Posted on NIH. 2 March, 2020
The National Institutes of Health (NIH) is our nation’s medical research agency and strives to make scientific discoveries that improve health and save lives. Founded in 1870, the NIH conducts its own scientific research through its Intramural Research Program (IRP), which supports approximately 1,200 principal investigators and more than 4,000 postdoctoral fellows conducting basic, translational and clinical research.
In this blog, we will highlight recent ground-breaking NIH research, while also providing links to upcoming NIH events designed to keep researchers abreast of the latest discoveries.
Drugs Targeting T Cells May Help Treat Cerebral Malaria
Over 200 million people are infected annually with parasites from mosquitoes that cause malaria. In around 1% of these cases, mostly in young children, the parasites infect brain blood vessels causing swelling in what is known as cerebral malaria (CM). CM is responsible for the deaths of around 400,000 African children annually, while the children who survive the infection often have long-lasting neurological issues.
While it is well-established that T cells known as cytotoxic lymphocytes (CTLs) drive the vasculature injury associated with CM in mice, lack of corroboration on this disease pathogenesis in humans has impeded the development of therapeutics. In order to investigate the biological pathways of CM in humans, researchers at the NIH led by Dorian McGavern, Ph.D and Susan Pierce, Ph.D. examined brain tissue from 23 children who died from CM and brain tissue from 11 children who died from other causes.
The study team found an increased concentration of CTLs along the walls of brain blood vessels in CM tissue samples compared to non-CM cases. In what appears to be an immunological accident, the CTL cells were found to release effector molecules meant to control the parasitic infection that ended up damaging the walls of the brain blood cells, leading to the brain swelling.
In separate studies, the research team discovered that treatment of mice infected with CM using a drug targeting T cells prevented death over 60% of the time. Given these findings, the team is excited that this drug may achieve first therapy status for CM. Additional studies are planned to further investigate targeting T cells in CM, while a clinical trial is being planned to test the effects of a T cell blocker in CM patients in Malawi.
Modified Hormone Shown to Provide Benefits for Damaged Hearts
The human body has a remarkable ability to cleanse itself of chemicals in order to prevent the buildup of toxins in tissues. While this ability has obvious benefits for human health, it also can serve to reduce the benefits of drugs by clearing medications out of the body before they can exert their full therapeutic effects.
Heart failure affects 26 million people worldwide. This condition is typically treated with drugs called angiotensin-converting enzyme (ACE) inhibitors that relax and widen blood vessels to reduce the heart’s workload. Unfortunately, ACE inhibitors do not provide significant benefits for patients in some cases.
In an effort to develop more effective treatments for people suffering from this condition, AstraZeneca created a synthetic version of a hormone naturally produced by the human body called relaxin that was known to reduce fibrosis (a process by which the body replaces dead heart tissue from a heart attack with stiffer material that does not beat as effectively), cell death and inflammation. While this drug showed promise in clinical trials, it was removed from the body so quickly that it did not provide lasting benefits for patients.
In mice, the unmodified relaxin molecule has a half-life (amount of time for the concentration in the blood to be reduced by half) of just a few minutes. In a new study led by IRP senior investigator Elizabeth Murphy, Ph.D., researchers tested a modified relaxin molecule (RELAX10) with a half-life between 3 and 7 days in mice, depending on dose and administration method. The mice in this study had their hearts damaged by two weeks exposure to a chemical called isoproterenol.
The isoproterenol caused significant cardiac hypertrophy (enlarged heart), fibrosis and reduced cardiac function in untreated mice. These effects were reduced, however, in mice that were also given a two-week course of RELAX10, relaxin or an ACE inhibitor will they received the isoproterenol. In addition, when the mice were given the RELAX10 after exposure to isoproterenol as opposed to at the same time, the drug mostly reversed the cardiac hypertrophy and fibrosis, suggesting that this drug could be used as both be preventative and also as a treatment for someone who already has mild hypertrophy.
Future studies will examine whether combining a relaxin-based drug with an ACE inhibitor could lead to synergistic effects that help patients’ hearts more than either treatment would by itself. Additionally, Dr. Murphy is interested in examining the effects of RELAX10 in animals with more severely damaged hearts. For their part, AstraZeneca is moving forward with testing relaxin-based therapy in clinical trials with human patients.
Drug Improves Glucose Metabolism in Healthy Women by Activating Brown Fat
Obesity is an epidemic in the United States, with the majority of adults now considered either overweight or obese. That said, the human body contains more than one kind of fat. White fat cells store extra energy and are associated with obesity. This kind of fat is known to increase risk for type 2 diabetes, high blood pressure and other diseases. On the other hand, brown fat cells can burn blood sugar and the fat inside of them to create heat and help maintain body temperature.
Given brown fat’s unique actions, boosting its activity the body could be a great way to improve health by mitigating unhealthy weight gain. In a new NIH study, researchers led by Dr. Aaron Cypess examined whether a drug called mirabegron (currently approved by the FDA to treat an overactive bladder) could increase brown fat activity in healthy women. Mirabegron binds to proteins on the surface of cells that are believed to stimulate brown fat and also improve white fat’s ability to break down and release stored fat into bloodstream.
In this study, 14 healthy women ages 18-40 of diverse ethnicities were given 100 mg of mirabegron (twice the FDA-approved dose) for 4 weeks. In addition to performing positron emission tomography (PET/CT) scanning before and after the study to measure brown fat activity, researchers also measured blood sugar and insulin sensitivity, metabolism, cholesterol and other markers of heart health.
After 4 weeks of treatment, the women’s metabolism at rest was 6% higher, and brown fat activity had increased as well, with the largest changes found in the women with lowest brown fat activity to begin with. In addition, the women had higher levels of good cholesterol (HDL) and other markers indicating reduced risk of heart disease at the end of the study. Remarkably, insulin sensitivity increased by 36% over the course of the study, indicating a dramatic reduction in diabetes risk.
Study participants also experienced increases in resting heart rate, blood pressure and oxygen consumption by the heart while on the medication, and two women did report mild heart palpitation side effects. Fortunately, these symptoms were gone within two weeks of discontinuing the treatments.
The researchers are encouraged by the results of this study and intend to conduct further studies to determine if mirabegron has metabolic benefits in a wider range of adults (e.g., older adults, people with obesity, etc.). In addition, future studies will explore other drugs to see if they can produce similar results without the negative side effects experienced in this study.
Brain Mitochondria May Play a Role in Fatigue Caused by Cancer Treatments
For many cancer patients, disease treatment can cause fatigue that does not improve with sleep or rest. While guidelines exist to manage this condition, a lack of complete understanding of the cause of the exhaustion has limited doctor’s ability to address this issue with their patients. Theories on why cancer treatment causes clinical fatigue include treatment-induced tissue inflammation and red blood cell reduction (i.e., anemia).
A new NIH study led by IRP researcher Leorey N. Saligan, Ph.D. R.N. helps to shed some light on cancer treatment-induced fatigue. In this study, 64 volunteers with non-metastatic prostate cancer (NMPC) received the standard of care treatment for this disease – androgen deprivation therapy (ADT) and radiation therapy (RT). Dr. Saligan’s team found that patients who received both ADT and radiation experienced worse fatigue than those who were treated with radiation alone. In addition, researchers found that patients who experienced the worst fatigue in the course of their treatment had lower mitochondrial activity in white blood cells.
Next, in order to test the theory that cancer-related fatigue may stem in part from malfunctioning mitochondria in the brain, researchers gave mice radiation treatment, an ADT-like treatment, or both. Researchers noted that the mice receiving both radiation and ADT ran significantly less on their wheels in the three days after receiving radiation than the three days beforehand, while the mice that only received ADT did not show this change in activity. In addition, the mice receiving the radiation treatment showed a marked decrease in levels of two markers of mitochondrial health in the animals’ brains, suggesting that brain mitochondria may play a role in cancer treatment-induced fatigue.
Going forward, Dr. Saligan’s team plans to try to replicate these findings in patients receiving treatment for other types of cancer. In addition, they are collaborating with other IRP researchers to examine how exercise affects fatigue symptoms and mitochondrial function in blood cells, and also how dopamine receptor activity in the brain might relate to fatigue. The ultimate goal is to understand the biology of cancer treatment-induced fatigue, and also identify potential therapeutic targets that could help patients combat this condition.
The NIH sponsors a wide variety of talks, webinars and other events designed to help keep NIH researchers abreast of the latest and most important medical research in the United States and beyond. NIH institute-sponsored or related events held at or near the NIH’s Bethesda, Maryland, campus in the month of March can be found here.
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