The National Institutes of Health (NIH) is our nation’s medical research agency. Its mission focuses on 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 innovative NIH research.

Recent NIH Research

ALS drug shows promise in mouse model of rare childhood genetic disorder

New IRP research showed promising results for slowing the progression of Niemann-Pick disease type C1 (NPC1) using riluzole, an FDA approved drug for the treatment of amyotrophic lateral sclerosis (ALS). Niemann-Pick disease type C1 is an inherited, neurogenerative disorder that causes a massive accumulation of lipids in the liver, brain, spleen and bone marrow. Approximately 50% of cases of NPC1 present in childhood, before 10 years of age. There is no known cure for this fatal disease, other than symptomatic relief.

This rare metabolic disorder leads to the progressive deterioration of the nervous system and loss of function of the brain and other organs. NPC1 results from the impaired ability to transport cholesterol and other lipids through cells, leading to difficulty controlling movements, liver and lung disease, impaired swallowing, intellectual decline and death. Much of the movement difficulties in NPC1 result from a gradual loss of brain cells known as Purkinje neurons.

The collaborative study was conducted by Dr. Forbes Porter, senior investigator at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and colleagues in the National Human Genome Research Institute (NHGRI) and National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS).

The team of researchers discovered that mice with a form of NPC1 have a diminished ability to lower the levels of glutamate, a brain chemical that stimulates neurons after it has bound to a neuron’s surface. The team believes that the buildup of glutamate contributes to the brain cell loss seen in the disease, as high levels of glutamate are known to cause cell toxicity.

Riluzole, while it is not a cure for ALS, delays the progression of the disease in humans by blocking the release of glutamate. As part of the current study, mice with NPC1 that were treated with riluzole had a survival rate of 12% longer than untreated mice. The research team hypothesizes that riluzole or similar drugs may provide a viable way to slow disease progression in patients with NPC1.

Inflammation Contributes to Cancer-Related Fatigue

A recent IRP study led by the National Institute of Nursing Research (NINR) suggests that intense exhaustion experienced by cancer patients may be caused in part by inflammation resulting from radiation therapy.

Chemotherapy, a drug therapy used to stop the growth of cancer cells and prevent them from spreading, introduces potent chemicals into the bloodstream. Since chemotherapy effects healthy cells as well as cancer cells, it can cause extreme fatigue as the body fights to repair the damage caused by the treatment. Total body irradiation is known to have severe side effects include excessive fatigue or tiredness. However, even when radiation is targeted to just one area, it can still lead to debilitating cancer-related fatigue.

Dr. Leorey Saligan, senior investigator at NINR has studied the effect of targeted radiation treatment on patients with prostate cancer and noted that while they initially do not experience cancer-related fatigue, they do, however, develop debilitating fatigue following radiation treatment targeted to the prostate. As many as 40% of the treated patients will continue to experience chronic fatigue for as long as one to two years after the end of their treatment period.

As patients in the study had not reported experiencing fatigue from the cancer itself, Dr. Saligan and his research team investigated how the radiation treatment might be a cause of the extreme fatigue. Although there have been frequent reports of significant inflammation in patients with cancer-related fatigue, none had determined this to be the potential source of the fatigue.

The researchers used a mouse model of cancer-related fatigue to further explore the effects of inflammation following radiation treatment. In this study, it was noted that healthy male mice that received radiation targeted to the pelvis spent significantly less time running on their wheels than control mice not exposed to radiation. However, mice that were given minocycline, an antibiotic that also reduces inflammation, showed a noticeably smaller decrease in their wheel running than mice not given the antibiotic, though they still ran much less than mice that were not exposed to radiation. Similarly, after pelvic radiation treatment, mice lacking a gene involved in the body’s inflammatory response ran more on their wheels than genetically normal mice.

“This is a big first step to really show some causality between fatigue and inflammation,” says Dr. Saligan. “We’re hoping that with these initial results that show a causal relationship, we can provide avenues to address the role of inflammation in cancer-related symptoms such as fatigue.”

Extreme eating problems in early childhood linked to increased likelihood of developmental delay

Researchers at the Epidemiology Branch of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) have determined that young children with a history of eating problems during their first three years of life had a higher likelihood of receiving low scores on assessments of child development.

The findings suggest that children with multiple eating problems such as frequent crying during meals, pushing food away, and gagging while eating may benefit from screening for developmental delay. Early diagnosis of developmental disorders is key to getting children the help they need.

In this new study, led by IRP scientist Dr. Diane Putnick, NICHD, a team of researchers analyzed data on more than 3,500 children from Upstate KIDS, a study of children born between 2008 and 2010 in New York State. Mothers responded to questionnaires, rating their children’s eating patterns and developmental milestones when the children were 18, 24 and 30 months old. Compared to children who did not have eating problems, those who scored high on eating problems at one or two time points were more than twice as likely to miss a developmental milestone. Children with feeding problems at all three ages were four or more times as likely to miss a milestone.

The researchers noted that while feeding problems are not likely the cause of developmental delay, the problems associated with developmental delay, such as undiagnosed neurological issues, communication difficulties or lack of fine motor skills may underlie feeding problems. Children with feeding problems only at 18 and 24 months could potentially be the result of temporary variations in maturation, while feeding problems that persist until 30 months are at greatest risk for developmental delay and are the strongest candidates for screening.

Researchers target a mouse’s own cells, instead of antibiotics, to treat pneumonia

Researchers at the National Institute of Environmental Health Sciences (NIEHS) have discovered a novel method for the treatment of pneumococcal pneumonia, the leading cause of pneumonia deaths worldwide as reported by the World Health Organization (WHO).

While antibiotics are prescribed as the common course of treatment for bacterial pneumonia, caused by Streptococcus pneumoniae, the treatment is not always successful, and in some cases the bacteria even become resistant.

IRP scientist and co-lead author of the study, Dr. Matthew Edin, wanted to find a way to augment the body’s own immune system as an alternative method to resolve the infection. The research team focused on developing a therapy targeting host cells rather than bacterial cells in rodents.

To keep tissues healthy, epoxyeicosatrienoic acids (EETs) work to limit inflammation within the body, but during infections, such as bacterial pneumonia, inflammation ramps up after lung cells induce certain substances that prompt macrophages to digest the bacteria. The research team found that one way to get macrophages to eat more bacteria is to decrease the ability of EETs to limit inflammation. Using a synthetic molecule called EEZE to block EET activity boosted the eating capacity of the macrophages, leading to a reduction in the amount of bacteria in the lungs of mice. The scientists saw the same result when they placed bacteria and macrophages harvested from lung and blood samples of human volunteers in test tubes at the NIEHS Clinical Research Unit.

“EEZE is safe and effective in mice, but scientists could develop similar compounds to give to humans,” said Dr. Edin. “These new molecules could be used in an inhaler or pill to promote bacterial killing and make the antibiotics more effective.”

Repurposed cancer treatments could be potential Alzheimer’s drugs

According to a recent IRP study, existing and emerging cancer drugs showed promise for being repurposed as therapies to be tested in clinical trials for people at genetic risk of Alzheimer’s disease. The analysis of brain protein alterations in these individuals as well as laboratory experiments in animal models and cell cultures could assist scientists in quickly identifying existing drugs to test their potential as Alzheimer’s interventions.

Researchers from the National Institute on Aging (NIA) in collaboration with NIA-supported teams at the University of California, San Francisco; Rush University, Chicago; and the Icahn School of Medicine at Mount Sinai, New York City identified brain protein changes related to the APOE4 genetic risk variant in young postmortem study participants (average age at death was 39 years) and compared these changes with those in the autopsied brains of people with Alzheimer’s and those without (average age at death was 89 years). The analyses included brain samples from the Baltimore Longitudinal Study of Aging, the Religious Orders Study, and other NIA-funded studies. Existing FDA-approved or experimental drugs for other diseases were then tested for activity upon these proteins.

Their findings show that an experimental drug for the treatment of liver cancer and Dasatinib, an approved for chronic myeloid leukemia, was found to act upon some of the Alzheimer’s disease related proteins, suggesting they could be potential Alzheimer’s therapies. The drugs also reduced neuroinflammation, amyloid secretion, and tau phosphorylation in cell culture experiments, underscoring their potential as candidates to be tested in Alzheimer’s clinical trials.

Lung autopsies of COVID-19 patients reveal treatment clues

Scientists at the National Institutes of Health and their collaborators have a clearer picture of how SARS-CoV-2, the virus that causes COVID-19 disease, spreads and damages lung tissue. These important findings could assist in predicting severe and prolonged cases of COVID-19 and inform effective treatments, particularly among those at high risk.

A small study using lung and plasma samples autopsied from people who died of COVID-19 and had at least one high-risk condition such as diabetes, obesity or being elderly, revealed trends that could help develop new COVID-19 therapeutics and fine-tune when to use existing therapeutics at various stages of disease progression or caring for high-risk patients. The findings of the study include details about how SARS-CoV-2 spreads in the lungs, manipulates the immune system, causes widespread thrombosis that does not resolve, and targets signaling pathways that promote lung failure, fibrosis and impair tissue repair.

The study included patients who died between March and July 2020, with time of death ranging from 3 to 47 days following the onset of symptoms. This enabled the scientists to compare short, intermediate, and long-term cases. Every case showed findings consistent with diffuse alveolar damage, which prevents proper oxygen flow to the blood and eventually makes lungs thickened and stiff. The scientists also determined that SARS-CoV-2 directly infected basal epithelial cells within the lungs, impeding their essential function of repairing damaged airways and lungs and generating healthy tissue. The process is different from the way influenza viruses attack cells in the lungs, which provides scientists with additional information to use in the development of antiviral therapeutics.

Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) led the project in collaboration with the National Institute of Biomedical Imaging and Bioengineering | (nih.gov) and the FDA. Other collaborators included the Institute for Systems Biology in Seattle; University of Illinois, Champaign; Saint John’s Cancer Institute in Santa Monica, California.; the USC Keck School of Medicine in Los Angeles; University of Washington Harborview Medical Center, Seattle; University of Vermont Medical Center, Burlington; and Memorial Sloan Kettering Cancer Center in New York City.

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