On World AIDS Day, scientific advances elicit optimism

December 1, 2012 | by Shawn Le

World AIDS Day is marked this year with a renewed optimism that science and medicine could soon change the course of the disease -- again.

First came the AIDS drug AZT, then the combinations of antiretroviral drugs known as AIDS cocktails. Both were significant advances that gave hope, and longer life expectancy, to patients with the virus. Now many experts are cautiously talking about cures as an eventuality rather than a dream. Part of that optimism is fueled by the gene therapies currently in development at City of Hope.

More than 30 years after a mysterious cancer hit the gay community, baffling physicians and scaring the general public, the virus behind that cancer, Kaposi’s sarcoma, is still a public health threat around the world.

Antiretroviral drug cocktails have shifted the disease from likely death sentence to a potentially lethal, but more manageable, chronic illness, but HIV infection rates are still dangerously high, especially in certain communities and in certain parts of the world. John Rossi, Ph.D., the Lidow Family Research Chair of Molecular Biology at City of Hope, has worked for decades to uncover HIV's weaknesses and develop a treatment that kills the virus.

"In an article in Science Translational Medicine ... we detailed our successful efforts in a unique, first-in-human gene therapy approach targeting HIV," said Rossi in an earlier interview. "It marks the first successful, long-term persistence of anti-HIV genes in patients with AIDS-related lymphoma. This is a very promising line of research that could lead to new treatment paradigms."

Daniela Castanotto, Ph.D., an associate research professor in Molecular and Cellular Biology, has worked with Rossi in exploring the use of RNA interference to selectively activate or inactivate specific genes that can make HIV more vulnerable to the immune system. She says their goal is a cure.

Castanotto and Rossi authored a paper in the journal Nature that reviewed the current state of RNA interference research in 2009. “Given the way that [RNA interference] has transformed basic research and the unprecedented speed with which it has reached the clinic,” they wrote, “the coming years promise to be exciting.”

City of Hope researchers were among the first to target a disease this way when they used ribozymes — sometimes called “molecular scissors” — to block HIV in patients with AIDS-related lymphoma. Their investigations led them to focus on RNA interference as a way to combat HIV and other diseases. Now, they’re conducting clinical trials assessing the use of RNA interference as a treatment for HIV — the first-ever RNA-interference-based gene therapy trial for treatment of HIV infection.

Other researchers are exploring different paths toward the same goal.

David DiGiusto, Ph.D., director of the Laboratory for Cellular Medicine, is leading development of another treatment that uses zinc-finger molecules to cut apart specific genes. Research has shown the CCR5 receptor plays a critical role in helping HIV infect immune cells. People with a mutation in their CCR5 gene have shown their immune systems to be more resistant to HIV infection.

DiGiusto is working with a biotech company, using its zinc-finger technology, to develop a treatment that cuts patients’ CCR5 gene, providing them similar resistance to infection as people with the natural mutation.

"Our goal is to develop potential new therapies and get them into clinical use," he said in an earlier interview. "City of Hope is ideal for this because it has a research institute, a clinical outlet and a way to get from one to the other."

In the early days of the AIDS epidemic, researchers were tireless and hopeful, but pragmatic. Revolutions in medicine are built on scientific investigations, which can take years, even decades, to reach patients.

Such diligence is paying off. HIV/AIDS research has been continuously supported over the years, and patients are seeing the benefits.

"There’s not going to be one 'boom' in people being cured," Rossi has said. "There may be one person a year, but once new processes are developed, we may be able to cure thousands of people a year. That is slow progress – but six years ago we thought that no one could be cured."

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