A new discovery led by the University of Maryland could spur the development of new and improved treatments for Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder with no known cure that causes accelerated aging in children.
Published in the magazine aged cell On October 18, 2024, in collaboration with researchers at the National Institutes of Health (NIH) and Duke University, the study identified a protein linked to cardiovascular health from animal models of progeria that could be translated into human treatments. Heart failure and stroke are the most common causes of death among people with HGPS, who typically have a life expectancy of between 6 and 20 years.
These new findings from the lab of UMD cell biology and molecular genetics professor Kan Cao are “very promising,” according to senior author and Ph.D. student Sahar Vakili.
“This could pave the way for new treatments targeting cardiovascular complications in HGPS, which are currently a major cause of mortality in affected children,” Vakili said. “Beyond progeria, the insights gained from this research could also be applicable to other age-related diseases in which endothelial dysfunction plays a role.”
Sometimes called “Benjamin Button disease,” HGPS causes a variety of symptoms associated with aging, including skin wrinkles, joint stiffness, and loss of hair and body fat. The disease is due to a mutation in the LMNA(lamin A), which produces a protein that helps keep cells healthy.
To better understand how progeria causes cardiovascular complications, the research team analyzed endothelial cells. These cells line the body’s vascular system, including the heart, and control substances that enter and leave the bloodstream. When endothelial cells malfunction, it can lead to a variety of conditions, including cardiovascular disease, stroke, blood clots, and atherosclerosis (plaque buildup inside the arteries).
More specifically, the researchers wanted to understand the signals sent by endothelial cells that ultimately lead to HGPS-related cardiovascular disease. For the first time, the team found that angiopoietin-2 (Ang2), a protein that regulates the formation of new blood vessels and the flow of substances through blood vessel walls, is significantly altered in individuals with progeria, which which affects the overall function. of its endothelial cells.
The researchers discovered that they could use Ang2 to “rescue” endothelial cells, improving their health despite the dysfunction resulting from HGPS. It improved blood vessel formation, normalized cell migration, and even restored nitric oxide levels, which are crucial for a healthy vascular system.
“Ang2 treatment also improves signaling from endothelial cells to vascular smooth muscle cells, suggesting that it could be a potential therapy for vascular dysfunctions in HGPS,” Vakili said.
Current treatments for HGPS can help reduce the risk of fatal complications such as heart attacks and strokes, but they do not target the underlying disease. Cao explained that his research is unlikely to offer a definitive cure for progeria, but it could buy patients more time by improving their health in other ways.
“While Ang2 only has receptors on endothelial cells, it may have a broader beneficial impact on additional tissue types beyond the cardiovascular systems, such as bone and fatty tissues, as blood vessels are essential for our body to transport nutrients, oxygen and waste.” said Cao, who began studying progeria during his postdoc in 2005, just two years after the cause of progeria was discovered.
As a next step, Cao plans to conduct a follow-up study in collaboration with a group at the NIH to explore different methods of delivering Ang2 to animal models of progeria.
While work continues, Cao is confident that each new study will bring researchers closer to identifying a cure.
“We are getting very close to a cure for progeria,” he said. “As for the investigation, we are pushing hard and I can see the light at the end of the tunnel.”