UCLA/Caltech scientists develop new gene therapy approach

December 23, 2002

UCLA and California Institute of Technology researchers have developed a new gene therapy approach that prevents the AIDS virus from entering human cells. The technique offers a potential way to treat HIV patients and could apply to any disease caused by a gene malfunction, including cancer. The Proceedings of the National Academy of Sciences will report the findings online the week of Dec. 23.

The research team created a new application for a genetic technology called small interfering RNA (siRNA). The synthetically designed siRNAs act as a catalyst to reduce the expression of specific genes and slow the progression of disease.

"Synthetic siRNAs are powerful tools, but scientists have been baffled at how to insert them into the immune system in stable form. You can't just sprinkle them on the cells," said Dr. Irvin S.Y. Chen, director of the UCLA AIDS Institute.

"Our research is the first to create a delivery system using a vehicle derived from HIV itself," he said. "This system allowed us to introduce the siRNAs into the cell, where they can protect against HIV infection."

Chen collaborated with Dr. David Baltimore, the Nobel laureate who is president of Caltech and a professor of biology there. Working closely with colleagues Dr. Don Sung An and Dr. Xiao-Feng Qin, the scientists constructed an innovative carrier from a disarmed version of the AIDS virus to deliver siRNAs into human cells. Their goal was to genetically erase a receptor -- a protein on the surface of the cell -- that HIV requires in order to spread.

"To penetrate a cell, HIV needs two receptors that operate like doorknobs and allow the virus inside," Baltimore said. "HIV grabs the receptor and forces itself into the cell. If we can knock out one of these receptors, we hoped to prevent HIV from infecting the cell."

One of the two receptors is CD4, which is found on the infection-fighting T-cell essential for proper immune function. However, the other receptor -- called CCR5 -- also plays a role in immune function, but is not necessary for normal body function.

In fact, roughly 1 percent of the white population is born without it. Large studies have shown that these people are naturally protected from HIV infection.

"People normally have two copies of every gene," Chen said. "When one copy of CCR5 is missing or defective, a person can still be infected with HIV, but their disease will develop more slowly. We hypothesized that knocking out CCR5 would curb progression of the disease."

The UCLA and Caltech teams cultured T-cells from healthy persons' blood and inserted siRNAs into the cells. Then they introduced HIV into the petri dish and incubated the culture for eight days. The experiment was repeated four times for accuracy.

When the teams examined the culture, they saw a tenfold drop in CCR5 expression. In fact, HIV managed to infect less than 20 percent of the cells. The rest of them were protected.

"Our findings raise the hope that we can use this approach or combine it with drugs to treat HIV in people -- particularly in persons who have not experienced good results with other forms of treatment," Baltimore said.

Now that scientists can introduce siRNAs into the cell, Chen and Baltimore propose that the technology will become a major therapeutic approach for many diseases in the future.

"We can easily make siRNAs and use the carrier to deliver them into different cell types to turn off a gene malfunction," Chen said. "This technology can be used to treat tumors or any disease in which a scientist wishes to knock out a malfunctioning gene."

The technology also holds implications for treating infectious, autoimmune and immunological diseases. "We can apply siRNAs to prevent a micro-organism from entering the body or appearing in the wrong place at the wrong time," Baltimore said. "We can also shut down excess production of a particular hormone. The possibilities are endless."
The National Institute of Allergy and Infectious Diseases and the Damon Runyon-Walter Winchell Fellowship helped support the research.

University of California - Los Angeles

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