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Stefan Behnisch has won awards for designing science labs and other buildings that are smart, sustainable, and...
- 12 December 2013 1:00 pm , Vol. 342 , #6164
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Novel Drug Shrinks Monkeys' Waistlines
9 November 2011 2:00 pm
More than 10 years ago, a husband-and-wife team came up with a novel way to fight disease: Look for small bits of protein that home in on specific tissues and attach a drug to them. Now, the work has brought the researchers close to a new therapy for obesity, which they report works well in monkeys and is edging toward human testing.
The couple, cancer biologists Renata Pasqualini and Wadih Arap, who run a lab together at M. D. Anderson Cancer Center in Houston, Texas, has a unique way of thinking about drug development. Rather than focus on specific compounds and how they might fight disease, the researchers cast a wide net. They take massive numbers of protein bits, known as peptides, and attach each one to the shell of a bacterial virus. The combo is then injected into people who have been declared brain dead—M. D. Anderson patients who often wished to be organ donors but weren't eligible, so their families agreed to this study instead—to see which blood vessels the peptide hooks up to.
The idea is that blood vessels in, say, the prostate have protein expression patterns different from those in vessels in the lung and that blood vessels in cancer tissue have expression patterns different from those in healthy tissue. Once Pasqualini and Arap know which blood vessels a peptide latches on to, they can attach a drug to that peptide; in the case of cancer, the drug might destroy the vessels that feed a tumor.
Although their work focused on treating cancer, the researchers wondered about other conditions in which destroying blood vessels might help. One was obesity, in part because an earlier study had suggested that giving rodents angiogenesis inhibitors, drugs that prevent growth of new blood vessels, could help them lose weight. In 2004, Arap and Pasqualini reported in Nature Medicine that they attached a cell-killing drug to a peptide that traveled to blood vessels in fat tissue. The treatment led to weight loss in mice.
In the new work, published today in Science Translational Medicine, the duo repeated the experiment in obese monkeys. The researchers gave the drug to 10 rhesus monkeys and compared them with five control monkeys. The treated animals lost between 7% and 15% of their body weight, and their waist circumference dropped by up to 14%. The animals received the drug for 4 weeks and were followed for another 4 weeks, and no reliable weight loss was seen in the controls.
The results in mice and monkeys run counter to current thinking about destroying body fat. "The idea of choking adipose tissue off from its blood supply to make an animal leaner seemed incredibly wrong," says Randy Seeley, a neuroscientist at the University of Cincinnati in Ohio, who was not involved in the study. That's because, although we might not view fat favorably, it serves as an important storage site for calories and nutrients—and making it disappear suddenly forces those calories and nutrients to go elsewhere, to other tissues where they can cause damage. Patients who have a rare gene mutation that leaves them with a shortage of adipose tissue, the major storage place for fat, look healthy but actually have serious metabolic problems, including fatty liver disease. "They no longer have a safe place to store their calories," Seeley says.
After replicating part of the Arap-Pasqualini rodent work himself, though, Seeley is now convinced that they're on to something, and the new finding confirms his view. One possibility, he says, is that the treatment doesn't kill blood vessels indiscriminately but targets only fine branches of vessels, putting fat cells under stress without destroying them. The disappearing blood vessels could also act as a feedback loop, signaling to the animals to eat less—and indeed, Arap and Pasqualini saw that the treated monkeys consumed less of their regular food but ate just as many treats as control monkeys, suggesting that they weren't feeling nauseous from the therapy. They didn't appear to have many side effects though did experience mild dehydration due to a modest decline in kidney function that ended when the therapy stopped.
One big question is whether the treatment will still be safe if patients receive it long term, as is likely to happen in obesity therapy. Another question is whether the peptide that carries the drug is as targeted as it seems. "It's certainly selective for adipose tissue, but is it 100% selective?" Seeley says. If it's not, it could be affecting blood vessels elsewhere, with untoward effects.
More studies could help answer those questions. A company called Ablaris Therapeutics has licensed rights to the obesity therapy and is working with the U.S. Food and Drug Administration to test it in people. Similar work, in cancer, has been spun off to a second company, Alvos Therapeutics. M. D. Anderson also recently finished an early trial on prostate cancer using this strategy but hasn't reported the results.