Unexpected benefit. White arrows indicate weak spots in the blood vessels of mice with HHT (middle) that healthy mice (left) don’t have. Thalidomide strengthens the vessel walls (right).

Lebrin et al, Nature Medicine, Advance Online Publication (2010)

Notorious Drug Stanches Bleeding

Despite its horrifying history of causing birth defects, thalidomide has recently made a comeback as a treatment for diseases such as the cancer multiple myeloma. Now, a new study suggests the drug may also ease the symptoms of a genetic disease called hereditary hemorrhagic telangiectasia—a discovery that could guide researchers to novel therapies for HHT and other vascular diseases.

In the late 1950s and early 1960s, doctors prescribed thalidomide as an antinausea drug for pregnant women with a regularity that proved tragic. More than 10,000 children in 46 countries were born with missing limbs and other deformities before thalidomide’s manufacturers pulled it from the market. Researchers have only recently begun to understand how the drug did its damage. They also know little about one of the drug’s benefits: Thalidomide appears to control angiogenesis, the growth of new blood vessels. That property makes it a powerful weapon for combating certain cancers, but scientists don’t know how it works.

In HHT, blood vessels grow without the right support cells to keep them stable and strong. Sufferers have leaky vessels and are prone to potentially life-threatening bleeding in the brain, lungs, liver, and gastrointestinal tract. People with the rare inherited disease also have frequent nosebleeds, as many as seven a day, that can become so severe that patients require skin grafts in their noses or even more desperate measures to lead normal lives. “HHT patients get their nostrils sewn up just so they can walk down the street,” says Christine Mummery, a developmental biologist at the Leiden University Medical Centre in the Netherlands.

Thalidomide’s penchant for targeting blood vessels in tumors made Mummery wonder whether the drug’s effect on angiogenesis could help HHT sufferers. When they gave thalidomide to seven HHT patients, six had significantly fewer nosebleeds within a month of their first dose, Mummery and colleagues report online today in Nature Medicine.

To find the mechanism underlying the patients’ improvement, the researchers tested the drug on mice bred to have HHT symptoms. They discovered that although high doses of thalidomide stop angiogenesis, lower doses actually fortify the blood vessels by spurring cell growth. Thalidomide appears to pair up with a growth factor called PDGF-B to produce more of the smooth muscle cells that repair vessel-wall defects.

Evidence suggests that the drug works the same way in humans. A nasal biopsy from the seventh participant (who also saw improvement but had to drop out of the study due to thalidomide-induced nerve damage) showed more smooth muscle cell layers than were present in samples from untreated HHT patients. The results offer new insight into how thalidomide affects blood vessels, says Mummery.

They also offer HHT sufferers hope for more effective therapies in the future, says S. Paul Oh, an experimental geneticist at the University of Florida, Gainesville, who was not involved in the study. “It’s possible thalidomide will help with all aspects of HHT,” he says. “This is the first major therapy the HHT community is working on.”

The study could point the way to a safer alternative as well, adds Rosemary Akhurst, a molecular biologist at the University of California, San Francisco. “Ultimately, we don’t want anyone to be using a drug as hazardous as thalidomide,” she says. “This can help us take the positive aspects of it and leave the negative.”