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:
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.
A small portion of adults in remission from a deadly blood cancer had persisting mutations that were detected, which predicted their risk of death from having the cancer return
Researchers at the National Institutes of Health show the benefits of screening adult patients in remission from acute myeloid leukemia (AML) for residual disease before receiving a bone marrow transplant. The findings, published in JAMA, support ongoing research aimed at developing precision medicine and personalized post-transplant care for these patients.
About 20,000 adults in the United States are diagnosed each year with AML, a deadly blood cancer, and about one in three live past five years. A bone marrow transplant, which replaces unhealthy blood-forming cells with healthy cells from a donor, often improves these chances. However, research has shown that lingering traces of leukemia can make a transplant less effective.
Researchers in the current study wanted to show that screening patients in remission for evidence of low levels of leukemia using standardized genetic testing could better predict their three-year risks for relapse and survival. To do that, they used ultra-deep DNA sequencing technology to screen blood samples from 1,075 adults in remission from AML. All were preparing to have a bone marrow transplant. The study samples were provided through donations to the Center for International Blood and Marrow Transplant Research.
After screening adults with variants commonly associated with AML, researchers showed that the two most common mutations in AML —NPM1 and FLT3-ITD — could be used to track residual leukemia. Among 822 adults with these variants detectable at initial diagnosis, 142 adults — about one in six — were found to still have residual traces of these mutations after therapy despite being classified as in remission.
The American Association for the Advancement of Science (AAAS) elected 505 scientists, engineers, and innovators from around the world and across all disciplines to its 2022 class of fellows. Ten NIH scientists are among the electees: Dr. Linda S. Birnbaum (NIEHS), Dr. Carmen Williams (NIEHS), Dr. Cynthia Dunbar (NHLBI), Dr. Howard Young (NCI), Dr. Eric Engels (NCI), Dr. Elodie Ghedin (NIAID), Dr. Paul Liu (NHGRI), Dr. Lee Scott Weinstein (NIDDK), Dr. Karen Faith Berman (NIMH), and Dr. Christopher McBain (NICHD).
AAAS is the world’s largest general scientific society and publisher of the Science family of journals. Newly elected fellows are recognized for scientific and socially notable achievements spanning their careers. Election is one of the most distinguished honors in the scientific community.
AAAS fellows are a distinguished cadre who have been recognized for their achievements across disciplines, from research, teaching and technology, to administration in academia, industry and government, to excellence in communicating and interpreting science to the public.
In a tradition stretching back to 1874, individuals are elected annually by the AAAS council. New fellows are recognized at a ceremonial forum during the AAAS annual meeting, where they are presented with a certificate and blue and gold rosette.
Newly discovered gene helps some yeast endure toxins and can help scientists understand toxin resistance
National Institutes of Health researchers have identified a gene that makes yeast resistant to a lethal toxin, according to a new study published in the Proceedings of the National Academy of Sciences. To study the evolution of toxin resistance, researchers at the National Human Genome Research Institute (NHGRI), part of NIH, used yeast — the kind commonly used for home baking — as a model organism. While researchers have long known about yeast’s remarkable ability to evade the effects of lethal toxins, the reason was a mystery until now.
“The intricacies of genomics that mediate these within-species battles are beautifully revealed by a study like this,” said Charles Rotimi, Ph.D., scientific director of the Intramural Research Program at NHGRI. “While this is a yeast story, the mechanisms will surely influence studies on toxins and their effects on humans.”
Throughout human history, people have combatted various toxins made by other organisms, like spiders, plants, snakes and even the cholera or anthrax bacteria. Understanding toxin resistance in yeast could lead to new avenues for protection against toxins in humans.
“We’re interested in understanding how genomic variation leads to differences between individuals, so in this study, we’re looking at the most basic biological mechanisms underlying resistance to toxins in simple organisms, such as yeast,” said Meru Sadhu, Ph.D., an investigator in the Genetic Disease Research Branch at NHGRI and senior author of the study. “An important way that organisms vary is in how much they’re affected by toxins.”
NIH researchers discover a possible cause for a rare facial malformation, bringing new hope for patients
Researchers at the National Institutes of Health and their colleagues have found that a toxic protein made by the body called DUX4 may be the cause of two very different rare genetic disorders. For patients who have facioscapulohumeral muscular dystrophy (FSHD), or a rare facial malformation called arhinia, this research discovery may eventually lead to therapies that can help people with these rare diseases.
FSHD type 2 (FSHD2) is an inherited form of muscular dystrophy that causes progressive muscle weakness. Arhinia is an extremely rare yet severe disorder that prevents the development of an external nose and the olfactory bulbs and tracts. Both diseases are caused by mutations in the SMCHD1 gene. In patients with FSHD2, there is overproduction of DUX4 which kills the muscle cells, and this leads to the progressive weakening of the muscles.
“It has been known for some time that DUX4 damages the muscle in patients with FSHD2, but what we found is that it can actually also kill the precursors of the human nose,” said Natalie Shaw, M.D., head of the Pediatric Neuroendocrinology Group at the National Institute of Environmental Health Sciences (NIEHS) and lead author of the new study in the journal Science Advances. NIEHS is part of NIH.
Software opens the door for a greater number of complete genome sequences
National Institutes of Health researchers have developed and released an innovative software tool to assemble truly complete (i.e., gapless) genome sequences from a variety of species. This software, called Verkko, which means 'network' in Finnish, makes the process of assembling complete genome sequences more affordable and accessible. A description of the new software was published today in Nature Biotechnology.
“We took everything we learned in the T2T project and automated the process,” said NHGRI associate investigator Sergey Koren, Ph.D., who led the creation of Verkko and is senior author on the paper. “Now with Verkko, we can essentially push a button and automatically get a complete genome sequence.”
National Institutes of Health researchers have developed and released an innovative software tool to assemble truly complete (i.e., gapless) genome sequences from a variety of species.
Scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health have removed a major roadblock to better understanding of mpox (formerly, monkeypox). They developed a mouse model of the disease and used it to demonstrate clear differences in virulence among the major genetic groups (clades) of mpox virus (MPXV). The research, appearing in Proceedings of the National Academy of Science, was led by Bernard Moss, M.D., Ph.D., chief of the Genetic Engineering Section of NIAID’s Laboratory of Viral Diseases.
Historically, mpox, a disease resembling smallpox, was only occasionally transmitted from rodents to non-human primates or people and was observed primarily in several African countries. Mpox rarely spread from person to person. That pattern changed in 2022 with an outbreak in which person-to-person mpox transmission occurred in more than 100 locations worldwide. To date, more than 80,000 cases of mpox have been diagnosed during this outbreak. Genome sequencing revealed that the strain causing the current outbreak, clade IIb, differs from two historic clades; clade I, which has a mortality rate of up to 10%, and clade IIa, which has a mortality rate of less than 1%. Mortality from Clade IIb MPXV is lower than either of the historic clades
Colorized scanning electron micrograph of monkeypox virus (blue) on the surface of infected VERO E6 cells (pink).
