Children's Hospital Boston: Study of Rare Disease Helps in Search for Clues on Aging

September 26, 2012

A drug first developed for cancer has shown promise as a treatment for progeria, a rare and fatal rapid-aging disease in children, and it may have implications in treating cardiovascular problems associated with normal aging.

A drug first developed for cancer has shown promise as a treatment for progeria, a rare and fatal rapid-aging disease in children. WSJ's Amy Dockser Marcus and the Progeria Research Foundation's Dr. Leslie Gordon discuss on Lunch Break. Photo: Aaron Vincent Elkaim for The Wall Street Journal

In a paper published Monday in Proceedings of the National Academy of Sciences, scientists reported results after a 2┬Ż-year trial of 28 children who took Merck MRK -0.22% & Co.'s lonafarnib. The drug appeared to slow, and in some cases reverse, damage caused by the disease, including arterial stiffness, which also is linked to heart problems in the normal aging population.

Although the number of participants in the study is small, the disease is so rare that the children represented 75% of the known cases of progeria in the world at the time they enrolled in the trial at Boston Children's Hospital in 2007. Since the trial began, more children with progeria have been identified, said Leslie Gordon, medical director of the Progeria Research Foundation.

Children with progeria, also known as Hutchinson-Gilford Progeria Syndrome, die of heart attacks or strokes at an average age of 13 because of the accumulation of a protein called progerin.

Researchers have long wondered whether progeria might offer clues into the normal aging process. Over the past few years, papers have been published demonstrating that progerin, a mutant form of the Lamin A protein, which is critical in organizing the genome inside the body's cells, accumulates in everyone as they age. The thinking is that a drug that mitigates cardiovascular problems in children with progeria might also affect cardiovascular problems more broadly.

"More data suggests that this mechanism at least in some cases may be related to things that happen in normal aging, and the study is of interest in that regard," said Brian Kennedy, president and chief executive of the Buck Institute for Research on Aging in Novato, Calif. Dr. Kennedy has tested other drugs for progeria and normal aging and wasn't involved in the lonafarnib study. "I also think for progeria this is an encouraging start."

None of the researchers involved in the trial think lonafarnib alone will arrest the disease, and the results raised questions that need to be addressed. For example, although all the children benefited from the drug, they didn't all benefit the same way, and researchers aren't sure why.

Children with progeria look healthy when they are born but usually start to show signs of the disease at 18 to 24 months, including failing to grow and a loss of hair and body fat.

Nine children showed greater than a 50% increase in annual rate of weight gain, a statistically significant result, but six children lost weight, perhaps because of disease progression or side effects of the medicine. Children also showed improvement in hearing, skeletal rigidity or cardiovascular changes such as decreased arterial stiffness and improved vessel-wall density. But researchers can't predict or explain yet why someone benefits in one area but not another.

"The drug prevents the abnormal protein collecting in places where it seems to do the most damage, but it doesn't stop the abnormal protein from being made," said Mark Kieran, principal investigator in the trial and director of pediatric medical neuro-oncology at the Dana-Farber/Children's Hospital Cancer Center in Boston.

Dr. Kieran said another trial, involving a cocktail of lonafarnib and two additional drugs, is under way at Boston Children's Hospital to try to achieve even greater benefits and that a fourth drug is being tested in mice and may be tried in the children in another trial.

Dr. Gordon, of the Progeria Research Foundation, which raised $2 million to fund the lonafarnib trial, said the foundation plans to ask the Food and Drug Administration to approve the drug for use in progeria because of the results released Monday. Dr. Gordon is an author of the paper published Monday and the mother of a child with progeria.

A spokeswoman for Merck said the company is supporting the filing and has agreed to supply the drug "for the foreseeable future," but the company isn't pursuing development of the drug more broadly. Merck developed the drug for cancer, but it failed to show efficacy in a trial with patients with advanced head-and-neck cancer.

Francis Collins, director of the National Institutes of Health and one of the discoverers of the gene that causes progeria, said the drug's usefulness for vascular stiffness in normal aging is an important question to study. But the drug "hits a lot of targets, and one concern is to make sure you are not inducing an untoward effect in people who are not as severe as kids with progeria," Dr. Collins said. He said his lab is testing a form of the drug rapamycin in mice with progeria that could eventually be tried as part of a drug-treatment cocktail.

The Buck Institute's Dr. Kennedy led a team earlier this year that found that another form of rapamycin was effective in increasing the life spans and improving symptoms in mice with two different diseases caused by other mutations in the progeria-connected Lamin A gene. Rapamycin also is being studied for its impact on the normal aging process.

Jamie Madley of Hamilton, Ontario, said her 16-year-old son, Devin Scullion, a high-school junior, was part of the lonafarnib trial and is part of the continuing triple-drug-cocktail trial. Devin has had arthritis since the age of 2 and suffered two major strokes when he was 6. He uses a walker to get around. Ms. Madley said Devin has shown improvement in the trials. He weighed 23 pounds at the start of the lonafarnib trial and is now up to 31 pounds. She said his eating habits, energy level and sleep also have improved.

When Devin was born, said Ms. Madley, she was told there were no treatments for progeria. "Now at least there is hope," she said. "We got our foot in the door."

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