WASHINGTON and RICHMOND, Calif., Oct. 28 /PRNewswire-FirstCall/ -- Sangamo BioSciences, Inc. announced today the presentation of data demonstrating that human CD4 T-cells can be made permanently resistant to HIV infection by treatment with zinc finger DNA-binding protein nucleases (ZFN(TM)) resulting in an increase in CD4 T-cell counts and a reduction in viral load in an animal model of HIV infection. The presentation, entitled, "Establishment of HIV Resistant CD4 T-cells Using Engineered Zinc Finger Protein Nucleases (ZFNs)" is taking place today 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.
"We are very excited about these data and our collaboration with Sangamo to develop an HIV/AIDS therapeutic," said Carl June, M.D., Director of Translational Research at the Abramson Family Cancer Research Institute at the University of Pennsylvania School of Medicine, and a co-author of the study. "The ability to prevent immune cells from becoming infected by HIV has the potential to provide long term control of both the opportunistic infections characteristic of AIDS as well as the virus itself. We look forward to bringing this program into the clinic."
Sangamo's ZFNs are designed to permanently modify the DNA sequence encoding CCR5, a co-receptor that enables HIV to enter and infect cells of the immune system. Individuals carrying a naturally occurring mutation of their CCR5 gene, a variant known as CCR5-delta32, have been shown to be resistant to HIV infection.
"These data provide good support for the evaluation of our first ZFN-based ZFP Therapeutic in man," commented Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "It was observed more than ten years ago that individuals carrying the natural CCR5-delta32 mutation were highly resistant to infection by HIV. Consequently, a variety of small molecule and antibody approaches have been tested as potential therapeutics. However, a small molecule or antibody approach requires the constant presence of a sufficiently high concentration of drug to block therapeutically relevant numbers of the CCR5 protein, which is present in thousands of copies on the surface of each T-cell and other tissues in the body. We believe that our ZFN technology provides an approach that circumvents the dosing and potential toxicity issues of a systemic therapy. By specifically modifying only CD4 T-cells, the principal target of HIV pathology, in a one-time exposure of the cells to ZFNs, we can generate a population of R5-tropic HIV-resistant T-cells.
We have shown that these ZFN-modified human cells are made permanently resistant to infection by HIV. Furthermore, the cells selectively survive and expand in an animal after HIV infection, providing a reservoir of healthy and uninfectable immune cells. In a patient, such cells could be available to fight both opportunistic infections characteristic of AIDS and HIV itself. The modified cells exhibited the expected properties of normal CD4 T-cells. These data also demonstrate that ZFN-modified human CD4 T-cells can be produced in the quantities required for the translation of this program into the clinic. We intend to file an investigational new drug (IND) application for this ZFP Therapeutic this year and begin a clinical trial as soon as possible."
Data Reported in the ICAAC/IDSA Presentation
The reported results demonstrate that a one-time exposure to CCR5-specific ZFNs resulted in the generation of an HIV-resistant population of primary human 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 exposure to virus. 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). It was also determined that 50 days after infection, mice given the ZFN-modified cells had increased numbers of CD4 cells and a statistically significant seven-fold reduction in viral load in their peripheral blood (P<0.001) compared to mice given control cells. A high level of specificity of the CCR5-ZFNs for their target site was demonstrated by immunochemistry and direct genomic sequence analysis of ZFN-treated human CD4 T-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.
In addition, Sangamo and its collaborators have demonstrated successful ZFN-modification of clinical-scale quantities of human CD4 T-cells and that these modified cells exhibited the expected properties of normal T-cells. This demonstrates that ZFN-modified human CD4 T-cells could be produced in quantities required for the translation of this program into the clinic.
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.
About Sangamo
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 cancer, HIV/AIDS, 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 outside of the human therapeutic space including Dow AgroSciences, Sigma-Aldrich Corporation and several companies applying its ZFP technology to enhance the production of protein pharmaceuticals. For more information about Sangamo, visit the company's web site at http://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 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.
CONTACT: Elizabeth Wolffe, Ph.D. of Sangamo BioSciences, Inc.,
+1-510-970-6000, ext. 271, ewolffe@sangamo.com
Web site: http://www.sangamo.com/
