Progeria Research Offers Hope for Rapidly Aging Children
Progeria, also known as Hutchinson-Gilford progeria syndrome, is a rare genetic disease that causes children to undergo rapid aging and die at an early age. Although no cure has yet been found for this devastating condition, several new research efforts are offering some hope.
What is progeria?
Progeria is a syndrome characterized by stunted growth, loss of body fat, alopecia (hair low), rapid onset of atherosclerosis (hardening of the arteries), thickened and hardened skin, skeletal dysplasia, dental abnormalities, and joint contractures, among other symptoms. Brain and cognitive function are typically normal. The average age of death for these children is 13 years, and the cause is usually a stroke or heart attack.
Although this rapid aging condition is extremely rare, affecting an estimated 200 to 250 children around the world, a better understanding of the syndrome will not only help these children but those who may be born with it in the future as well as help researchers better understand related conditions and aging itself.
In 2003, researchers at the National Human Genome Research Institute, along with experts at the Progeria Research Foundation, the New York State Institute for Basic Research in Developmental Disabilities, and the University of Michigan, identified a mutation on a single gene (lamin A, or LMNA) as a cause of Hutchinson-Gilford progeria. The LMNA is responsible for encoding two proteins, prelamin A and lamin C. Researchers observed that the genetic mutation seems to always occur in the sperm before conception.
New research on progeria
Among the research efforts regarding progeria is a phase II drug trial conducted at Boston Children’s Hospital in which investigators used a drug called lonafarnib, which is a farnesyl transferase inhibitor (FTI). Lonafarnib focuses on the buildup of a mutant protein called progerin in individuals who have the syndrome.
Previous studies with lonafarnib revealed that the drug improved cardiovascular defects, weight, and mineralization of bone in the lab and in mice. Researchers even saw extended survival in the mice.
Twenty-five children from 16 countries completed two years of treatment with lonafarnib taken twice a day orally. Here are the changes observed by the investigators:
- Nine children achieved a greater than 50% increase in the yearly rate of weight gain
- Six children had a 50% decrease in weight gain rate and 10 had no change
- In 18 children who had abnormally high carotid-femoral pulse wave velocity (a cardiovascular risk factor for stroke and heart attack) before treatment, there was an average improvement of 35%. According to Leslie Gordon, MD, MPH, the study’s lead author, the average pulse wave velocity (which is a marker of arterial stiffness) before treatment was like that of people in their 60s but had improved to a level comparable to individuals in their 40s after treatment
- Bone mineral density in some areas of the body improved by at least 3% in 19 of 25 children, although some children also experienced bone loss in other areas
- Hearing also improved in some of the children
- Skeletal rigidity improved in the subset of 11 children who could be tested
- Use of lonafarnib did not appear to have any positive effect on other factors associated with progeria, such as hair growth, low body fat, dental problems, joint contractures, and rate of insulin resistance. It is too early to know if the drug had any impact on survival.
Other research on progeria treatment
Could a component of red wine be helpful? Two studies published recently point to a possible role of resveratrol in progeria. While the biochemistry is complex, basically researchers found that resveratrol improves the binding of A-type lamins with a factor called SIRT1 (sirtuin1), and that resveratrol also can slow down loss of body weight, improve bone mineral density and structure, and significantly extend the lives of mice.
The drug rapamycin (also known as sirolimus), an immunosuppressant typically given to organ transplant patients to prevent organ rejection, has demonstrated an ability to reduce levels of progerin in an in vitro study conducted by experts at the National Human Genome Research Institute.
Experts observed that rapamycin enhanced the destruction of progerin in progeria cells as well as reduced the formation of certain progerin aggregates, among other benefits. These findings led the authors to note that “rapamycin treatment could provide clinical benefit for children with HGPS [Hutchison-Gilford progeria syndrome].”
For now, Gordon and her colleagues are proceeding with a trial that includes 45 children with progeria and a cocktail of lonafarnib, pravastatin (Pravachol, which lowers cholesterol), and zoledronic acid (Zometa, a bisphosphonate that inhibits the release of calcium from bone). The latter two drugs have an inhibitory effect on the production of progerin.
The wheels of medical research often grind slowly, but for children who have rapidly aging syndrome called progeria, time moves much more quickly. Hopefully the current and future research on progeria will provide more than hope for children born with this syndrome.
Cao K et al. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. Science Translational Medicine 2011 Jun 29; 3(89): 89ra58
Ghosh S et al. Resveratrol activates SIRT1 in a lamin A-dependent manner. Cell Cycle 2013 Feb 25; 12(6)
Gordon LB et al. Clinical trial of farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Proceedings of the National Academy of Sciences USA 2012 Oct 9; 109(41): 16666-71
Liu B et al. Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria. Cell Metabolism 2012 Dec 5; 16(6): 738-50
National Human Genome Research Institute
Image: WIkimedia Commons