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  51th ICAAC
Chicago, IL
September 17-20, 2011
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Sangamo HIV Gene Therapy Data Reported at ICAAC Sept 19 2011

Sangamo BioSciences of Richmond, California, says it has found a way to protect the T cells that

HIV attacks first, so they can live to fight another day. The approach entails temporarily stopping a patient's antiretroviral therapy and removing T cells carrying the CD4 receptor. This surface protein is the doorway by which the virus gains entry into the cell. The collected T cells are exposed to zinc finger nuclease, an enzyme designed to remove the gene for a coreceptor of CD4 called CCR5. The cells are then reinfused into the patient. Once they're back in the body, the new study shows, the cells persist and travel in the body just like normal T cells.

Experts unaffiliated with Sangamo and its clinical trials agree that the scientific achievement is impressive, but they question the notion that it could yield a functional cure. Sangamo is also exploring the potential of stem-cell modification with City of Hope researchers, but the company does not concede that modified stem cells will be necessary or any better than T cells. "Yes, T cells turn over," says Geoff Nichol, who joined Sangamo as executive vice president of R&D a few months ago to commercialize the platform, "but there are some very long-lasting subsets that can live for years and years and remember the epitope they came up against. We are feeling bullish about T cells because of our data." Sangamo's news is "certainly scientifically interesting," observes Warner Greene, director of the Gladstone Institute at the University of California, San Francisco. But, he points out, no cell therapy, whether it involves T cells or stem cells, is a practical approach to treating HIV/AIDS throughout the developing world, where seven out of 10 new infections are occurring. "We really need to be looking for therapies that can benefit the millions of individuals with HIV, not just a select few who might be able to afford cellular therapies."

Sangamo's approach is based on the observation that some people have a naturally occurring mutation in the CCR5 gene that protects them against HIV. Ordinarily, humans have two copies of every gene. It turns out that individuals with a mutation in both copies of the CCR5 gene cannot be infected by the most common HIV strains. In people with the so-called Delta-32 mutation in just one copy of the gene, infection rarely progresses to AIDS. In the U.S., about 1 percent of the population is thought to carry the helpful mutation, which some researchers believe arose as protection against the Black Death. Previous evidence existed showing that CCR5-negative cells could help AIDS patients. In 2007, an American man with AIDS and lymphoma received, as treatment for the cancer, a bone-marrow transplant from a person with the CCR5 mutation. The marrow recipient has been free of both AIDS and cancer since then. Sangamo's method treats a patient's own cells, with less risk than a marrow transplant.


"Functional Cure" For HIV/AIDS Glimpsed In Small Trial, Sangamo is still a long way from proving that SB-728 is safe and effective.


Researchers testing a potential new gene therapy for HIV/AIDS say they are excited by early results that represent significant progress towards a "functional cure" for the disease. They have presented the data from the phase 1 clinical programs to develop the treatment known as SB-728-T, from Sangamo BioSciences, Inc. of Richmond, California, at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), which is being held in Chicago this week, from 17 to 20 September.

Sangamo is a biotech company that specializes in developing technology that switches genes on and off by manipulating a class of transcription factors called zinc finger DNA-binding proteins (ZFPs). They also develop technology that can fine tune or edit gene expression using zinc finger nucleases (ZFNs) that insert, delete or change specific sequences of DNA.

One of the reasons HIV is able to infect cells in the human immune system is because of the CCR5 gene: it codes for a receptor that the virus uses to gain entry.

Sangamo has developed its experimental treatment SB-728-T to modify this facility in both copies of the CCR5 gene (each person has two copies or alleles of a gene, one from each biological parent).

The idea is to modify enough genes in enough cells that the viral load is considerably diminished, thus removing the need to continue with highly active antiretroviral therapy (HAART).

Dr Carl June, Director of Translational Research at the Abramson Family Cancer Research Institute at the University of Pennsylvania School of Medicine is an investigator on the trial:

June told the press that:

"The statistically significant relationship between estimated modification of both copies of the CCR5 gene and viral load during the treatment interruption suggests that the next step is to increase the frequency of the modified cells in HIV-infected patients with the ultimate hope that if we do, we will achieve a 'functional cure' and eliminate the need for continued HAART."

The trial involved 10 patients who were on HAART when they joined.

Four weeks after treatment with a single dose of SB-728-T, six of them underwent treatment interruption (TI), where they stopped taking the HAART medication for 12 weeks.

Viral load went down in three of the six patients. In one patient the viral load became practically undetectable, to the point where he was considered "aviremic" at the end of the treatment interruption. This patient already had a naturally mutated copy of the CCR5 gene (so his genes were already half-way to the finishing post as far as this treamtent was concerned).

The researchers estimated that the percentage of CCR5 genes (counting both copies) that were switched off (thus denying HIV entry to cells) in this patient was twice that of the other patients (none of whom had already modified copies of the gene when they joined the study).

Dr Ronald Mitsuyasu, Professor of Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA) is a principal investigator on this part of the trial. He said they were "very encouraged by this early demonstration" of an antiviral effect, and also the "marked improvement" in the overall CD4+ immune T-cell counts of the patients.

"While their viral loads are well controlled on HAART, these subjects experienced incomplete restoration of their T-cell counts. Improvement and preservation of the immune system is of paramount importance in HIV and those seen in this study show an improvement over that seen after several years of HAART," said Mitsuyasu.

Dr Dale Ando, Sangamo's vice president of therapeutic development and chief medical officer said:

"SB-728 treatment results in unprecedented improvement in immune system health as measured by increased CD4+ T-cell levels and improved CD4+: CD8+ T-cell ratios, even in subjects that entered the trial with poor CD4+ counts."

Sangamo's executive vice president of research and development, Geoff Nichol, said they are continuing to "collect valuable data about the parameters essential for optimization of this novel drug candidate".

The company plans to expands its clinical trials and do confirmatory studies in patients who carry a natural already modified copy of the CCR5 mutation.

"We will also explore other mechanisms to enhance engraftment and maximize the impact of the HIV resistant cells on viral load and the overall immune system of HIV patients," said Nichol.

Sangamo's statement pointed out that Mitsuyasu and June have no financial ties with the company.



The Sangamo gene therapy, known as SB-728, is designed to genetically alter a patient's T cells to eliminate a protein known as CCR5 that is commonly used by HIV to invade and infect cells.

If successful and ultimately approved, the SB-278 gene therapy might be a "functional cure" for HIV, meaning patients would no longer need to take daily regimens of anti-retroviral drugs to keep the virus in check.

Sangamo is still a long way from proving that SB-728 is safe and effective. The data presented Sunday came from a small phase I study in which six HIV patients were infused with the genetically modified T cells and then stopped taking their anti-retroviral drugs for 12 weeks. The study was designed to determine if the modified T cells could take up residence safely in the patients; and then to see if the patients' newly altered immune system could fight off HIV on its own.

Results from the study found a "statistically significant" relationship between the number of genetically modified immune cells in the patients and suppression of viral load, or the amount of HIV in the body.

In one SB-278-treated patient, viral load increased initially after anti-retroviral medicines were stopped. After about six weeks, however, viral loads began falling, a sign that the patient's genetically altered T cells were fighting off HIV. At 12 weeks, the patient's viral load returned to baseline levels and was undetectable.

Further analysis showed that this patient had the highest level of modified T cells in his blood of all the patients enrolled. Importantly, this patient already carried a naturally occurring genetic mutation against the CCR5 protein that gave him a built-in advantage against the virus.

SB-728 - Sangamo BioSciences


HIV infection results in the death of immune system cells, particularly CD4+ T-cells ... There are now over 33 million people living with HIV and AIDS worldwide