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.

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Written by Catharine Paddock PhD