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Cholesterol plaque in artery

Looking for atherosclerosis’ root cause

Cholesterol plaque in artery

A multi-institutional team led by research faculty at Children’s National in Washington, D.C., finds that extracellular vesicles derived from kids’ fat can play a pivotal role in ratcheting up risk for atherosclerotic cardiovascular disease well before any worrisome symptoms become visible.

According to the Centers for Disease Control and Prevention, about one in five U.S. kids aged 6 to 19 is obese, boosting their risk for a variety of other health problems now and later in life.

One of these is atherosclerosis, a term that translates literally as hardening of the arteries. Atherosclerosis causes blood vessels that carry oxygen-rich blood throughout the body to become inflamed. White blood cells called macrophages settle in the vessel wall, which becomes overloaded with cholesterol. A plaque forms that restricts blood flow. But it remains a mystery how fat cells residing in one place in the body can trigger mayhem in cells and tissues located far away.

Small, lipid-lined sacs called extracellular vesicles (EVs), released by cells into the bloodstream, are likely troublemakers since they enable intercellular communication. Now, a multi-institutional team led by research faculty at Children’s National in Washington, D.C., finds that EVs derived from kids’ fat can play a pivotal role in ratcheting up risk for atherosclerotic cardiovascular disease well before any worrisome symptoms become visible. What’s more, the team showed that EVs found in the body’s fat stores can disrupt disposal of cholesterol in a variety of kids, from lean to obese, the team reports online July 22, 2019, in the Journal of Translational Medicine.

“We found that seven specific small sequences of RNA (microRNA) carried within the extracellular vesicles from human fat tissue impaired the ability of white blood cells called macrophages to eliminate cholesterol,” says Robert J. Freishtat, M.D., MPH, senior scientist at the Center for Genetic Medicine Research at Children’s National and the study’s senior author. “Fat isn’t just tissue. It can be thought of as a metabolic organ capable of communicating with types of cells that predispose someone to develop atherosclerotic cardiovascular disease, the leading cause of death around the world.”

Research scientists and clinicians from Children’s National, the George Washington University, NYU Winthrop Hospital and the National Heart, Lung and Blood Institute collaborated to examine the relationship between the content of EVs and their effect on macrophage behavior. Their collaborative effort builds on previous research that found microRNA derived from fat cells becomes pathologically altered by obesity, a phenomenon reversed by weight-loss surgery.

Because heart disease can have its roots in adolescence, they enrolled 93 kids aged 12 to 19 with a range of body mass indices (BMIs), including the “lean” group, 15 youth whose BMI was lower than 22 and the “obese” group, 78 youths whose BMI was in the 99th percentile for their age. Their median age was 17. Seventy-one were young women. They collected visceral adipose tissue during abdominal surgeries and visited each other’s respective labs to perform the experiments.

“We were surprised to find that EVs could hobble the macrophage cholesterol outflow system in adolescents of any weight,” says Matthew D. Barberio, Ph.D., the study’s lead author, a former Children’s National scientist who now is an assistant professor at the George Washington University’s Milken Institute School of Public Health. “It’s still an open question whether young people who are healthy can tolerate obesity—or whether there are specific differences in fat tissue composition that up kids’ risk for heart disease.”

The team plans to build on the current findings to safeguard kids and adults against future cardiovascular risk.

“This study was a huge multi-disciplinary undertaking,” adds Allison B. Reiss, M.D., of NYU Winthrop Hospital and the study’s corresponding author. “Ultimately, we hope to learn which properties belonging to adipose tissue EVs make them friendly or unfriendly to the heart, and we hope that gaining that knowledge will help us decrease morbidity and mortality from heart disease across the lifespan.”

In addition to Dr. Freishtat, additional study co-authors include Samuel B. Epstein, Madeleine Goldberg, Sarah C. Ferrante, and Evan P. Nadler, M.D., director of the Bariatric Surgery Program, all of Children’s National’s Center for Genetic Medicine Research; Lead Author, Matthew D. Barberio, of Millken Institute School of Public Health at the George Washington University; Lora J. Kasselman, Heather A. Renna, Joshua DeLeon, Iryna Voloshyna, Ashley Barlev, Michael Salama and Allison B. Reiss, all of NYU Winthrop Hospital; and Martin P. Playford and Nehal Mehta, of the National Heart, Lung and Blood Institute.

Financial support for research described in this post was provided by the National Institutes of Health National Center for Advancing Translational Sciences under award number UL1TR000075, the National Heart, Lung and Blood Institute under award number Z1AHL-06193-4, the American Heart Association under award number 17POST33670787, the Clark Charitable Foundation, the Elizabeth Daniel Research Fund, and Robert Buescher.

macrophage

Improving treatment success for Duchenne muscular dystrophy

macrophage

Macrophages, white blood cells involved in inflammation, readily take up a new medicine for Duchenne muscular dystrophy and promote its sustained delivery to regenerating muscle fibers long after the drug has disappeared from circulation.

Chronic inflammation plays a crucial role in the sustained delivery of a new type of muscular dystrophy drug, according to an experimental model study led by Children’s National Health System.

The study, published online Oct. 16, 2017 in Nature Communications, details the cellular mechanisms of morpholino antisense drug delivery to muscles. Macrophages, white blood cells involved in inflammation, readily take up a new medicine for Duchenne muscular dystrophy (DMD) and promote its sustained delivery to regenerating muscle fibers long after the drug has disappeared from circulation.

Until recently, the only approved medicines for DMD targeted its symptoms, rather than the root genetic cause. However, in 2016 the Food and Drug Administration approved the first exon-skipping medicine to restore dystrophin protein expression in muscle: Eteplirsen, an antisense phosphorodiamidate morpholino oligomer (PMO). The drug had shown promise in preclinical studies but had variable and sporadic results in clinical trials.

The Children’s National study adds to the understanding of how this type of medicine targets muscle tissue and suggests a path to improve treatments for DMD, which is the most common and severe form of muscular dystrophy and currently has no cure, explains study co-leader James S. Novak, Ph.D., a principal investigator in Children’s Center for Genetic Medicine Research.

Because the medication vanishes from the blood circulation within hours after administration, Children’s research efforts have focused on the mechanism of delivery to muscle and on ways to increase its cellular uptake – and, by extension, its effectiveness. However, researchers understand little about how this medication actually gets delivered to muscle fibers or how the disease pathology impacts this process, knowledge that could offer new ways of boosting both its delivery and effectiveness, says Terence Partridge, Ph.D., study co-leader and principal investigator in Children’s Center for Genetic Medicine Research.

To investigate this question, Novak, Partridge and colleagues used an experimental model of DMD that carries a version of the faulty DMD gene that, like its human counterparts, destroys dystrophin expression. To track the route of the PMO into muscle fibers, they labeled it with a fluorescent tag. The medicine traveled to the muscle but only localized to patches of regenerating muscle where it accumulated within the infiltrating macrophages, immune cells involved in the inflammatory response that accompanies this process. While PMO is rapidly cleared from the blood, the medication remained in these immune cells for up to one week and later entered muscle stem cells, allowing direct transport into regenerating muscle fibers. By co-administering the PMO with a traceable DNA nucleotide analog, the research team was able to define the stage during the regeneration process that promotes heightened uptake by muscle stem cells and efficient dystrophin expression in muscle fibers.

“These macrophages appear to extend the period of availability of this medication to the satellite cells and muscle fibers at these sites,” Partridge explains. “Since the macrophages are acting as long-term storage reservoirs for prolonged delivery to muscle fibers, they could possibly represent new therapeutic targets for improving the uptake and delivery of this medicine to muscle.”

Future research for this group will focus on testing whether macrophages might be used as efficient delivery vectors to transport eteplirsen to the muscle, which would avert the rapid clearance currently associated with intravenous delivery.

“Understanding exactly how different classes of exon-skipping drugs are delivered to muscle could open entirely new possibilities for improving future therapeutics and enhancing the clinical benefit for patients,” Novak adds.