Reversal of the cellular phenotype in the premature aging disease HGPS

Published online on March 6, 2005 in Nature Medicine (www.nature.com)

Cells from patients with Hutchinson-Gilford Progeria Syndrome (HGPS) can be made healthy again, according to findings by scientists at the National Cancer Institute, part of the National Institutes of Health. Using specially modified short segments of DNA, NCI researchers Paola Scaffidi, PhD, and Tom Misteli, PhD (both 2003 PRF Workshop participants), reversed the defects seen in HGPS cells by eliminating the lamin A protein that is faulty in HGPS. By demonstrating that HGPS cellular phenotypes are reversible, this study brings scientists one step closer to curing this devastating childhood disease.

“We set out to ask whether these cellular changes associated with Progeria are permanent or can be reversed,” said Scaffidi. The researchers designed a “molecular Band-Aid®,” said Misteli (a chemically stable DNA oligonucleotide -so the cell wouldn’t be able to degrade it.) One week later, the mutant lamin A protein had been eliminated and more than 90 percent of progeria cells looked normal; and the activity of several genes that are misregulated in HGPS patients were also restored to normal. “It’s amazing that we could take a sick cell and a few days later it’s healthy and ready to divide again,” said Misteli.

He noted that these results demonstrate a proof-of-principle that the cellular effects of Progeria can be reversed, meaning his laboratory’s method might someday be used as a therapeutic strategy.

Decreased levels of “good” cholesterol in children with Progeria may contribute to premature heart disease. Adiponectin – a hormone that regulates the metabolism of fat and sugar – may be helpful in finding treatments.
The Journal of Pediatrics, March 2005

A team of researchers led by PRF’s Medical Director and Tufts University School of Medicine Assistant Professor Leslie Gordon, MD, PhD, discovered that children with Progeria in their mid- and later years have decreased levels of HDL cholesterol – or “protective” cholesterol” – and adiponectin, a hormone that regulates the metabolism of fat and sugar. Both factors work to remove fat from plaques in arteries, and the lower levels may contribute to accelerated plaque formation. “All children with Progeria die between the ages of 6 and 20 years from heart failure or stroke,” said Dr. Gordon. “Studying heart disease as it relates to children with Progeria can help us better understand how atherosclerosis will affect the aging population while also helping these precious children.”

“These findings are important for the potential development of a treatment for Progeria,” said senior study author Alice H. Lichtenstein, DSc, Human Nutrition Research Center on Aging at Tufts University. “If reliable drugs used to increase HDL cholesterol and adiponectin levels become available, they may prove beneficial in preventing the progression of atherosclerosis in children with Progeria.”

“These data also reinforce the importance of adipose tissue as an active tissue which secretes hormones which can influence metabolic function of the entire body – a concept important not only for Progeria but also for more common diseases such as obesity and diabetes”, comments author Mary Elizabeth Patti, MD, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, MA