By Margarita Nahapetyan
The first clinical trial of gene therapy in patients infected with HIV has produced promising results, according to scientists who reported that the largest experiment appeared to safely and beneficially increase the number of immune system cells normally attacked by the virus.
"This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product," the researchers wrote in the February 15 advance online issue of Nature Medicine.
The treatment consisted in giving a patient special infusions that would stimulate a growth of white blood cells. Then the stem cells were taken from a person's blood, and after that were being separated out and placed in cell culture dishes.
Later, in the culture, the person's own blood stem cells were infected with OZ1, a genetically engineered mouse virus that gives them an anti-HIV gene. This gene encodes something called an RNA enzyme, or ribozyme for short - a small molecule that is intended to block HIV from replicating once it infects a cell.
As soon as the blood stem cells were equipped with the anti-HIV gene, they were transfused back into the patient. The idea was to see whether these stem cells, by being shielded from HIV with the help of the ribozyme, would survive the body's immune defenses and whether HIV, denied a possibility for reproduction, would retreat. Stem cells are progenitor cells, meaning that when they replicate, future generations of those cells will be carrying the same genetic code.
Researchers led by Ronald Mitsuyasu, director of the University of California, Los Angeles Center for Clinical AIDS Research and Education, recruited 74 HIV-positive people for the experiment, and divided them into two groups. Thirty eight patients got infusions with OZ1-equipped stem cells, and thirty six patients got inactive placebo infusions. The patients then cycled on and off their HIV drugs so the researchers could see if the virus rebounded.
Forty eight weeks after the so-called OZ1 experiment started, the researchers found that there was no statistically significant difference in the amount of HIV circulating in the blood of both groups of patients. However, after 100-week period, the patients who received the gene therapy had higher levels of CD4+ cells - immune cells that are depleted by HIV.
The stock of new blood cells, though, became rather depleted. Four weeks after they were introduced, a DNA test showed that the modified cells which were present in 94 per cent of volunteers in the OZ1 group, were reduced to 12 per cent by the 48th week and to just seven per cent by week 100.
Professor Ronald Mitsuyasu, said that the research was the first to come through tightly controlled trials in which patients did not have any idea whether they were getting the therapy or the placebo. He said: "Gene therapy has the potential of needing only a one-time or infrequent administration of product and would allow the patients to control their own HIV internally without the need for continuous drug therapy.
"While this treatment is far from being perfected, it is not yet as effective or as complete as current antiretroviral therapy in controlling HIV, the study did show proof of concept that inserting and administering a single anti-HIV gene in the patients' own blood stem cells and giving it back to them could reduce viral replication to some degree when anti-HIV medications are stopped."
However, Professor Mitsuyasu noted that a long-term follow up was needed to make sure that the therapy was safe. The findings, while encouraging, need to be repeated and much more research has to be done before an effective new treatment arrives. "We know it works, but we need to make it better before we launch a later study," he explained.
Existing treatments work well enough for many people infected with HIV, the virus that causes AIDS. However, patients have to buy expensive drugs for their entire lives, and in addition suffer side effects that can really be significant. HIV gene therapy is considered as a possible alternative to drug treatment. If it works, doctors hope patients may be able to quit, or at least reduce, their regimen of antiretroviral drugs. Researchers try to do their best in order to be able to fight the virus by inserting a gene or genes into the body of an infected patient.
"This study in-di-cates that cell-delivered gene trans-fer is safe and bi-o-log-ic-ally ac-tive in in-di-vid-u-als with HIV and can be de-vel-oped as a con-ven-tion-al ther-a-peu-tic pro-duc-t," concluded Mit-suyasu.