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First Successful Treatment for Progeria, Rare Childhood Disease

Results of the first clinical drug trial for children with a rare rapid-aging disease, known as Progeria, has shown successfulness with a farnesyltransferase inhibitor (FTI), a drug first used to treat cancer.

The clinical trial results showed significant improvements in bone structure, weight gain, and most importantly, the cardiovascular system, according to new research published in Proceedings of the Natural Academy of Sciences.

Also known as Hutchinson-Gilford Progeria Syndrome (HGPS), Progeria is a rare and fatal genetic disease displaying an appearance of rapid aging in children. The disease becomes fatal when those affected develop the same heart disease (atherosclerosis), as millions of normal aging adults. Instead of this occurring at 60 or 70 years of age, children with Progeria can suffer heart attacks or strokes starting at the age of 5, with the average age of death being 13.

Leslie Gordon, MD, PhD, lead author of the study, medical director for PRF, and mother of a child with Progeria, says:

"To discover that some aspects of damage to the blood vessels in Progeria can not only be slowed by the FTI called lonafarnib, but even partially reversed within just 2.5 years of treatment is a tremendous breakthrough, because cardiovascular disease is the ultimate cause of death in children with Progeria."

Hutchinson-Gilford Progeria Syndrome is a childhood disorder caused by mutations in one of the major architectural proteins of the cell nucleus. Photo source: The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. Scaffidi P, Gordon L, Misteli T. PLoS Biology Vol. 3/11/2005, e395 The two and a half year drug study consisted of 28 children from 16 different countries, accounting for 75 percent of Progeria cases worldwide. Twenty-six of the 28 children had the classic form of the disease. All 28 children traveled to Boston every four months to receive extensive medical testing through Children's Hospital's Clinical and Translational Study Unit.

The oral medication, the FTI lonafarnib, was given twice daily over the course of the study. The research team assessed the children's rate of weight gain, compared to their pre-study rate. They viewed this as the primary outcome because these kids suffer from critical failure to thrive, characterized by extremely slow weight gain over time. Researchers also inspected stiffness of the arteries (a predictor of heart attack and stroke), as well as bone rigidity and density (a predictor of osteoporosis). Every child participating in the study showed significant improvement in weight gain ability, bone structure, or flexibility of blood vessels. Noteworthy Improvements Weight: One in three children demonstrated a greater than 50 percent increase in annual rate of weight gain, or switched from weight loss to weight gain, because of increased muscle and bone mass. Bone Structure: Bone rigidity improved to normal levels after FTI treatment. Cardiovascular: Arterial stiffness, associated with atherosclerosis, decreased by 35 percent. Vessel wall density also improved. A Blueprint For Progeria Treatment After the discovery of the gene that causes Progeria, FTIs were suggested as a potential drug treatment. These kids have a genetic mutation that produces the protein progerin, which is responsible for the disease. Progerin blocks normal cell function and causes harm to the body via a farnesyl group, a molecule that attaches itself to the protein. FTIs prevent this attachment from happening.

Mark Kieran, MD, PhD, the study's senior author and associate professor of Pediatrics at Harvard Medical School explains:

"In the early stages of planning for this clinical trial, we realized that my team's experience using FTIs to treat children with brain cancer could bring together PRF's preclinical research efforts and the expertise we needed to study the drug in children with Progeria. The premise behind studying this drug was that by stopping the attachment of the farnesyl group onto progerin in children with Progeria, progerin may be inactivated, reducing some effects of the disease."
The results of this study are extremely encouraging. A second clinical trial funded by the Progeria Research Foundation and the National Institutes of Health is under way, while more are expected to follow.

Previous research has shown that progerin is produced in all humans and increases in the body with age. Several earlier studies have seen associations with normal aging and progerin, including a link between progerin and genetic instability. Investigators plan to continue researching FTIs and their effects, which may help lead to more information about cardiovascular disease as well as the normal aging process that affects every population.

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