Sangamo BioSciences Initiates Phase 1 Trial of CCR5-ZFP Therapeutic to Treat HIV/AIDS
Therapeutic Approach Provides HIV-Resistant Immune Cells
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
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
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
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
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
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.
Sangamo BioSciences, Inc. is focused on the research and development of novel DNA-binding proteins for therapeutic gene regulation and modification. The most advanced ZFP Therapeutic(TM) development program is currently in Phase 2 clinical trials for evaluation of safety and clinical effect in patients with diabetic neuropathy and ALS. Other therapeutic development programs are focused on HIV/AIDS, cancer, neuropathic pain, nerve regeneration, Parkinson’s disease and monogenic diseases. Sangamo’s core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). By engineering ZFPs that recognize a specific DNA sequence Sangamo has created ZFP transcription factors (ZFP TF(TM)) that can control gene expression and, consequently, cell function. Sangamo is also developing sequence-specific ZFP Nucleases (ZFN(TM)) for gene modification. Sangamo has established strategic partnerships with companies in non-therapeutic applications of ZFPs including Dow AgroSciences, Sigma-Aldrich Corporation and several companies applying Sangamo’s ZFP technology to enhance the production of protein pharmaceuticals. For more information about Sangamo, visit the company’s web site at www.sangamo.com.
This press release may contain forward-looking statements based on Sangamo’s current expectations. These forward-looking statements include, without limitation, references to clinical trials of SB-728-T, the potential for further study and development of SB-728-T for the treatment of HIV/AIDS, the research and development of novel ZFP TFs and ZFNs as ZFP Therapeutics, applications of Sangamo’s ZFP TF technology platform, strategic partnerships with collaborators and clinical trials of ZFP Therapeutics. Actual results may differ materially from these forward-looking statements due to a number of factors, including but not limited to, technological challenges, uncertainties relating to the initiation and completion of stages of ZFP Therapeutic clinical trials for Sangamo’s HIV/AIDS therapeutic development program, Sangamo’s ability to develop commercially viable products and technological developments by our competitors. See Sangamo’s SEC filings, and in particular, the risk factors described in Sangamo’s Annual Report on Form 10-K and its most recent quarterly report on Form 10-Q. Sangamo assumes no obligation to update the forward-looking information contained in this press release.
SOURCE Sangamo BioSciences, Inc.