Protein discovery could pave way for improved treatment of premature aging disease

A University of Maryland-led discovery 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 journal Aging cell On October 18, 2024, in collaboration with researchers from the National Institutes of Health (NIH) and Duke University, the study identified a protein linked to cardiovascular health of animal models with progeria that could translate into treatments humans. Heart failure and stroke are the most common causes of death in people with HGPS, whose life expectancy is typically between 6 and 20 years.

These new findings from Professor Kan Cao’s laboratory of cell biology and molecular genetics at UMD are “very promising,” according to the lead author and Ph.D. in biological sciences. student Sahar Vakili.

“This could pave the way for new treatments targeting the cardiovascular complications of HGPS, which are currently a major cause of mortality in affected children,” Vakili said. “Beyond progeria, the knowledge gained from this research could also apply 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 wrinkling, joint stiffness, and loss of hair and body fat. The disease arises from a mutation in the LMNA (lamin A) gene, which produces a protein that helps keep cells healthy.

To better understand how progeria causes cardiovascular complications, the research team looked at endothelial cells. These cells line the body’s vascular system, including the heart, and control substances entering and leaving the bloodstream.

When endothelial cells function poorly, it can lead to a range of problems, including cardiovascular disease, stroke, blood clots, and atherosclerosis (buildup of plaque in the arteries).

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 discovered 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 impaired in affected individuals. of progeria, thus affecting the overall functioning of their immune system. endothelial cells.

The researchers found that they could use Ang2 to “rescue” endothelial cells, thereby improving their health despite dysfunction originating from HGPS. It improved blood vessel formation, normalized cell migration, and even restored nitric oxide levels, essential for vascular system health.

“Ang2 treatment also enhances signaling from endothelial cells to vascular smooth muscle cells, suggesting that it may be a potential treatment for vascular dysfunction in HGPS,” Vakili said.

Current treatments for HGPS can help reduce the risk of life-threatening complications like heart attacks and strokes, but they do not target the underlying disease. Cao explained that their research is unlikely to offer a definitive cure for progeria, but could buy patients more time by improving their health in other ways.

“Although Ang2 only has receptors on endothelial cells, it may have a broader beneficial impact on other tissue types beyond cardiovascular systems, such as bone and adipose tissues, because blood vessels are essential for our body to transport nutrients, oxygen and waste,” said Cao, who began studying progeria during his postdoctoral fellowship 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 NIH to explore different methods of delivering Ang2 to animal models of progeria.

As the work continues, Cao is confident that each new study will bring researchers closer to identifying a cure.

“We are getting really close to a cure for progeria,” she said. “In terms of research, we are working hard and I see the light at the end of the tunnel.”