Clad in a yellow gown, blue foot covers, hair net, face mask and latex gloves, Paula Cannon pushed open the door to the animal room. "I hate this smell," she said, wrinkling her nose.
The stink came from scores of little white mice scurrying about in cages. Some of the cages were marked with red biohazard signs, indicating mice that had been injected with HIV.
Yet, in some of the animals — ones with a small genetic change — the virus never took hold.
Like mouse, like man? Maybe so.
In early 2007, a patient in Berlin needed a bone marrow transplant to treat his leukemia. He was also HIV positive, and his doctor had an idea: Why not use the marrow from one of the rare individuals who are naturally resistant to HIV and try to eradicate both diseases at once?
It worked. Sixty-one days after the patient's transplant, his virus levels were undetectable, and they've stayed that way.
Since news of the man's cure broke, HIV patients have been telephoning doctors to ask for bone marrow transplants. But it's not that simple. The treatment is too risky and impractical for widespread use.
"A bone marrow transplant — it's a horrible process you would not wish on your worst enemy unless they needed one to save their life," said Cannon, a biology professor at USC's Keck School of Medicine. There are grueling treatments to prepare a patient for transplant; the danger of rejecting the marrow; and the risk of graft-versus-host disease, wherein the marrow attacks the patient.
And that's assuming the patient can find a matching donor — a difficult proposition in itself — with the right HIV-resistant genetic constitution, which is present in only about 1% of the Caucasian population.
But there could be another way.
Instead of sifting through the sands for a rare donor and then subjecting a patient to the dangers of a bone marrow transplant, Cannon and her colleague Philip Gregory, chief scientific officer at the Richmond, Calif.-based biotech company Sangamo BioSciences, began to think: They could use gene therapy instead, to tweak a patient's own cells to resistance — and recovery.
The mouse "cure," they say, suggests they're on the right track.
Now, with $14.5 million from the California Institute for Regenerative Medicine, the San Francisco-based stem cell research-funding center created by 2004's Proposition 71, Cannon, Gregory and researchers at the City of Hope cancer center in Duarte are working toward bringing the technique to clinical trials within four years.
Cannon and other HIV researchers insist that, despite cancers and deaths associated with past gene therapy trials, it's the right way to target the disease. They cite recent successes, including treatments that cured children with the "bubble boy" syndrome and helped blind children regain their vision.
"I don't think anyone would want to do gene therapy if there were an alternative," said Caltech biologist David Baltimore, one of the many L.A.-based researchers pursuing gene therapy strategies to prevent or cure HIV. "I think it's absolutely necessary. Nothing else will work."
Since AIDS emerged in the early 1980s, development of anti-HIV medications has turned the disease from a virtual death sentence into a chronic, manageable condition.
But the clamor for a cure hasn't quieted.
Vaccine trials have failed; drug-resistant strains are on the rise; and the meds, which can have uncomfortable side effects such as fatigue, nausea and redistribution of body fat that creates a so-called buffalo hump, cost about $20,000 a year.
A bone marrow transplant is about five times as expensive, but it would have to be done only once.
The question was, could researchers create bone marrow stem cells that — just like the marrow the Berlin patient received — lack the crucial gene, CCR5, that normally lets HIV into the key immune cells it destroys?
In 2006, Gregory asked Cannon if she was interested in testing whether a tool his company developed, called a zinc finger nuclease, could do the trick.
Zinc finger nucleases are genetic scissors, cutting DNA at a specific site — say, in the middle of the CCR5 gene. When the cell glues the gene back together, it usually makes a mistake, resulting in a gene that no longer works.
"It just jumped out at me as, 'Oh my gosh, that's actually something that could work,' " Cannon said.
The team spent about a year optimizing the procedure for treating delicate stem cells with the CCR5 snippers.
They tested the method using so-called humanized mice — ones engineered to have a human immune system — because HIV doesn't infect normal mice. When stem cells were treated with the molecular scissors before being injected into mice, the resulting immune system lacked CCR5, exactly as the scientists had hoped.
These mice acted just like the Berlin patient — they fought off the virus.