Data shows correlation between new therapeutic approach,
By Enrique Rivero
October 4, 2011 - Data from a clinical trial involving UCLA researchers suggest that a new therapy
may potentially serve as a "functional cure" for HIV/AIDS.
The therapy, called SB-728-T, involves the modification of both copies of a patient's CCR5 gene, which encodes
the major co-receptor used by HIV to infect immune system cells.
In the Sangamo BioSciences' phase 1 trial, SB-728-T was given to HIV patients who were on highly active antiretroviral
therapy (HAART) but were considered to be "non-responders" - that is, their CD4+ T-cell levels, a key measure of immune system
health, remained low. The patients' HAART therapy was interrupted when they received the SB-728-T therapy.
The researchers found a statistically significant relationship between the suppression of HIV viral load and the
level of circulating CD4+ T-cells that had undergone the CCR5 gene modification in patients treated with SB-728-T.
The scientists recently presented these and others findings from their dose-escalation study (SB-728-902) at the 51st Interscience
Conference on Antimicrobial Agents and Chemotherapy, held from Sept. 17 to 20 in Chicago. The study involves subjects on HAART whose
CD4+ counts remain below 500 cells per cubic millimeter - and below 450 cells in one cohort - after several years of therapy.
"We are very encouraged by both this early demonstration of an antiviral effect of SB-728-T, as well as the marked improvement
in the overall CD4+ T-cell counts in treated subjects in the SB-728-902 trial," said Dr. Ronald Mitsuyasu, a principal
investigator for the study who directs the UCLA Center for Clinical AIDS Research and Education and is an associate
director of the UCLA AIDS Institute. "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."
The modification of the CCR5 gene that generates SB-728-T is accomplished using a zinc finger nuclease, or ZFN. ZFN modification
disrupts the expression of this key co-receptor for HIV entry and renders cells resistant to HIV infection. The approach is based
on the observation that a naturally occurring mutation in the CCR5 gene, CCR5 delta-32, provides protection from HIV infection.
Individuals who have the delta-32 mutation in both copies of the CCR5 gene are generally not susceptible to the most
common strain of HIV. Those with only one copy of the mutation are identified as "elite controllers" because of their immune
systems' ability to resist the progression of HIV without the need for HAART.
Other findings described by the scientists included:
- The viral load of one SB-728-T-treated subject decreased to undetectable levels during a treatment interruption. This subject
was found to be an "elite controller."
- Unprecedented improvements in overall CD4+ T-cell counts and the ration of CD4+ to CD8+ cells, as well as engraftment, expansion, trafficking and persistence of the ZFN-modified cells.
- SB-728-T treatment continues to be safe and well tolerated.
"The data obtained in our treatment-interruption studies are very exciting and represent significant progress toward
a 'functional cure' for HIV/AIDS," said Dr. Carl June, director of translational research at the Abramson Family Cancer Research
Institute at the University of Pennsylvania School of Medicine, one of the study sites. "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."
No other drug has been shown to have the same dramatic effect on the immune system in this setting, said Dr. Dale Ando,
Sangamo's chief medical officer and vice president of therapeutic development.
"SB-728 treatment results in unprecedented improvement in immune system health, as measured by increased CD4+ T-cell
levels and improved CD4+-to-CD8+ T-cell ratios, even in subjects that entered the trial with poor CD4+ counts," Ando said.
"Moreover, the interesting kinetics in viral load that we observed in the first few subjects that underwent a treatment
interruption have been borne out and have allowed us to correlate a statistically significant effect of the rate of
biallelic ZFN-modification of the CCR5 gene on viral load during treatment interruption."
Mitsuyasu and June have no financial relationship with Sangamo BioSciences Inc.
The UCLA AIDS Institute , established in 1992,
is a multidisciplinary think tank drawing on the skills of top-flight researchers in the worldwide fight against HIV and AIDS,
the first cases of which were reported in 1981 by UCLA physicians. Institute members include researchers in virology and
immunology, genetics, cancer, neurology, ophthalmology, epidemiology, social sciences, public health, nursing and disease
prevention. Their findings have led to advances in treating HIV, as well as other diseases, such as hepatitis B and C,
influenza and cancer.