Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced the publication of data demonstrating the preclinical efficacy of a human stem cell therapy for human immunodeficiency virus (HIV) based on its proprietary zinc finger DNA-binding protein nuclease (ZFN) technology. The ZFN approach enables the permanent disruption of the CCR5 gene, which encodes an important receptor for HIV infection, in all the cell types comprising the immune system that develop from hematopoietic stem cells (HSCs), and is the basis for a promising therapeutic strategy for the treatment of HIV/AIDS. Sangamo has two ongoing Phase 1 clinical trials to evaluate the safety and clinical efficacy of this approach in CD4+ T-cells.

The work, which was carried out in the laboratory of Paula Cannon, Ph.D., Associate Professor of Molecular Microbiology & Immunology at the Keck School of Medicine of the University of Southern California (USC), in collaboration with Sangamo scientists, was published on July 2, 2010, as an Advance Online Publication in Nature Biotechnology.

"These are very exciting data that provide proof of concept for a new approach to HIV treatment," said John Zaia, M.D., the Aaron D. and Edith Miller Chair in Gene Therapy and Chair of Virology, City of Hope. "The recent example of the 'Berlin Patient' who appears to have been cured of both his HIV and leukemia by receiving a bone marrow transplant (BMT) of stem cells from a donor that had a naturally occurring CCR5 mutation that makes them resistant to HIV infection, provided the model for this approach. However, the paucity of human donors with this natural CCR5 mutation and the risks of allogeneic BMT mean that we need a more practical solution to make this a therapeutic option. Modification of HSCs using ZFNs to recreate the CCR5 mutation is a potential solution."

Dr. Zaia is the leader of the recent $14.5 million Disease Team Research Award granted by the California Institute for Regenerative Medicine (CIRM) to a multidisciplinary team of investigators which includes City of Hope, Dr. Cannon and her colleagues at USC, and Sangamo scientists. The award funds the preclinical development of a ZFN CCR5-targeted approach which aims to complete an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) for clinical testing of this ZFN method.

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. Building on this observation, a study published in the New England Journal of Medicine in 2009 reported a potential "cure" when an AIDS patient with leukemia received a bone marrow transplant from a "matched" donor with this delta-32 CCR5 mutation. This approach transferred the HSCs residing in the bone marrow from the delta-32 donor, and provided a self-renewable and potentially lifelong source of HIV-resistant immune cells. After transplantation, the patient was able to discontinue all anti-HIV drug treatments, CD4 counts increased, and viral load dropped to an undetectable level, demonstrating effective transplantation of protection from HIV infection. The data reported in the Nature Biotechnology publication replicate these findings for a ZFN-based treatment in a preclinical model.

"The data described in this paper are an important demonstration of the potential therapeutic possibilities of ZFN modification of human stem cells," commented Philip Gregory, D. Phil., Sangamo's vice president of research and chief scientific officer. "We have demonstrated efficient and specific modification of human hematopoietic stem cells, rendering them resistant to infection with HIV-1 while retaining their 'stemness' and ability to differentiate. These data pave the way for the use of this technology in other diseases for which HSC modification may be therapeutically useful."

Data Reported in the Nature Biotechnology Paper

The reported results demonstrate that a one-time exposure to CCR5-specific ZFNs resulted in the generation of an HIV-resistant population of human HSCs by the permanent genetic modification of the CCR5 gene. These ZFN-modified stem cells engrafted in NSG (NOD/SCID/IL2rγnull) mice, which lack a normal immune system and are able to tolerate engraftment of human cells and tissues. After 8-12 weeks the engrafted ZFN-modified human cells could be identified as different immune cell types in the peripheral blood, and various tissues of the mouse suggesting that they were functionally normal. Furthermore, the ZFN-modified HSCs produced progeny that could be harvested from one mouse and engrafted into a second animal, demonstrating that the modified HSCs retain their 'stemness' and ability to differentiate. In addition, the animals did not experience any obvious toxicity or ill-health. In HIV challenge experiments, researchers found that the ZFN-modified cells had a selective advantage over unmodified HSCs and not only survived infection but expanded and appeared to traffic normally to various tissues in the mouse. Moreover, the presence of ZFN-modified cells controlled HIV replication in the animals. These data suggest that human HSCs can be modified with ZFNs, expand and differentiate and have a selective advantage in the presence of HIV allowing them to evade infection and destruction leaving them able fight opportunistic infections and HIV itself.

About HIV/AIDS and CCR5

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 people. According to UNAIDS/WHO, over 2.7 million people were newly infected with HIV in 2007. An estimated 2.0 million people died of AIDS in the same year. There are now over 33 million people living with HIV and AIDS worldwide. The CDC estimates that, in the United States alone, there were 1.2 million people living with HIV/AIDS, approximately 54,000 new infections and 23,000 deaths in 2007.

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 results in a truncated CCR5 protein which cannot be used by HIV as a co-receptor. Individuals that have mutant delta 32 versions of both of their CCR5 genes 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™ development program is currently in a Phase 2b clinical trial for evaluation of safety and clinical effect in patients with diabetic neuropathy and a Phase 2 trial in ALS. Sangamo also has two Phase 1 clinical trials to evaluate safety and clinical effect of a treatment for HIV/AIDS and another Phase 1 trial to evaluate safety and clinical effect of a treatment for recurrent glioblastoma multiforme. Other therapeutic development programs are focused on 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) that can control gene expression and, consequently, cell function. Sangamo is also developing sequence-specific ZFP Nucleases (ZFN) for gene modification. Sangamo has established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciences and Sigma-Aldrich Corporation.

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 technology platform, the therapeutic potential of ZFNs for the treatment of HIV/AIDS, 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 technological challenges, uncertainties relating to the initiation and completion of stages of ZFP Therapeutic clinical trials, Sangamo's ability to develop commercially viable products and technological developments by our competitors. See the company's SEC filings, and in particular, the risk factors described in the Sangamo's Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo BioSciences, Inc. assumes no obligation to update the forward-looking information contained in this press release.

Source: Sangamo BioSciences, Inc

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