Preclinical efficacy data of Sangamo's ZFN based human stem cell therapy for HIV published

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.  


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