Stem cell study could bring us closer to a “functional” HIV cure

December 1, 2015 | by Abe Rosenberg

It's an educated guess, from an expert whose “guesses” carry considerable weight:

“We could see a functional cure for HIV in the next five to ten years,” predicts John Zaia, M.D., a world-renowned genetic researcher and director of the Center for Gene Therapy at City of Hope's Hematologic Malignancies and Stem Cell Transplantation Institute.

The building blocks, asserts Zaia, are already in place, with increased use of gene editing opening up exciting new possibilities. For the 35-year City of Hope veteran, this is a moment many years in the making.

“For me,” says Zaia, “the 'Aha!' moment came decades ago with the notion that we could manipulate, or 'edit' T-cells to control HIV infection.

“Now we've begun editing the stem cells that create those T cells, putting us on a more achievable and scalable path to a functional cure, where the HIV in the body is rendered irrelevant, incapable of growing or developing into AIDS. It's not a so-called 'sterilizing cure,' where the virus is eradicated, but the practical results are the same: control of HIV without taking anti-retroviral pills every day.”

To reach that goal, Zaia, the Aaron D. Miller and Edith Miller Chair in Gene Therapy, and his fellow researchers are building on the knowledge gained from the case of Timothy Ray Brown, the so-called “Berlin patient” whose HIV infection vanished after he received a stem cell transplant for treatment of leukemia. The donor's CCR5 gene (HIV's typical pathway into the body) had a mutation which blocked the virus.

“Nobody's been able to reproduce the Berlin patient's results ... yet,” says Zaia. But he's optimistic about delivering HIV-blocking technology through stem-cell transplantation. Zaia's newest clinical trial uses a zinc finger nuclease, or ZFN, to “cut out” the CCR5 gene entirely, leaving HIV with no place to go. This research, says Zaia, could lead to the Holy Grail of HIV therapy: “A one-time treatment which produces a lifetime change.”

The trial is now enrolling patients, vetting them through a meticulous, multi-week FDA-mandated screening process, as well as informing them of the considerable risks.

“This is not your father's clinical trial,” Zaia is fond of declaring at the many Town Hall meetings he attends, including a recent gathering in West Hollywood. Simply put, says Zaia, “You could die,” because of the inherently hazardous nature of the transplant procedure.

“This is our biggest hurdle," says Zaia. “It's revolutionary to even consider stem-cell transplants for patients who don't otherwise desperately need them, say for leukemia treatment. A transplant patient must receive a major dose of radiation or chemotherapy first, to clear a space for the transplanted cells. Subjecting someone with HIV – essentially a chronic, controllable ailment - to such a highly toxic and potentially deadly procedure raises medical and ethical questions ... not the least of which is, exactly how much, and how strong, should the dosage be?” This is an ongoing debate in the medical community.

Another critical question: How to prevent unexpected negative genetic consequences once you begin “snipping out” parts of a human being's DNA. Zaia is reassuring here. “We've moved along quite a bit since our first editing attempts,” he says. “We're starting to see which treatments are more, and less likely to produce unintended results.”

The urgency to find a cure may have diminished over the decades but it still remains: More than 1 million Americans are living with HIV/AIDS right now. Each year, 50,000 new infections are reported and 13,000 people with AIDS die. Zaia and all responsible researchers strongly believe it's more important to do this right than to do it fast, accepting, even embracing the sometimes frustrating array of mandated regulations and protocols. Those built-in safeguards, says Zaia, exist for the most important reason of all: “To protect the public from the 'mad scientist.' ”

Zaia praises the state of California and its Institute for Regenerative Medicine (CIRM), which is funding his trials as well as City of Hope's new Alpha Clinic for Cell Therapy and Innovation, aimed at rapidly delivering breakthrough genetic treatments through a financially sustainable model. “Others are limping along,” says Zaia. “California is ahead of the curve, changing the culture of gene therapy, approaching the issue of how to make such novel therapies more acceptable, even attractive, to third party payers who ultimately must be involved.”

He reserves his highest praise for the courageous volunteers who are coming forward now to take part in the trials. “They accept the risks. They also realize it's unlikely they'll benefit directly,” says Zaia.

“They are the true humanitarians.”

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Learn more about HIV research at City of Hope.

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