Unlike cells elsewhere in the body, the cells that form the inner walls of our arteries become inflamed when transforming growth factor-β (TGF-β) proteins circulate. This observation, made by scientists based at Yale University, suggests that interfering with TGF-β receptors could lessen chronic inflammation in blood vessels, which is believed to cause atherosclerosis. The Yale scientists, in fact, have developed a drug that relies on RNA interference (RNAi) to silence TGF-c receptor genes in endothelial cells—and only endothelial cells. This cell-level selectivity is achieved by packing the RNAi drug into an endothelial-cell-targeting nanoparticle.
Atherosclerosis, a condition in which plaque accumulates and arteries become hardened, can be slowed by current treatments, but it cannot be stopped or reversed. Although the physical manifestations of atherosclerosis are all too familiar, the condition’s molecular drivers have been obscure. To shed light on these drivers, the Yale scientists, led by professor of medicine Michael Simons, MD, focused on TGF-β signaling, which is known to regulate a wide range of cells and tissues throughout the body.
The scientists presented their findings August 26 in the journal Nature Communications, in an article titled, “Endothelial TGF-β signaling drives vascular inflammation and atherosclerosis.” The article describes how experiments with cultured human cells and mouse models revealed that TGF-β signaling is one of the primary drivers of atherosclerosis-associated vascular inflammation.
“Inhibition of endothelial TGF-β signaling in hyperlipidemic mice reduces vessel wall inflammation and vascular permeability and leads to arrest of disease progression and regression of established lesions,” the article’s authors wrote. “These proinflammatory effects of endothelial TGF-β signaling are in stark contrast with its effects in other cell types and identify it as an important driver of atherosclerotic plaque growth and show the potential of cell-type-specific therapeutic intervention aimed at control of this disease.”
To test this approach as a potential therapy, the scientists used an RNA interference (RNAi) drug developed at Yale to disrupt TGF-β receptors. Interfering RNA use a gene’s own DNA sequence to turn off or silence the gene. To deliver the drug only to endothelial cells in the blood vessel walls of mice, the scientists employed microscopic particles, or nanoparticles, created by their colleagues at MIT. This strategy reduced inflammation and plaque as effectively as the genetic technique.
Based on this discovery, investigators at Yale and MIT have launched a biotech company, VasoRX, to develop this targeted approach, using the RNAi drug delivered by nanoparticles as a potential therapy for atherosclerosis in people.