The potential of a gene-silencing technique called RNA interference has long enticedÂ biotechnology researchers. Itâ€™s used routinelyÂ in the laboratory to shut down specific genes in cells. Still, the challenge of delivery has held back RNA-based drugsÂ inÂ treating human disease.
RNA is unstable and cumbersome, and just getting it into the body without having it break down is difficult. One that hurdle is met, there is another: the vast majority of the drug is taken upÂ by the liver. Many current RNA-based approaches turnÂ this apparent bug into a strength, because they seek to treat liver diseases. See these articles in The Scientist and in Technology Review for more.
But what if you need to deliver RNA somewhere besides the liver?
Biomedical engineer Hanjoong Joâ€™s lab at Emory/Georgia Tech, working with Katherine Ferraraâ€™s group at UC Davis, has developed technologyÂ to broadenÂ the liver-dominantÂ properties of RNA-based drugs.
Hanjoong Jo, PhD
The results were recently published in ACS Nano. The researchers show they can selectively target an anti-microRNAÂ agent to inflamed blood vessels in mice while avoiding other tissues.
â€œWe have solved a major obstacle of using anti-miRNA as a therapeutic by being able to do a targeted delivery to only inflamed endothelial cells while all other tissues examined, including liver, lung, kidney, blood cells, spleen, etc showed no detectable side-effects,â€ Jo says. Read more
If someone living in America and eating a typical diet and leading a sedentary lifestyleÂ lets a few years go by, we can expect plaques of cholesterol and inflammatory cells to build up in his or her arteries. We’re not talking “Super-size Me” here, we’re just talking average American. But then let’s say that same person decides: “OK, I’m going to shape up. I’m going to eat healthierÂ and exercise more.”
Let’s leave asideÂ whether low-carb or low-fat is best, and let’s say that person succeeds in sticking to his or her declared goals. How “locked in” are the changes in the blood vesselsÂ when someone has healthy or unhealthy blood flow patterns?
Biomedical engineer Hanjoong Jo and his colleagues published aÂ paper in Journal of Clinical Investigation that touches on this issue. They have an animal model where disturbed blood flow triggers the accumulation of atherosclerosis. They show that the gene expression changes in endothelial cells, which line blood vessels, have an epigenetic component.Â Specifically, the durable DNA modification known asÂ methylation is involved, and blocking DNA methylation with a drug used for treating some forms of cancer can prevent atherosclerosis in their model.Â This suggests that blood vessels retain an epigenetic imprint reflecting the blood flow patterns they see.
Although treating atherosclerosis with theÂ drug decitabine is notÂ a viable option clinically, Jo’s team was able to find severalÂ genes that are silenced by disturbed blood flow and that need DNA methylation to stay shut off. A handful of thoseÂ genes have aÂ common mechanism of regulationÂ and may be good therapeutic targets for drug discovery.
For years, scientists like Hanjoong Jo have been telling us that blood vessels are like rivers and streams. Fluid dynamics are important; the patterns of curvature and current influence where sediment — or atherosclerosis — builds up.
One of the biggest possible perturbations of fluid dynamics in a blood vessel would be to stick a metal tube into it. Of course, cardiologists do this all the time.Â During percutaneous coronary intervention (PCI), doctors place a stent, basically a metal tube, inside a blood vessel to relieve an obstruction and restore blood flow to the heart muscle.
Habib Samady, Emory Healthcareâ€™s director of interventional cardiology, is leading a clinical trial looking at the effects of stent introduction on blood vessels that are not straight, but curved or angulated. To be eligible for the study, the patient’s blocked vessel has to bend more than 30 degrees. The study will look at patients who have undergone PCI for a heart attack and follow them over the course of a year. Less â€œdisturbed flowâ€ should mean better heart healing for the patient down the road.Â The study uses OCT (optical coherence tomography) and IVUS (intravascular ultrasound) to monitor the blood vessel and see how healing is affected by fluid dynamics after stent placement. Read more