Research advances from the National Institutes of Health (NIH) Intramural Research Program (IRP) often make headlines. Read the news releases that describe our most recent findings:
Whether you’re shedding pounds with the help of effective new medicines, slimming down after weight loss surgery or cutting calories and adding exercise, there will come a day when the numbers on the scale stop going down, and you hit the dreaded weight loss plateau.
In a recent study, Kevin Hall, a researcher at the National Institutes of Health who specializes in measuring metabolism and weight change, looked at when weight loss typically stops depending on the method people were using todrop pounds. He broke down the plateau into mathematical models using data from high-quality clinical trials of different ways to lose weight to understand why people stop losing when they do. The study published Monday in the journal Obesity.
For patients with cancers that do not respond to immunotherapy drugs, adjusting the composition of microorganisms in the intestines — known as the gut microbiome — through the use of stool, or fecal, transplants may help some of these individuals respond to the immunotherapy drugs, a new study suggests. Researchers at the National Cancer Institute (NCI) Center for Cancer Research, part of the National Institutes of Health, conducted the study in collaboration with investigators from UPMC Hillman Cancer Center at the University of Pittsburgh.
In the study, some patients with advanced melanoma who initially did not respond to treatment with an immune checkpoint inhibitor, a type of immunotherapy, did respond to the drug after receiving a transplant of fecal microbiota from a patient who had responded to the drug. The results suggest that introducing certain fecal microorganisms into a patient’s colon may help the patient respond to drugs that enhance the immune system’s ability to recognize and kill tumor cells. The findings appeared in Science on February 4, 2021.
“In recent years, immunotherapy drugs called PD-1 and PD-L1 inhibitors have benefited many patients with certain types of cancer, but we need new strategies to help patients whose cancers do not respond,” said study co-leader Giorgio Trinchieri, M.D., chief of the Laboratory of Integrative Cancer Immunology in NCI’s Center for Cancer Research. “Our study is one of the first to demonstrate in patients that altering the composition of the gut microbiome can improve the response to immunotherapy. The data provide proof of concept that the gut microbiome can be a therapeutic target in cancer.”
An experimental single-dose, intranasal influenza vaccine was safe and produced a durable immune response when tested in a Phase 1 study published in the Journal of Clinical Investigation. The investigational vaccine, called Ad4-H5-VTN, is a recombinant, replicating adenovirus vaccine designed to spur antibodies to hemagglutinin, a protein found on the surface of influenza viruses that attaches to human cells.
The investigational vaccine was developed by Emergent Biosolutions Inc., (Gaithersburg, Maryland). It was administered intranasally (28 study participants), as an oral capsule (10 participants) and via a tonsillar swab (25 participants) to healthy men and non-pregnant women ages 18 to 49 years.
The participants who received the vaccine intranasally or via tonsillar swab showed significantly higher H5-specific neutralizing antibody levels compared to the group receiving the vaccine capsule orally. The participants who received the intranasal vaccine shed viral DNA for two-to-four weeks, but virus could be cultured for a median of only one day. Participants had evidence of H5-specific CD4+ and CD8+ T-cell responses. Additionally, volunteers who received the intranasal vaccine had high levels of serum neutralizing antibodies at 26 weeks after vaccination, and this level was unchanged at three to five years after a single intranasal dose of the vaccine. The duration of viral shedding correlated with a high magnitude of neutralizing antibody response at week 26. In addition, the intranasal vaccine induced a mucosal antibody response in the nose, mouth, and rectum.
3D print of influenza virus. The virus surface (yellow) is covered with proteins called hemagglutinin (blue) and neuraminidase (red) that enable the virus to enter and infect human cells.
Researchers at the National Institutes of Health and their collaborators found that inhaling unfragmented hyaluronan improves lung function in patients suffering from severe exacerbation of chronic obstructive pulmonary disease (COPD). Hyaluronan, a sugar secreted by living tissue that acts as a scaffold for cells, is also used in cosmetics as a skin moisturizer and as a nasal spray to moisturize lung airways. Utilized as a treatment, hyaluronan shortened the amount of time COPD patients in intensive care needed breathing support, decreased their number of days in the hospital, and saved money by reducing their hospital stay.
The study, published online in Respiratory Research, is a good example of how examining the impacts of environmental pollution on the lungs can lead to viable treatments. Several years ago, co-senior author Stavros Garantziotis, M.D., medical director of the Clinical Research Unit at the National Institute of Environmental Health Sciences (NIEHS), part of NIH, showed that exposure to pollution causes hyaluronan in the lungs to break down into smaller fragments. These fragments irritate lung tissue and activate the immune system, leading to constriction and inflammation of the airways. He determined that inhalation of healthy, unfragmented hyaluronan reduces inflammation by outcompeting the smaller hyaluronan fragments.
Garantziotis offered an analogy for how the inflammation occurs. He said hyaluronan surrounds cells like mortar surrounds bricks. Introducing pollution causes cracks in the mortar, breaking it into smaller chunks.
"These smaller chunks irritate the body and activate the immune system, leading to inflammation," Garantziotis said. "Reintroducing the full-length hyaluronan, like a fresh coat of mortar, means it is less irritating and reduces the amount of inflammation."
Research shows that inhaling hyaluronan interferes at almost every step of the COPD cycle, making it a potent treatment for chronic lung disease.
Findings indicate cones precede rods as targets for infection
The earliest eye damage from prion disease takes place in the cone photoreceptor cells, specifically in the cilia and the ribbon synapses, according to a new study of prion protein accumulation in the eye by National Institutes of Health scientists. Prion diseases originate when normally harmless prion protein molecules become abnormal and gather in clusters and filaments in the human body and brain.
Understanding how prion diseases develop, particularly in the eye because of its diagnostic accessibility to clinicians, can help scientists identify ways to slow the spread of prion diseases. The scientists say their findings, published in the journal Acta Neuropathologica Communications, may help inform research on human retinitis pigmentosa, an inherited disease with similar photoreceptor degeneration leading to blindness.
Prion diseases are slow, degenerative and usually fatal diseases of the central nervous system that occur in people and some other mammals. Prion diseases primarily involve the brain, but also can affect the eyes and other organs. Within the eye, the main cells infected by prions are the light-detecting photoreceptors known as cones and rods, both located in the retina.
(left panel) Early in prion infection, a prion protein aggregate (magenta) blocks the entrance to a cilium (green) in a retinal photoreceptor. (lower right) In prion-infected retina, prion protein (magenta) accumulates under the horseshoe-shaped ribbon synapses (green) found in photoreceptor terminals.
Approach could provide new path for difficult-to-treat forms of Leber congenital amaurosis
Scientists at the National Eye Institute (NEI) have developed a promising gene therapy strategy for a rare disease that causes severe vision loss in childhood. A form of Leber congenital amaurosis, the disease is caused by autosomal-dominant mutations in the CRX gene, which are challenging to treat with gene therapy. The scientists tested their approach using lab-made retinal tissues built from patient cells, called retinal organoids. This approach, which involved adding copies of the normal gene under its native control mechanism, partially restored CRX function. The study report appears today in Stem Cell Reports. NEI is part of the National Institutes of Health.
“Our treatment approach, which adds more copies of the normal gene, could potentially treat autosomal-dominant LCA caused by a variety of mutations,” said Anand Swaroop, Ph.D., chief of the NEI Neurobiology, Neurodegeneration and Repair Laboratory and senior author of the report.
The U.S. Food and Drug Administration approved Luxturna in 2017 for the treatment of LCA patients with mutations in a gene called RPE65. Although hailed as a major advance in gene therapy, Luxturna is ineffective against other forms of LCA, including those caused by autosomal-dominant mutations in CRX.
Fluorescently labeled organoid showing columnal cells in outer ring.
Results will inform development of long-acting antibody-based HIV prevention tools
An investigational anti-HIV antibody delivered intravenously once every eight weeks safely and effectively prevented acquisition of HIV strains sensitive to that antibody, but did not significantly reduce overall HIV acquisition after 80 weeks among participants in two multinational clinical trials. Known as the Antibody-Mediated Prevention (AMP) Studies, the Phase 2b trials are sponsored and funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The studies are being conducted jointly by the HIV Vaccine Trials Network (HVTN) and HIV Prevention Trials Network (HPTN).
While currently available HIV treatment and prevention tools have greatly reduced transmission of the virus, there remains a need for long-acting HIV prevention strategies that are acceptable and desirable to people from diverse communities worldwide. Broadly neutralizing antibodies (bNAbs), which arise naturally in some people living with HIV and can stop a wide range of HIV strains from infecting human cells in the laboratory, are considered promising candidates for long-acting HIV prevention. These antibodies could be given directly by either infusion or injection or could be elicited by an HIV vaccine.
Launched in 2016, the AMP Studies aimed to establish whether infusions of a bNAb called VRC01 are safe, tolerable and effective at preventing HIV acquisition. The NIAID Vaccine Research Center (VRC) discovered VRC01 in 2010 in the blood of a person living with HIV and subsequently manufactured the antibody for the AMP Studies. The two trials included more than 4,600 participants. Men and transgender people who have sex with men were enrolled in the Americas and Europe — geographic regions where HIV subtype B predominates. Women were enrolled in sub-Saharan Africa, where HIV subtype C is dominant. Results will be discussed at a press conference and oral presentation during the 4th HIV Research for Prevention Conference.
Scanning electromicrograph of an HIV-infected T cell.
Contrary to previous findings, low-dose aspirin therapy before conception and during early pregnancy may increase pregnancy chances and live births among women who have experienced one or two prior miscarriages, suggests a study by researchers at the National Institutes of Health. Rather than looking solely at the difference in pregnancy rates between women who were given aspirin and those receiving a placebo, the study also accounted for differences in total aspirin use between women who deviated from the daily regimen and those who adhered to it.
Published in 2014, the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial included more than 1,000 women between 18 and 40 years old with one or two previous miscarriages. The women received either daily low-dose aspirin (81 milligrams) or a placebo while trying to conceive. If they did conceive, they would continue to receive this regimen through the 36th week of pregnancy. Although the study found no overall difference in pregnancy loss rates between the two groups, there was a higher birthrate for the subgroup of women who had experienced only one previous miscarriage before the 20th week of pregnancy.
Unlike the original analysis, the current reanalysis considered whether a participant adhered to the treatment or skipped days or discontinued it entirely for side effects such as bleeding, nausea or vomiting. Compared to the placebo group, for every 100 women, adhering to the aspirin regimen for five to seven days a week led to eight more positive pregnancy tests, six fewer pregnancy losses, and culminated in 15 more live births. Women who adhered to the therapy four days per week experienced similar results. The researchers concluded that taking low-dose aspirin at least four days per week could improve the odds for pregnancy and live birth in this group of women.
Analysis of patients with rare condition uncovers key pathway for human development
Researchers at the National Institutes of Health have discovered a new genetic disorder characterized by developmental delays and malformations of the brain, heart and facial features. Named linkage-specific-deubiquitylation-deficiency-induced embryonic defects syndrome (LINKED), it is caused by a mutated version of the OTUD5 gene, which interferes with key molecular steps in embryo development. The findings indicate that the newly identified pathway may be essential for human development and may also underlie other disorders that are present at birth. The information will help scientists better understand such diseases — both common and rare — and improve patient care. The results were reported Jan. 20, 2021 in Science Advances.
“Our discovery of the dysregulated neurodevelopmental pathway that underlies LINKED syndrome was only possible through the teamwork of geneticists, developmental biologists and biochemists from NIH,” said Achim Werner, Ph.D., an investigator at the National Institute of Dental and Craniofacial Research (NIDCR) and lead author. “This collaboration provided the opportunity to pinpoint the likely genetic cause of disease, and then take it a step further to precisely define the sequence of cellular events that are disrupted to cause the disease.”
The project began when David B. Beck, M.D., Ph.D., a clinical fellow in the laboratory of Dan Kastner M.D., Ph.D., at the National Human Genome Research Institute (NHGRI) and co-first author, was asked to consult on a male infant who had been born with severe birth defects that included abnormalities of the brain, craniofacial skeleton, heart and urinary tract. An in-depth examination of siblings’ and family members’ genomes, combined with genetic bioinformatics analyses, revealed a mutation in the OTUD5 gene as the likely cause of the condition. Through outreach to other researchers working on similar problems, Beck found seven additional males ranging from 1 to 14 years of age who shared symptoms with the first patient and had varying mutations in the OTUD5 gene.
Compared to a disease-free mother (left), differentiated LINKED patient cells (right) lack markers of normal development of the brain, spinal cord and craniofacial skeleton (pink, green and yellow). Image credit: Werner lab, NIDCR
People on a low-fat, plant-based diet ate fewer daily calories but had higher insulin and blood glucose levels, compared to when they ate a low-carbohydrate, animal-based diet, according to a small but highly controlled study at the National Institutes of Health. Led by researchers at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the study compared the effects of the two diets on calorie intake, hormone levels, body weight, and more. The findings, published in Nature Medicine, broaden understanding of how restricting dietary carbohydrates or fats may impact health.
“High-fat foods have been thought to result in excess calorie intake because they have many calories per bite. Alternatively, high-carb foods can cause large swings in blood glucose and insulin that may increase hunger and lead to overeating,” said NIDDK Senior Investigator Kevin Hall, Ph.D., the study’s lead author. “Our study was designed to determine whether high-carb or high-fat diets result in greater calorie intake.”
The researchers housed 20 adults without diabetes for four continuous weeks in the NIH Clinical Center’s Metabolic Clinical Research Unit. The participants, 11 men and nine women, received either a plant-based, low-fat diet or an animal-based, low-carbohydrate diet for two weeks, immediately followed by two weeks on the alternate diet. The low-fat diet was high in carbohydrates. The low-carbohydrate diet was high in fats. Both diets were minimally processed and had equivalent amounts of non-starchy vegetables. The participants were given three meals a day, plus snacks, and could eat as much as desired.
Examples of dinners given to study participants: low-carb, animal-based diet (left) and low-fat, plant-based diet (right). Image credit: Amber Courville and Paule Joseph
NIH study finds biggest increase among American Indians and Alaska Natives
Methamphetamine overdose deaths surged in an eight-year period in the United States, according to a study that will published today in JAMA Psychiatry. The analysis revealed rapid rises across all racial and ethnic groups, but American Indians and Alaska Natives had the highest death rates overall. The research was conducted at the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health.
Deaths involving methamphetamines more than quadrupled among non-Hispanic American Indians and Alaska Natives from 2011-2018 (from 4.5 to 20.9 per 100,000 people) overall, with sharp increases for both men (from 5.6 to 26.4 per 100,000 from 2011-2018) and women (from 3.6 to 15.6 per 100,000 from 2012-2018) in that group. The findings highlight the urgent need to develop culturally tailored, gender-specific prevention and treatment strategies for methamphetamine use disorder to meet the unique needs of those who are most vulnerable to the growing overdose crisis. Long-term decreased access to education, high rates of poverty and discrimination in the delivery of health services are among factors thought to contribute to health disparities for American Indians and Alaska Natives.
“While much attention is focused on the opioid crisis, a methamphetamine crisis has been quietly, but actively, gaining steam—particularly among American Indians and Alaska Natives, who are disproportionately affected by a number of health conditions,” said Nora D. Volkow, M.D., NIDA director and a senior author of the study. “American Indian and Alaska Native populations experience structural disadvantages but have cultural strengths that can be leveraged to prevent methamphetamine use and improve health outcomes for those living with addiction.”
Non-Hispanic American Indians and Alaska Natives: Overdose deaths involving methamphetamine rose from 4.5 to 20.9 per 100,000 people ages 25 to 54 during 2011-2018.
