By Beige Luciano-Adams, Staff Writer
Posted: 01/23/2011 07:02:05 AM PST
Updated: 01/23/2011 06:19:22 PM PST
DUARTE - After several years in the lab, researchers at City of Hope are reporting positive results in animal trials of a new treatment designed to both hunt down HIV-infected cells and stop the virus from spreading, according to a study published last week in the journal, "Science Translational Medicine."
John Rossi, chair of molecular and cellular biology at City of Hope and a lead author on the study, likens the molecular compound his team designed to a "smart bomb."
It works against the virus itself, while delivering a potent "weapon" to the inside of infected cells, where HIV multiplies.
"This particular approach is pretty different than almost everything else out there recently," said Rossi, who had previously developed small RNA molecules (siRNAs) capable of targeting and stopping the genes that HIV commonly uses to replicate itself.
But this time, Rossi and his colleagues designed an RNA sequence called an "aptamer," which strategically delivers those siRNAs to the cell. The result, he said, is a potentially powerful, two-headed weapon in the fight against HIV.
"We found that this aptamer not only binds to (the cell) and blocks it but also if the cell is infected... the aptamer will recognize that and get dragged into the cell. We found we could use this to deliver a second therapeutic molecule."
What he found was that both the aptamer and the siRNA it delivered to the infected cells appeared to stop the virus in its tracks
"What they've developed is a two-part warhead, and either part works very well," said Paula Cannon, an associate professor at USC's Keck School of Medicine, who researches genetic therapies for HIV and is familiar with Rossi's body of work.
"What I like about it is the fact that this isn't just something that happened overnight. Rossi and his team have been working on strategies to stop HIV replicating using these very cutting-edge technologies based on RNA."
In the past, she said, "they've made nice, steady, incremental progress."
"Now, in this study, they show the latest actually works really well in the context of a live animal - which is a huge step."
Rossi's team created "humanized" mice - mice with engineered human immune systems - infected them with high loads of HIV and then injected them with the treatment.
"We give them a single injection once a week for several weeks and found out it completely knocks out the virus," he said. "There was no detectable virus during injection, and it doesn't come back to its normal level after."
The animals, which would normally show a decline in T-cells as the virus continued to spread, were protected from T-cell decline, with or without the aptamer, Rossi said. The study reported that both the siRNA and the aptamer - together called a "chimaera" - decreased high viral loads in all treated animals within a week of injection.
The fact that the chimaera was tested in animals with "humanized" immune systems, authors of study argue, will make the development of a human application easier.
"The first niche it could fill is patients whose virus has become resistant to the drug," Rossi said. "We can evolve these aptamers to target a variety of (strains) of HIV."
Rossi thinks the new treatment, which is administered by injection and produced no toxic side effects in the lab, could be a useful alternative for people who become sick from taking ARV pills. He's also thinking about how to make the effects last longer.
For Cannon, the power and potential is in the delivery system, engineered to only target infected cells.
"Lots of people are trying to develop those (kinds of treatments) that can work against HIV. But I think what's nice about this one is that he has a better delivery system to get the RNA into the cell," said Cannon, who thinks the method could be used to build on for the next generation of anti-HIV molecules.
In the mouse study, Rossi and his team used an siRNA that stops the virus - but they are already into the next phase of testing, in which he hopes to develop an aptamer to selectively kill infected cells.
Cannon says this "more extreme" method sounds promising.
"The virus uses the cell as an incubator, makes lots of baby HIV and then kills the cell. That cell is history anyway, so you might as well get in there and kill (it)."
But she stops short of hopes that such a treatment could completely wipe out a reservoir of HIV in an infected patient, explaining that a fraction of the virus can "hide out" and become dormant, evading the aptamer.
"It's highly unlikely to be 100-percent successful," she said. "(Those dormant cells), they're not going to be touched by this therapy, or any sort of therapy we have now. Then the virus wakes up and kicks off the whole infection again."
Cannon noted that there there is currently a lot of interest and research in latent cells, mostly focused on drugs that would "wake up" all the cells in a body to make the latently infected ones detectable.
"As people are developing ways to wake up these latently infected cells, which are the reason HIV persists, then certainly anything people develop could be used in combination to target and kill specific infected cells," she said.
Rossi, who has been researching genetic therapies for HIV since the 1980s, would like to eventually bring the trials to humans, but that will depend on corporate sponsorship needed to fund the couple of million dollars it will take to first test monkeys.
"Right now, we're collaborating with a group at the National Institute of Health to see if we can use this approach to purge infected cells isolated from patients (outside the body), and we're also looking to do this in the mouse model," said Rossi.
"So we're continuing on but trying now to prove we can use this approach to completely eradicate the virus - with a couple of injections."
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