January 10, 2023
The National Institutes of Health (NIH) is our nation’s medical research agency. Its mission focuses on scientific discoveries that improve health and save lives. Founded in 1870, the NIH conducts its own scientific research through its Intramural Research Program (IRP). It 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 innovative NIH research.
Recent NIH Research
NIH researchers use 3D bioprinting to create eye tissue
National Eye Institute (NEI) scientists used patient stem cells and 3D bioprinting to create eye tissue. The researchers combined cellular material from the outer blood-retina barrier and printed tissue that supports photoreceptors in the retina. This new method provides an unlimited supply of patient-derived tissue for research on degenerative retinal diseases. The NIH team is hopeful that this new technique will help lead to treatments for these debilitating conditions.
“We know that AMD starts in the outer blood-retina barrier,” said Kapil Bharti, Ph.D., who heads the NEI Section on Ocular and Stem Cell Translational Research. “However, mechanisms of AMD initiation and progression to advanced dry and wet stages remain poorly understood due to the lack of physiologically relevant human models.”
They observed similar indications of wet AMD when oxygen levels were reduced, marked by the presence of out-of-control choroid vessels underneath the RPE layer. Fortunately, anti-VEGF drugs – a mainstay treatment for AMD – effectively suppressed these growths and restored normal tissue morphology.
“By printing cells, we’re facilitating the exchange of cellular cues that are necessary for normal outer blood-retina barrier anatomy,” said Bharti. “For example, presence of RPE cells induces gene expression changes in fibroblasts that contribute to the formation of Bruch’s membrane – something that was suggested many years ago but wasn’t proven until our model.”
Bharti’s team encountered various technical hurdles while developing their project, such as creating a biodegradable scaffold and refining the printing pattern by establishing an environmentally sensitive hydrogel.
Co-author Marc Ferrer, Ph.D. (Director of the 3D Tissue Bioprinting Laboratory at NIH’s National Center for Advancing Translational Sciences) and his research team provided their invaluable expertise in biofabrication techniques to create outer blood-retina barrier tissues “in-a-well” along with analytical measurements that enabled drug screening.
“Our collaborative efforts have resulted in very relevant retina tissue models of degenerative eye diseases,” Ferrer said. “Such tissue models have many potential uses in translational applications, including therapeutics development.”
Bharti and colleagues are utilizing printed blood-retina barrier models to examine AMD, with the idea of increasing cell types in the printing process, such as immune cells; this may effectively reflect native tissue better.
Friendly Virus Could Deliver Gene Therapy Under Immune System’s Radar
In a new study, IRP researchers revealed that most people have a non-reactive immune system to an innocuous virus, which can serve as a successful delivery vector for gene therapy treatments targeting life-threatening genetic diseases. This novel discovery is highly promising and could offer new hope for those affected by such conditions.
During his time at Children’s Hospital of Philadelphia, Charles Venditti, M.D., Ph.D., Senior IRP investigator, explored technology capable of recognizing methylmalonic acidemia (MMA) in infants only days after birth; however, finding the illness at an early stage did not change its eventual outcome.
“I was involved with meeting families and their babies that had methylmalonic acidemia and were diagnosed in the first one or two weeks of life,” he recalls. “The families would ask, ‘What’s going to happen to my baby?’ As a practitioner of metabolic medicine, I knew that the outlook was predicted to be grim, with a high chance of death and disability. The conversations were difficult.”
In a recent study, the labs of Dr. Chiorini, Ph.D. an IRP senior investigator, and Dr. Venditti partnered to explore if an immune response could neutralize andeo-associated viruses (AAVs) called AAV44.9, which has a unique capsid discovered by Dr. Chiorini’s lab several years ago with the expectation that it will evade detection from the body’s immunity and effectively deliver genes into cells required for treating MMA or other similar genetic ailments.
“The capsid is the molecular truck of the gene therapy vector,” Dr. Chiorini says. “It dictates where the gene is going to be delivered and when it is going to be active, so it’s a really critical component of gene transfer technology.”
After examining blood samples of adults and children who have MMA for AAV44.9 antibodies, researchers discovered that only 26% of adults and 13% of children possessed enough antibodies to fight the virus. Remarkably, these levels were too low to combat it effectively. Additionally, a study of mice found that AAV44.9 was effective in delivering the gene and very promising in correcting a mutation that causes MMA-like symptoms.
The results of the recent study have demonstrated that AAV44.9 may be a remarkably successful technique for gene therapy for MMA; however, further research needs to be done. Dr. Venditti is currently planning on initiating a clinical trial involving a gene therapy utilizing an alternate viral vector which his laboratory has been researching longer than AAV44.9.
Additionally, the study showed a low number of antibodies against AAV44.9 in the studied population of MMA patients; this virus can serve as a valuable alternative vector for gene therapy treatments if existing patient antibodies neutralize other AAVs utilized to deliver these therapies.
“Our collective goal is to widely enable gene therapies for patients with MMA and related disorders because we hope they will be ‘one and done’ treatments,” Dr. Venditti says. “Any new class of vector could help, especially ones that are very potent in living organisms, like AAV44.9”.
NCI clinical trial leads to atezolizumab approval for advanced alveolar soft part sarcoma
Recently, the U.S. Food and Drug Administration granted permission for Atezolizumab (Tecentriq) to be used as an immunotherapy drug on adults and children aged two or older with advanced sarcoma that has metastasized. This decision was based on findings from a non-randomized phase 2 trial supported by the National Cancer Institute (NCT03141684).
The study was conducted by Dr. Alice Chen of the Developmental Therapeutics Clinic in NCI’s Division of Cancer Treatment and Diagnosis (DCTD). Genentech, part of the Roche Group and creator of atezolizumab, supplied NCI with the drug through a cooperative research agreement – results are currently being prepared for publication.
This is the most extensive study on ASPS and the first NCI-funded Experimental Therapeutics Clinical Trials Network study that led to drug approval. This is also the first time atezolizumab has been approved for children due to the participation of the Pediatric Oncology Branch in NCI’s Center for Cancer Research.
“This is a major milestone for investigators in the Experimental Therapeutics Clinical Trials Network, as well as for the ASPS patient community, and for research on rare cancers,” said Elad Sharon, M.D., of DCTD, who is one of the study leaders.
49 ethnically diverse patients aged two and up with metastatic alveolar soft part sarcoma were given an infusion of atezolizumab in the trial on a 21-day rotation. According to doctor evaluations, approximately one-third of the patients saw a positive response to their treatment with noticeable tumor shrinkage. For most other patients, their condition remained stable.
“This approval represents a victory for rare diseases, which are understudied in clinical trials,” said Dr. Chen. “For this approval to go through in a rare disease, and to be able to make an impact on these young people’s lives, is very significant.”
Currently, research teams are further exploring the potential of atezolizumab as a treatment for ASPS. This includes testing its efficacy when combined with other therapies.
Toxic Protein and Aging Combine Forces to Drive Brain Disease
A recent IRP study has potentially located new therapeutic targets for two age-related illnesses. Alpha synuclein, a protein that accumulates in the brains of those with Parkinson’s disease and some forms of dementia, appears to be particularly prevalent among elderly individuals – offering vital insight into developing more effective treatments for these conditions.
Dr. Eliezer Masliah, Senior Investigator of the NIH’s National Institute on Aging (NIA) worked with co-author and IRP senior investigator Dr. Ranjan Sen, PH. D and his group to study how aging interacts with alpha-synuclein in the brains of mice. The researchers injected alpha-synuclein ‘protofibrils’ into young and older mice’s brains.
The IRP study revealed that alpha-synuclein spread far more quickly in the brains of older mice, significantly diminishing their fear response to a sound cue they had been previously conditioned to associate with an electric shock. This shows that memory can be detrimentally affected by such injections. In younger mice, however, injections of alpha-synuclein had a much weaker effect on their reaction to the fear-inducing sound. Interestingly, while IRP researchers observed alpha-synuclein’s impact on cognition in both genders of mouse subjects, they only noticed that it decreased motor coordination in males.
“There has been a lot of interest at NIA about understanding sex differences in neurodegenerative disorders,” Dr. Masliah says. “We know in Lewy body dementia that women are affected differently than men, and Alzheimer’s disease tends to be more common in women than in men. There may be a difference in how sex hormones affect the disease or some other factor that we don’t understand, but that’s why it’s important when designing these sorts of experiments to include both sexes.”
The alpha-synuclein injections had a noticeable effect on the production and activity of T cells and microglia among treated mice compared to untreated ones. Upon examining gene expression in affected microglia, researchers observed changes in numerous genes associated with inflammation; these modifications were more intense for older vs. younger rodents even when they did not receive any injection.
After examining how specific genes are regulated, scientists discovered that colony-stimulating factor 2 (CSF2) considerably influences them. This chemical is generated by T cells and other immune system components, verifying recent studies which have linked CSF2 to neurological disorders.
“I think the fact that we found a link to CSF2 suggests that all these excess T cells that are getting into the brain might be secreting more CSF2, and this CSF2 is detected by microglia,” Dr. Masliah explains. “The microglia become activated, and then we see dysregulation in all these other inflammatory pathways. That’s very important because it suggests that targeting either CSF2 or its receptor in microglia might prevent the acceleration of aging in microglia that appears to be triggered by alpha-synuclein.”
To study these factors’ effects, researchers plan to observe mice that lack T cells or microglia in their brains. They will then explore how alpha-synuclein and aging affect those mice with immune cells unable to produce or respond to CSF2.
“Our findings suggest that pro-inflammatory pathways that are triggered by aging could also be triggered in a similar way by accumulation of alpha-synuclein,” Dr. Masliah says. “They are running in parallel and also probably feeding into each other. I think we can develop therapeutic strategies for diseases like Parkinson’s and Lewy body dementia by looking at these age-related inflammatory pathways.”
Endocarditis in patients with cocaine or opioid use disorder saw marked increase between 2011 to 2022
From 2011 to 2022, the number of patients with cocaine or opioid use disorder diagnosed with infective endocarditis drastically grew, showing a particularly striking rise from 2021 to 2022. According to the latest research published in Molecular Psychiatry and NIH-funded, there is an ever-growing risk of endocarditis among drug injectors amplified due to COVID-19. These findings highlight the need for public health initiatives and interventions targeting those who have substance abuse disorders.
“People with substance use disorder already face major impediments to proper healthcare due to lack of access and stigma,” said NIDA Director and co-corresponding study author Nora D. Volkow, M.D. “Proven techniques like syringe service programs, which help people avoid infection from re-used or shared injection equipment, can help prevent this often fatal and costly condition.”
Dr. Volkow and researchers from Case Western Reserve University in Cleveland, Ohio, conducted an extensive study that analyzed electronic health record data from more than 109 million individuals collected between January 2011 and August 2022. In 2011, 4 endocarditis cases occurred daily for every 1 million people suffering from opioid use disorder. By 2022, this rate had skyrocketed to 30 cases per day per 1 million individuals with opioid dependence. The same trends were found with cocaine users; the number of endocarditis incidences jumped from 5 cases in 2011 to 23 out of every one million people struggling with cocaine addiction in 2022.
Patients with cocaine or opioid use disorder clinically diagnosed with COVID-19 were twice as likely to be diagnosed with endocarditis than those without. In addition, patients previously diagnosed with COVID-19 were 68% more likely to be hospitalized within 6 months following their endocarditis diagnosis. Furthermore, those infected with coronavirus faced 9% mortality rate in 180 days after a new diagnosis of endocarditis, compared to 8% for people not affected by the virus.
“As the scientific understanding of long COVID develops, we can now include endocarditis as one long-term effect on key organ systems for people who inject drugs. Our study is one of the first to show this,” said Rong Xu, Ph.D., professor of biomedical informatics at Case Western University and co-corresponding author of this study. “It’s critical that we continue to monitor long term, broad impacts of COVID-19 on people who use drugs.”
Canine brain wiring influenced by human-driven breeding practices
The latest research funded by NIH and published in journal cell uncovered that dog-breeding practices driven by humans have an impact on their brains. The conclusions of this study may help researchers to comprehend further how genetic variation can influence various behaviors in human beings.
Researchers discovered that genomic distinctions between dog breeds are linked to the formation of their nervous systems. An example is herding dogs – they have different genomes, which influence how neurons join together to form neural networks during the early stages of development.
The similarities between the genes associated with various canine lineages and those of other species, including humans, suggest that dogs may possess similar biological pathways which account for the varying behaviors within a species. This research sheds light on the potential parallels between dog brain function and the behavior of human brains.
“The results of this study may point us toward how differences in the human genome can contribute to behavioral diversity among humans. Further research can help us draw a stronger link between genes that are important for behavior in dogs and genes that may play a role in human behavioral conditions,” said Elaine Ostrander, Ph.D., distinguished senior investigator and chief of the Cancer Genetics and Comparative Genomics Branch within NHGRI’s Intramural Research Program and corresponding author on the study.
Dr. Emily Dutrow, a research fellow in Dr. Ostrander’s team, spearheaded the study by leveraging genomic data from 4 thousand dogs and behavioral information supplied by the University of Pennsylvania School of Veterinary Medicine’s survey on over 46 thousand canines, which studied traits such as trainability, energy levels and fear towards strangers to track breed evolution through time.
“One of the most surprising findings was that many of the genomic changes that define the major dog lineages can also be found in modern wolves. This indicates that humans co-opted ancient variations among wild ancestors of dogs to create unique types of dogs suited for performing specific tasks,” said Dr. Dutrow.
Until recently, the distinct behavioral traits and personalities associated with various dog breeds, along with how they are connected to their genetic makeup, have been a mystery.
“To study the genomic basis of breeds, researchers typically compare different breeds with different behavior. But the difficulty with that is finding meaningful results among the variation in dog behavior,” said Dr. Ostrander. “Instead of looking at a snapshot in time, our study mapped out how dog breed lineages diversified over hundreds of years and explains how the different breeds we see today are a result of human selection.”
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