National Institutes of Health (NIH) Research Updates – May 2020

Posted on NIH. 5 May, 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.

Recent NIH Research

Antiviral Remdesivir prevents Disease Progression in Monkeys with COVID-19

The experimental antiviral drug remdesivir, developed by Gilead Sciences Inc., has been shown to significantly reduce clinical disease and lung damage in SARS-Cov-2 infected rhesus macaques with treatment during the early stages of the disease.

In a current study supported by NIH’s National Institute of Allergy and Infectious Diseases (NIAID), scientists reported significant health improvements in monkeys treated with remdesivir while the untreated control group demonstrated symptoms of rapid and difficult breathing.  This finding coincided with decreased levels of virus and damage to the lungs of the treated group than in the untreated animals.

One group of monkeys received remdesivir while the second group served as an untreated comparison model. Scientists infected both groups with SARS-CoV-2. Following a twelve-hour period, the treatment group received a dose of remdesivir intravenously, followed by a daily intravenous booster dose thereafter for the next six days. The scientists timed the initial treatment to occur shortly before the virus reached its peak level as measured in the lungs.

In a multi-center clinical trial led by NIAID researchers, investigative data supports therapeutic remdesivir treatment following current dosing and treatment procedures in COVID-19 positive patients shows clear clinical benefit to slow progression of the disease. The findings in this preliminary report are pending peer review and should not be considered clinical advice but are being shared to assist the public health response to COVID-19.

Investigational chimp adenovirus MERS-CoV vaccine protects monkeys

An investigational vaccine called ChAdOx1 MERS has been shown to protect rhesus macaques from disease caused by Middle East respiratory syndrome coronavirus (MERS-CoV).  MERS-CoV is a relative of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease.

National Institutes of Health researchers are pursuing similar studies with ChAdOx1 SARS2, a vaccine candidate against SARS-CoV-2. Cases of MERS-CoV were first reported in humans in Saudi Arabia in 2012. The virus was likely transmitted to the human population from dromedary camels and can lead to pneumonia in infected individuals. the World Health Organization has received reports of 2,519 MERS-CoV cases and 866 deaths in 27 countries through January 2020.  Currently there are no commercially available vaccines to aid in the prevention of this disease.

In the recent study, one group of animals was vaccinated 28 days prior to infection, while a second group received two vaccinations—a prime-boost strategy—56 and 28 days prior to infection.  An untreated group of monkeys served as controls.  None of the vaccinated animals in the two groups developed signs of MERS-CoV disease. The prime-boost group clearly had less virus in lung tissue compared to the control group along with no evidence of replicating virus, while the prime-only group showed significantly less virus present in tissue than the control group. Neither of the treatment groups showed signs of lung damage and were protected from disease, unlike the control group.

Phase 1 human clinical trials are underway for the MERS vaccine in the United Kingdom and Saudi Arabia. The same chimpanzee adenovirus vaccine platform also is being evaluated for its effectiveness against malaria, HIV, influenza, hepatitis C, tuberculosis and Ebola.  Efforts are also underway to expedite the testing of a promising vaccine candidate against SARS-CoV-2.

NEI researchers link age-related DNA modifications to susceptibility to eye disease

Vision loss associated with age-related eye diseases are reportedly linked to changes in the regulation of gene expression.  Researchers at the National Eye Institute (NEI) are currently investigating the role of molecular changes and biological pathways associated with the aging rod photoreceptors, which are the light-sensing cells within the retina.  Findings from these studies will lead to a better understanding of how to prevent or delay further vision loss in the aging population while reducing the risk of macular degeneration.

The dynamic between an individual’s genome and the epigenome evolves throughout the aging process.  Information stored in DNA is responsible for the formation of protein and other molecules.  The epigenome modulates and tags the DNA code resulting in a modification of gene expression.  DNA methylation is an epigenetic mechanism that is necessary for the normal development and differentiation of cells. This mechanism is also interconnected with the potential formation of cancer throughout the aging process.

Dr. Anand Swaroop’s team at the NEI explored the impact that DNA modifications might have on visual function during biological aging.  Their work focused on whole genome sequencing of DNA methylation changes in mouse rod photoreceptors at four separate stages over the animal’s lifetime. The sequencing was performed at three stages across the 2-year lifespan of a mouse. The researchers then analyzed the differentially methylated regions with RNA sequencing data to observe how the mouse genes were transcribing proteins differently in the retina as the animals aged. The team uncovered distinct shifts in how the genes produced proteins relevant to energy metabolism, mitochondria function, and the longevity of rod photoreceptors, indicating their contribution to age-related disease susceptibility.

Age related macular degeneration (AMD) is the leading cause of vision loss in people aged 50 and older and can progress even in the absence of detectable vision loss.  Very few studies to date have looked at DNA methylation changes as a major contributing factor to the progression of this disease.

“Future studies will assess whether DNA methylation contributes to alterations in the expression of metabolic genes and thus introduce epigenomic editing as a therapeutic possibility for age-related retinal disease,” said the study’s first author, Ximena Corso-Díaz, Ph.D., a postdoctoral fellow in the Neurobiology, Neurodegeneration, and Repair Laboratory.

Single mutation leads to big effects in autism-related gene

A recent study conducted by a team of researchers at the National Institute of Neurological Disorders and Stroke (NINDS) shed light on why autism spectrum disorder (ASD) is more prevalent in boys than girls.  One of the key drivers associated with the development of ASD is the NLG4 gene.

The team compared the chromosomal differences between the NLGN4X and NLGNY genes which are important for maintaining neuronal communication points. Until recently the two genes were thought to be identical in functionality. It was discovered, however that the proteins encoded by these genes display different functions. The NLGN4Y protein is less able to move to the cell surface in brain cells and is therefore unable to assemble and maintain synapses, making it difficult for neurons to send signals to one another. When this error in functionality was scientifically manipulated, the researchers were able to restore much of its correct functionality.

Dr. Roche’s team found that the problems with NLGN4Y were due to a single amino acid. The researchers also discovered that the region surrounding that amino acid in NLGN4X is sensitive to mutations in the human population. There are a cluster of variants found in this region in people with ASD and intellectual disability and these mutations result in a deficit in function for NLGN4X that is indistinguishable from NLGN4Y. In females, when one of the NLGN4X genes has a mutation, the other one can often compensate. However, in males, diseases can occur when there is a mutation in NLGN4X because there is no compensation from NLGN4Y.  If a mutation is present in the NLGN4X gene the affects the protein levels, the NLGN4Y gene is not able to take over, as it functionally a different protein. The inability of NLGN4Y to compensate for mutations in NLGN4X can account for the reason why males, who only have one X chromosome tend to have a higher incidence of ASD than females.

As the study suggests that mutations in the NLGN4X may result in the occurrence of autism spectrum disorder, gaining a better understanding of these proteins will inform clinical treatment decisions for patients experiencing this disorder.

Autoimmunity may be rising in the United States

Autoimmunity, a condition in which the body’s immune system reacts with components of its own cells, appears to be increasing in the United States, according to researchers at the National Institute of Environmental Health Sciences (NIEHS). Autoimmune diseases represent a group of more than 100 chronic, debilitating conditions.

Antinuclear antibodies (ANA), the most common biomarker of autoimmunity, was found to be significantly increasing in the United States overall, particularly within certain demographic groups. These groups include males, non-Hispanic whites, adults 50 years and older, and adolescents. The study is the first to evaluate ANA changes over time in a representative sampling of the U.S. population.

In a study that included 14,211 participants, 12 years and older, scientists used immunofluorescence, a technique that uses fluorescent dye to visualize antibodies, to examine the frequencies of ANAs in subjects from three time periods. They found that ANA prevalence for 1988-1991 was 11.0%, while for 1999-2004 it was 11.5%, and for 2011-2012 it was 15.9%. These percentages corresponded to 22, 27, and 41 million affected individuals, respectively.

“The reasons for the increases in ANA are not clear, but they are concerning and may suggest a possible increase in future autoimmune disease,” said corresponding and senior author Frederick Miller, M.D., Ph.D., deputy chief of the Clinical Research Branch at the National Institute of Environmental Health Sciences (NIEHS), part of NIH. “These findings could help us understand more about the causes of these immune abnormalities and possibly learn what drives development of autoimmune diseases and how to prevent them.”

The findings in the adolescent group were the most worrisome to the research team. Young people, ages 12-19, had the largest ANA increases in the study, going from a two-fold to a three-fold increase over the three timeframes.

“These new findings may have important public health implications and will help us design studies to better understand why some people develop autoimmune diseases,” said Christine Parks, Ph.D., co-author and staff scientist in the NIEHS Epidemiology Branch.

 

About Jason Blaine

Jason Blaine Jason Blaine is the Managing Director of Astrix Technology Group’s Federal Division and is a recruiting expert in the Scientific field. He joined Astrix in 2011 and has been responsible for the startup and success of the division by growing it from its infancy and into an emerging leader in the NIH contracting arena. Mr. Blaine helps NIH’s Investigators: 1) navigate the process of recruitment and retention of highly qualified candidates, 2) navigate the contracting process at NIH and 3) navigate the immigration process of hiring scientific personnel who require visa sponsorship. Mr. Blaine brings to the role over 15 years of experience in contracting personnel with NIH specifically in the scientific, clinical research, clinical, professional, and administrative fields.

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