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National Institutes of Health (NIH) Research Updates – November 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

NIH begins large clinical trial to test immune modulators for treatment of COVID-19

The National Institutes of Health has launched an adaptive Phase 3 clinical trial to evaluate the safety and efficacy of three immune modulator drugs in adults that have been hospitalized due to COVID-19. Some COVID-19 patients experience an elevated immune response, known as a cytokine storm, in which the immune system unleashes excessive amounts of proteins that trigger inflammation. This condition can lead to acute respiratory distress syndrome, multiple organ failure and other life-threatening complications. The clinical trial is focused on determining if modulating that immune response can reduce the need for ventilators and shorten hospital stays. The trial, known as ACTIV-1 Immune Modulators (IM), will determine if the therapeutics are able to restore balance to an overactive immune system.

The trial expects to enroll approximately 2,100 hospitalized adults with moderate to severe COVID-19 at medical facilities throughout the United States and Latin America. The National Center for Advancing Translational Sciences (NCATS) will coordinate and oversee the trial as part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative, which focuses efforts on therapies that hold the greatest promise in the treatment of COVID-19.  “Immune modulators provide another treatment modality in the ACTIV therapeutic toolkit to help manage the complex, multi-system conditions that can be caused by this very serious disease” said NIH Director Dr. Francis Collins.

ACTIV-1 IM is an adaptive master protocol an adaptive master protocol that allows a coordinated and efficient evaluation of multiple investigational agents as they become available. This enables maximum flexibility to quickly eliminate drugs that do not demonstrate effectiveness, identify those that do in a short time frame and rapidly incorporate additional experimental agents into the trial.

The ACTIV consortium selected three agents for the study from a pool of over 130 immune modulators.  The initial review of these modulators was based upon their relevance to COVID-19, strong evidence for use against inflammatory reaction resulting from cytokine storm, and the availability for large-scale clinical studies. The initial agents are infliximab (REMICADE), developed by Janssen Research & Development, LLC.; abatacept (ORENCIA), developed by Bristol Myers Squibb; and Cenicriviroc (CVC), developed by AbbVie.

All trial participants will receive remdesivir, developed by Gilead Sciences, which is the current standard of care treatment of hospitalized patients with COVID-19. Convalescent plasma and dexamethasone will be allowed at the discretion of the site investigator and in accordance with national guidelines. The study participants will be randomly assigned to receive either a placebo or one of the immune modulators as an add-on treatment. The trial will then evaluate the various combinations of treatment regimens with respect to the severity of illness, speed of recovery, mortality rate and utilization of hospital resources.

The trial is expected to last for approximately six months and is currently open for enrollment.  The results from the study will be made available upon completion of the trial, or possibly sooner if analysis conducted during the trial indicates that one or more of the drugs has shown beneficial results.  An independent data and safety monitoring board will oversee the trial, while performing periodic reviews of the data to ensure that the trial is conducted in a safe and effective manner.

The NIH announced the ACTIV initiative in April 2020 to develop a national research response to prioritize and speed the development of the most promising COVID-19 treatments and vaccines. Coordinated by the Foundation for the National Institutes of Health, ACTIV brings together partners from government, industry, academia and non-profit organizations.

Using Flatworm Regeneration to Study Stem Cells

In a recent study by the National Cancer Institute (NCI), investigator Erin Davies is the first IRP researcher to use flatworm stem cells to unlock the mysteries surrounding regenerative medicine.  Planaria (Schmidtea mediterranea), otherwise known as flatworms, have an amazing capacity to self-regenerate.  If you were to cut a planarian down the middle, each half would reform its missing parts, and you would have two planarians in a matter of weeks. Although humans and other mammals have some regenerative ability, such as the ability to heal wounds, we are not nearly as capable as these flatworms.

Planarians, a long-lived species that can reproduce both sexually and asexually, have adult pluripotent stem cells (PSCs) that promote tissue homeostasis and regeneration. In the majority of animals, including mammals, PSCs are only present in embryos and are primarily responsible for the development of organs, limbs, and tissues.

“The planarian has found a way to sustain embryonic pluripotency programs throughout [its] life cycle,” Davies explained. What’s more, planarian PSCs can readily proliferate without causing the organism to age or develop cancer.

Davies research is focused on exploring whether the nature of planarian pluripotency changes throughout the life cycle and how that pluripotency is maintained. Using the planarian as an animal model to explore stem cells at varying developmental stages could lead to a greater understanding of the regenerative system, thereby having implications for the treatment of cancer, degenerative diseases, and other conditions.

“I think that there are a number of unique opportunities in not only planarians, but other lower invertebrates…to address key concepts and principles, like the evolution of tumor suppression or other facets,” said Davis. The extraordinary system of regeneration in the planarian offers a compelling new tool for studying stem-cell biology that could provide important insights into many diseases including cancer.

Scientists use clues in the human genome to discover new inflammatory syndrome

Chronic inflammation is a condition resulting from tissue damage due to autoimmune disorders, trauma, infection or exposure to toxic substances. Nearly 125 million people in the U.S. are living with chronic inflammatory conditions.  Many of these diseases have overlapping symptoms, making it difficult for researchers to diagnose the specific inflammatory disease in a given patient.

Researchers from the National Institutes of Health (NIH) have discovered a new inflammatory disorder called vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome (VEXAS), which is caused by mutations in the UBA1 gene. VEXAS causes symptoms that included blood clots in veins, recurrent fevers, pulmonary abnormalities and vacuoles (unusual cavity-like structures) in myeloid cells.

“We had many patients with undiagnosed inflammatory conditions who were coming to the NIH Clinical Center, and we were just unable to diagnose them,” said Dr. David Beck, clinical fellow at NHGRI and lead author of the paper. “That’s when we had the idea of doing it the opposite way. Instead of starting with symptoms, start with a list of genes. Then, study the genomes of undiagnosed individuals and see where it takes us.”

The research team at the National Human Genome Research Institute (NHGRI), along with collaborators from other NIH Institutes studied genome sequences from over 2,500 individuals with undiagnosed inflammatory diseases.  Their focus was on a set of over 800 genes related to the process of ubiquitylation, which helps regulate both various protein functions inside a cell and the immune system overall. They found a gene that is closely linked to VEXAS, a disease which can be life-threatening, resulting in the death of 40% of the VEXAS patients in the study.

“Our objective was to see if any of the 2,560 patients shared variations in the same gene,” said Dr. Daniel Kastner, scientific director of the Intramural Research Program at NHGRI.  “Instead of looking at clinical similarities, we were instead taking advantage of shared genomic similarities that could help us discover a completely new disease.”

Out of the 800 genes, one stood out. Three middle-aged males appeared to have two copies of the UBA1 gene, one copy having rare and potentially damaging genomic variants. While humans usually have two copies of every gene, the UBA1 gene resides in the X chromosome, and males have only one X chromosome (and one Y chromosome).  “We were amazed to see this and wondered what it could mean. And that’s when it clicked—this was only possible if there was mosaicism in these men,” said Dr. Beck.

Mosaicism occurs when a person has two or more genetically different sets of cells in their body.  The team predicted that there were specific cells in the patients’ bodies that carried the UBA1 gene in its normal form while other cells carried the gene in its mutated form.  Through DNA-sequencing, the researchers discovered that mosaicism was in fact present in the patients’ myeloid cells, which are responsible for systemic inflammation and act as the front line of defense against infections.

The researchers then analyzed the genome sequences of individuals from various NIH cohorts and databases, leading to the discovery of an additional 22 adult males with the UBA1 gene mutations. The majority of those individuals were symptomatic for blood clots in veins, recurrent fevers, or pulmonary abnormalities and vacuoles in the myeloid cells.

Out of the combined 25 individuals, researchers identified a link between the various clinical rheumatologic and blood-related diagnoses made for the patients. Because these conditions exist in people with UBA1 mutations, the team grouped the various conditions into a new disease: VEXAS.  “By using this genome-first approach, we have managed to find a thread that ties together patients carrying all of these seemingly unrelated, disparate diagnoses,” Dr. Kastner said.

This new genome-first strategy shows promise for helping healthcare professionals to improve disease assessments and provide targeted treatments for thousands of patients who have various inflammation-related conditions. The study may also lay the foundation for a new and more appropriate classification of inflammatory diseases.

Postpartum depression may persist three years after giving birth

In a recent study conducted by researchers at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), it was found that approximately 1 in 4 women, from a group of 5,000 women, experienced high levels of depressive symptoms within three years after giving birth. The rest of the women in the study experienced low levels of depression throughout the three-year span.

The American Academy of Pediatrics recommends that pediatricians screen mothers for postpartum depression at well-child visits at one, two, four and six months following childbirth. The team identified four trajectories of postpartum depressive symptoms along with the factors that may increase a woman’s risk for elevated symptoms. Their findings suggest that extending screening for postpartum depressive symptoms for at least two years after childbirth may be beneficial.

Researchers assessed women’s symptoms through a five-item depression screening questionnaire, but the study did not clinically diagnose depression in the women. It was also noted that women with underlying conditions, such as mood disorders and/or gestational diabetes, were more likely to have higher levels of depressive symptoms that persisted throughout the study period.

“Our study indicates that six months may not be long enough to gauge depressive symptoms,” said Dr. Diane Putnick, scientist in the NICHD Epidemiology Branch and primary author of the study. Longer term studies will play an important role in improving our understanding of the mental health of women post childbirth, which is critical to the well-being of the mother and child.

Calendar of Events

Friday, November 6, 2020, 11:00 am to 3:25 pm
NIH SARS-CoV-2 Antiviral Therapeutics Summit

Monday, November 16, 2020 to Tuesday, November 17, 2020 (registration required)
Enhancers, Gene Regulation and Genome Organization

Monday, November 16, 2020 to Thursday, December 17, 2020 (registration required)
Multidisciplinary Approaches to Understand Cancer Treatment Resistance