model. The modified cells were infused into mice that lack a normal immune system and thus do not reject human cells. After 33 days, the mice were sacrificed and 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 greater than two to three fold higher in mice in the presence of HIV infection (p=0.008). In additional experiments it was determined that 50 days after infection, mice given the ZFN-modified cells had increased numbers of CD4 cells and a statistically significant reduction in viral load in their peripheral blood (P<0.001) compared to mice given control cells. These data suggest that, in the presence of HIV, the ZFN-modified cells have a selective advantage allowing them to evade infection and destruction leaving them able fight opportunistic infections and HIV itself.

About HIV/AIDS and CCR5

HIV stands for Human Immunodeficiency Virus. HIV infection kills or impairs cells of the immune system progressively destroying the body's ability to fight infections and certain cancers resulting in AIDS (Acquired Immune Deficiency Syndrome). Individuals diagnosed with AIDS are susceptible to life-threatening diseases called opportunistic infections, which are caused by microbes that usually do not cause illness in healthy individuals. According to UNAIDS/WHO, over 2.7 million people were infected with HIV in 2007. There are now over 33 million people living with HIV and AIDS worldwide.

CCR5 is the chemokine receptor that HIV uses as a co-receptor to gain entry into immune cells. CCR5 is perhaps the most important of the known co-receptors for HIV, since the most commonly transmitted strains of HIV are strains that bind to CCR5 -- so-called "R5" strains. A small fraction of the population carries a mutation in their CCR5 gene, called the delta32 mutation. This mutated version of the gene produces malformed CCR5 proteins, which cannot be used by HIV as a co-receptor. Individuals that have two copies of this mutant form of CCR5 (delta32) are resistant to infection by R5 HIV strains.

Dr. June is not affiliated with Sangamo BioSciences in any capacity beyond his role as a clinical collaborator on this project.


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