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.
NIH study highlights the need to proactively screen for, prevent, and treat cannabis use disorder especially among young people
Young men with cannabis (marijuana) use disorder have an increased risk of developing schizophrenia, according to a study led by researchers at the Mental Health Services in the Capital Region of Denmark and the National Institute on Drug Abuse (NIDA) at the National Institutes of Health. The study, published in Psychological Medicine, analyzed detailed health records data spanning five decades and representing more than six million people in Denmark to estimate the fraction of schizophrenia cases that could be attributed to cannabis use disorder on the population level.
Researchers found strong evidence of an association between cannabis use disorder and schizophrenia among men and women, though the association was much stronger among young men. Using statistical models, the study authors estimated that as many as 30 percent of cases of schizophrenia among men aged 21-30 might have been prevented by averting cannabis use disorder.
Cannabis use disorder and schizophrenia are serious, but treatable, mental disorders that can profoundly impact people’s lives. People with cannabis use disorder are unable to stop using cannabis despite it causing negative consequences in their lives. Schizophrenia is a serious mental illness that affects how a person thinks, feels, and behaves. People with schizophrenia may seem like they have lost touch with reality, and the symptoms of schizophrenia can make it difficult to participate in usual, everyday activities. However, effective treatments are available for both cannabis use disorder and schizophrenia.
“The entanglement of substance use disorders and mental illnesses is a major public health issue, requiring urgent action and support for people who need it,” said NIDA Director and study coauthor Nora Volkow, M.D. “As access to potent cannabis products continues to expand, it is crucial that we also expand prevention, screening, and treatment for people who may experience mental illnesses associated with cannabis use. The findings from this study are one step in that direction and can help inform decisions that health care providers may make in caring for patients, as well as decisions that individuals may make about their own cannabis use.”
Idiopathic CD4 lymphocytopenia leaves immune system vulnerable to other diseases, cancers
In an 11-year study, researchers at the National Institutes of Health have further characterized idiopathic CD4 lymphocytopenia (ICL), a rare immune deficiency that leaves people vulnerable to infectious diseases, autoimmune diseases and cancers. Researchers observed that people with the most severe cases of ICL had the highest risk of acquiring or developing several of the diseases associated with this immune deficiency. This study, published in the New England Journal of Medicine, was led by Irini Sereti M.D., M.H.S., and Andrea Lisco, M.D., Ph.D., of the HIV Pathogenesis Section in the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, and conducted at the NIH Clinical Center.
ICL is a condition marked by too few CD4+ T-cells, which are a type of white blood cell. The clinical definition of ICL is a CD4+ T-cell count of less than 300 cells per cubic millimeter (mm³) of blood for at least six weeks, in the absence of any disease or therapy associated with reduced white blood cells. Unlike HIV, a virus that suppresses the immune system if left untreated, there is no evidence that ICL is transmitted from person to person, and it has no known cause. There are limited therapeutic options for ICL.
In this observational study, the NIAID researchers quantified immune cells and noted the presence of opportunistic infections—infections that typically only affect people with suppressed immune systems—and other clinical conditions among 91 participant volunteers with ICL. The most prevalent opportunistic infections were human papillomavirus-related diseases (in 29 percent of participants), cryptococcosis (24 percent), molluscum contagiosum (9 percent), and mycobacterial diseases other than tuberculosis (5 percent). Participants with CD4+ T-cell counts below 100 cells per mm³ had a more than five-fold higher risk of opportunistic infections than those with CD4+ T-cell counts above 100 cells. Cancer risk was also higher in individuals with the lowest CD4+ T-cell counts, but the risk of autoimmune disease was lower.
Scanning electron micrograph of a human T cell from the immune system of a healthy donor. In multiple sclerosis, certain kinds of T cells are involved in the immune system’s attack on the central nervous system.
Researchers have found the “Eat, Sleep, Console” (ESC) care approach to be more effective than using the Finnegan Neonatal Abstinence Scoring Tool (FNAST) to assess and manage opioid-exposed newborns, according to a national, randomized controlled clinical trial funded by the National Institutes of Health. Newborns cared for with ESC were medically ready for discharge approximately 6.7 days earlier and 63% less likely to receive medication as part of their treatment, compared to newborns cared for with FNAST. ESC prioritizes non-pharmacologic approaches to care, such as a low-stimulation environment, swaddling, skin-to-skin contact and breastfeeding. ESC also encourages parental involvement in the care and assessment of their infants. These findings are based on the hospital outcomes of a large and geographically diverse group of opioid-exposed infants. A two-year follow-up study of a subset of infants is ongoing. The current findings are published in the New England Journal of Medicine.
“Medical care for newborns who were exposed to opioids during pregnancy varies widely across hospitals,” said Diana W. Bianchi, M.D., director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), which co-led the study with the NIH Environmental Influences on Child Health Outcomes (ECHO) Program. “These findings are an important step toward standard, evidence-based guidance for the care of these infants.”
Opioid-exposed newborns may develop symptoms of neonatal opioid withdrawal syndrome (NOWS), which includes tremors; excessive crying and irritability; and problems with sleeping and feeding. For the past 50 years, FNAST has been the traditional assessment tool for infants with NOWS. FNAST is an extensive scoring system that assesses signs of withdrawal in more than 20 areas. Concerns have been raised about its subjectivity and overestimation of the need for opioid medication.
Results from a clinical trial conducted by researchers at the National Institutes of Health (NIH) show that people with low-grade lymphomatoid granulomatosis who are treated with interferon alfa-2b, a type of immunotherapy, can live for decades after diagnosis. Lymphomatoid granulomatosis is a rare precancerous condition triggered by Epstein-Barr virus infection. Left untreated, the disease can progress to a high-grade form, which has a poorer prognosis and can quickly turn into an aggressive and fatal B-cell lymphoma.
In the phase 2 trial, led by researchers in the Center for Cancer Research at the National Cancer Institute (NCI), part of NIH, patients treated with interferon alfa-2b lived for a median of about 20 years. By contrast, past studies reported a median survival of less than two years for people with lymphomatoid granulomatosis.
The findings suggest that immunotherapy can prevent the progression of low-grade disease to high-grade disease. The results were published March 31, 2023, in Lancet Haematology.
“We have shown in this rare disorder that using a novel immunotherapy-based approach for low-grade disease is effective and improves survival compared with historical treatments such as chemotherapy and corticosteroids,” said Christopher J. Melani, M.D., of NCI’s Center for Cancer Research, who co-led the study. “I think the results of this study represent a significant contribution to determining the standard-of-care treatment for this rare disease.”
Treatment with interferon alfa-2b led to the disappearance of a large lesion (top image) in the lungs of a patient with lymphomatoid granulomatosis, as shown in this computed tomography chest scan.
Medication is the first to reduce bone-weakening process in patients with fibrous dysplasia
A clinical trial at the National Institutes of Health found that a medication, denosumab, significantly reduced abnormal bone turnover in adults with fibrous dysplasia, a rare disease marked by weak and misshapen bones. Bone turnover, a process in which old bone is continuously replaced with new bone, is unusually accelerated in fibrous dysplasia and contributes to bone abnormalities. The study of eight participants was carried out by researchers from the National Institute of Dental and Craniofacial Research (NIDCR) and the NIH Clinical Center. The results, which showed that denosumab may improve patients’ quality of life by enabling healthy bone formation, were published as a correspondence report in the New England Journal of Medicine.
Fibrous dysplasia stems from gene mutations that cause scar-like (fibrous) tissue to replace healthy bone starting in early childhood. These fibrous lesions, which are marked by accelerated bone turnover, weaken bones, leading to bone deformities, fractures, physical disabilities, and pain. In some cases, the lesions can press up against organs and nerves, impairing functions like vision and breathing.
“Surgery is still the standard treatment for fractures and deformities caused by fibrous dysplasia,” said senior author Alison Boyce, M.D., a clinical investigator at NIDCR. “Denosumab is the first medication that appears to affect how fibrous dysplasia lesions behave and improves patients’ disease outcomes.”
Bone scans of a patient before (left) and after (right) a six-month denosumab treatment show reduced turnover within fibrous dysplasia lesions (dark-colored patches).
A study from the National Eye Institute (NEI) identified rare genetic variants that could point to one of the general mechanisms driving age-related macular degeneration (AMD), a common cause of vision loss in older adults. The variants generate malformed proteins that alter the stability of the membrane attack complex (MAC), which may drive a chronic inflammatory response in the retina. The findings, published in the journal iScience, point to MAC as a potential therapeutic target to slow or prevent the development of AMD. NEI is part of the National Institutes of Health.
There are many known genetic variants that raise or lower an individual’s risk of getting AMD; however, the contribution of each of these genetic changes to AMD is small.
To discover genetic variants — and proteins — with a direct tie to the disease, Anand Swaroop, Ph.D., chief of NEI’s Neurobiology, Neurodegeneration and Repair Laboratory, and lead author of the study, undertook a collaboration with Michael Klein, M.D., a leading AMD clinician at the Oregon Health Sciences University (OHSU), Portland. Klein has collected clinical information for hundreds of patients, as well as families with a high number of individuals with AMD. Swaroop, Klein and colleagues looked for families carrying very rare AMD-causing variants, where the effect of the gene variant is very strong, and where the variant directly affects protein structure and function. This type of rare variant can reveal the root cause of disease.
Strategy may speed delivery of therapeutic options relative to time it would take to develop gene therapies
A National Institutes of Health team has identified a compound already approved by the U.S. Food and Drug Administration that keeps light-sensitive photoreceptors alive in three models of Leber congenital amaurosis type 10 (LCA 10), an inherited retinal ciliopathy disease that often results in severe visual impairment or blindness in early childhood.
LCA 10 is caused by mutations of the cilia-centrosomal gene (CEP290). Such mutations account for 20% to 25% of all LCA — more than any other gene. In addition to LCA, CEP290 mutations can cause multiple syndromic diseases involving a range of organ systems.
Using a mouse model of LCA10 and two types of lab-created tissues from stem cells known as organoids, the team screened more than 6,000 FDA-approved compounds to identify ones that promoted survival of photoreceptors, the types of cells that die in LCA, leading to vision loss. The high-throughput screening identified five potential drug candidates, including Reserpine, an old medication previously used to treat high blood pressure.
In LCA10, CEP290 mutations lead to defects in the photoreceptor outer segment. Consequently, the building blocks of the primary cilium accumulate in the photoreceptors, which activates autophagy (shown left, untreated). Reserpine restores the balance between autophagy and the ubiquitin-proteasome system histone deacetylase 6 and improves primary cilium assembly.
Scientists have identified an autoinflammatory disease caused by mutations in the LYN gene, an important regulator of immune responses in health and disease. Named Lyn kinase-associated vasculopathy and liver fibrosis (LAVLI), the identification sheds light on how genes linked to certain illnesses can potentially be targets for treatment by repurposing existing drugs. The research, published in Nature Communications, was led by Adriana A. de Jesus, M.D. Ph.D., and Raphaela Goldbach-Mansky, M.D., M.H.S., of the Translational Autoinflammatory Diseases Section of the Laboratory of Clinical Immunology and Microbiology at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
LAVLI was first discovered in a pediatric patient through genetic testing, which detected a mutation in LYN, the gene that encodes the Lyn kinase protein. Two additional, unrelated pediatric patients were later discovered to have two more mutations in the same gene. All three patients developed diseases linked to the LYN genetic mutation shortly after birth. Two patients developed liver fibrosis — excessive amounts of scar tissue caused by inflammation and repeated liver damage — in the first year of life. All three patients had perinatal onset of neutrophilic cutaneous small vessel vasculitis. This is an immune disorder characterized by inflammation from high numbers of neutrophils — white blood cells of the immune system — that can damage small blood vessels. The study revealed Lyn kinase was always active and unable to shut down in the three patients with the LYN mutation, which increased neutrophil migration, altered inflammatory signals and activated scar and fibrosis-inducing liver cells. The results of this study suggest that Lyn kinase may be a potential therapeutic target for drugs that treat forms of non-syndromic small vessel vasculitis and other types of inflammation-induced liver fibrosis.
Lesional skin biopsy shows co-expression of the endothelial marker CD31 and the activation/adhesion marker, ICAM1, in focal areas of a small vessel in the skin in Patient 1.
New mouse model may inform potential therapeutic options for Down syndrome
National Institutes of Health researchers compared a new genetic animal model of Down syndrome to the standard model and found the updated version to be more similar to the changes seen in humans. The new mouse model shows milder cognitive traits compared to a previously studied Down syndrome mouse model. The results of this study, published in Biological Psychiatry, may help researchers develop more precise treatments to improve learning and memory in people with Down syndrome.
Scientists found that the new mouse model, known as Ts66Yah, had memory difficulties and behavior traits, but the symptoms were not as severe as seen with the previous mouse model. Scientists often use different strains of mice as animal models to study human diseases because most genes in humans have similar counterparts in mice.
The new mouse model, known as Ts66Yah, has a minichromosome with over a hundred genes from mouse chromosome 16 attached to the centromere region of mouse chromosome 17. These genes are most relevant to human chromosome 21.
Results in cell and mouse studies may have implications for the development of a new class of anticancer drugs
Scientists at the National Institutes of Health and Massachusetts General Hospital in Boston have uncovered a potential new approach against liver cancer that could lead to the development of a new class of anticancer drugs. In a series of experiments in cells and mice, researchers found that an enzyme produced in liver cancer cells could convert a group of compounds into anticancer drugs, killing cells and reducing disease in animals.
The researchers suggest that this enzyme could become a potential target for the development of new drugs against liver cancers, and perhaps other cancers and diseases as well.
“We found a molecule that kills cells in a rare liver cancer in a unique way,” said translational scientist Matthew Hall, Ph.D., one of the leaders of the work at NIH’s National Center for Advancing Translational Sciences (NCATS). “It emerged from a screening to find molecules that selectively kill human liver cancer cells. It took a lot of work to figure out that the molecule is converted by an enzyme in these liver cancer cells, creating a toxic, anticancer drug.”
NCATS scientists used the Center’s drug screening capabilities, including drug screening plates like those shown here, to identify a molecule that was effective in killing liver cancer cells. Researchers determined that a specific enzyme was key to turning the molecule into a potential anticancer drug.
