September 1, 2021
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), 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 innovative NIH research.
Recent NIH Research
Breakthrough Treatment Brings Hope to Children with Tumor Disorder
September marks the annual Childhood Cancer Awareness month in which many organizations raise funds, host events and create awareness regarding cancers that have taken the lives of thousands of children. These donations help to fund critical research leading to the prevention and cure of childhood cancer in the hopes of reducing the mortality rate of children that are affected by these diseases.
One such disease is Neurofibromatosis type 1 (NF1), a disorder which usually appears in childhood and is predominantly inherited but can arise from a spontaneous genetic mutation. Symptoms are often noticeable as early as birth and almost always before age ten. This rare genetic disorder is characterized by light brown (café au lait) spots on the skin and non-cancerous nerve and skin tumors that can be painful, debilitating and at risk of becoming malignant. Treatment for this disease has been primarily focused on managing
the symptoms and often include surgery or radiation for the removal of tumors. Many of these tumors are inoperable within a tangle of nerves and generally grow back following surgery.
However, a breakthrough treatment is on the horizon. An IRP research team, led by Dr. Brigitte Widemann, senior investigator at the National Cancer Institute (NCI), Pediatric Oncology Branch, developed the first-ever drug approved by the FDA for the treatment of NF1. In honor of this ground-breaking work, Dr. Widemann, her IRP research team, and her collaborators outside NIH were named as finalists for the 2020 Samuel J. Heyman Service to America Medals, also known as the ‘Sammies,’ an award that honors exceptional work by government employees.
Dr. Widemann is a pediatric oncologist with the primary interest of developing effective therapies for children and adults with genetic tumor predisposition syndromes, such as NF1 and rare solid tumors for which there are no effective treatments. Prior research has shown that the mutation disrupts the RAS signaling pathway responsible for controlling normal cell growth and division. Mutations can keep the RAS pathway permanently switched on, leading to uncontrolled cell division and growth which result in the formation of tumors. Dr. Widemann and her colleagues set their focus on small molecule drugs that could inhibit or turn off the RAS pathway and ultimately slow or even stop progression of NF1 and possibly other tumor predisposition conditions.
Following a series of largely unsuccessful early-stage clinical trials with various therapies for children and young adults with NF1 and inoperable plexiform neurofibromas, Dr. Widemann and her team turned to a drug developed by AstraZeneca called selumetinib (Koselugo™) that inhibits the activity of an enzyme involved in the RAS pathway. Although selumetinib had failed in a clinical trial for the treatment of metastatic breast cancer, it showed promising results for NF1 in a Phase I clinical trial conducted by Dr. Widemann’s group.
“For the first time ever, we were able to show that in the majority of patients, not only did the tumor stop growing, but there was actually shrinkage,” Dr. Widemann says. “That was really an amazing finding after many years of work, not only here in the Intramural program, but also with colleagues at our other study sites.”
In partnership with colleagues in NCI’s Cancer Therapy Evaluation Program, collaborators outside NIH, and AstraZeneca, Dr. Widemann and her team subsequently ran a second clinical trial with the intention of applying for FDA approval if results were positive. The trial was ultimately a success.
To further support the findings from the second clinical trial, the team also utilized data from a ‘natural history’ study of NF1, which provided a baseline understanding of how plexiform neurofibromas progress without treatment. Researchers could then compare that baseline with the rates of tumor growth seen in clinical trials. That long-term observational study followed 259 children over 10 years, and comparing tumor growth in children treated with selumetinib to children of the same age in the natural history study revealed that selumetinib not only shrank existing tumors, but also delayed the growth of new ones. As a result of their work, the FDA approved selumetinib as a treatment for children with NF1 and inoperable symptomatic plexiform neurofibromas in April 2020, with approval in Brazil and Europe following in 2021.
To continue their work, Dr. Widemann and her team are moving forward with additional clinical trials to determine if selumetinib is effective in adults with NF1, as well as looking for an effective therapy for patients whose NF1 tumors become aggressively cancerous. The team is also applying the knowledge learned from their work with NF1 to medullary thyroid cancer and other rare tumors. After years of working so closely with researchers both within and outside NIH, Dr. Widemann is pleased to see the group’s efforts recognized by the Sammy awards.
The American Childhood Cancer Organization (ACCO) encourages everyone to wear gold for the kids – all the survivors, the victims, as well as those who are still fighting the disease.
Monoclonal antibody prevents malaria in small NIH trial
Malaria is a serious and sometime fatal mosquito-borne disease caused by a parasite that commonly infects female Anopheles mosquitos that feed on humans. People with malaria often experience a flu-like illness, including a high fever and shaking chills.
In 2019 an estimated 229 million cases of malaria occurred worldwide and 409,000 people died, mostly children in the African Region. About 2,000 cases of malaria are diagnosed in the United States each year. The vast majority of cases in the United States are in travelers returning from countries where malaria transmission occurs, many from sub-Saharan Africa and South Asia.
In a new study, researchers from the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center (VRC) discovered and developed a new one-dose monoclonal antibody treatment capable of preventing malaria for up to nine months in people who were exposed to the malaria parasite. The small, carefully monitored clinical trial is the first to demonstrate that a monoclonal antibody can prevent malaria in people.
“Malaria continues to be a major cause of illness and death in many regions of the world, especially in infants and young children; therefore, new tools are needed to prevent this deadly disease,” said NIAID Director Dr. Anthony Fauci. “The results reported suggest that a single infusion of a monoclonal antibody can protect people from malaria for at least nine months. Additional research is needed, however, to confirm and extend this finding.”
Malaria is caused by Plasmodium parasites, which are transmitted to people through the bite of an infected mosquito. The mosquito injects the parasites in a form called sporozoites into the skin and bloodstream. These travel to the liver, where they mature and multiply, spreading throughout the body via the bloodstream to cause illness. P. falciparum is the species most likely to cause severe malaria infections and may lead to death if not promptly treated.
Prior studies have determined that antibodies can prevent malaria by neutralizing the sporozoites of P. falciparum in the skin and blood before they can infect liver cells. The NIAID clinical trial tested whether a neutralizing monoclonal antibody called CIS43LS could safely provide a high level of protection from malaria in adults following careful, voluntary, laboratory-based exposure to infected mosquitos in the United States.
A team of researchers led by Dr. Robert Seder, chief of the Cellular Immunology Section of the VRC, isolated a naturally occurring neutralizing antibody called CIS43 from the blood of a volunteer who had received an investigational malaria vaccine. The scientists found that CIS43 binds to a unique site on a parasite surface protein that is important for facilitating malaria infection and is common to all variants of P. falciparum sporozoites worldwide. The research team derived CIS43LS through modification to the CIS43 antibody, enabling it to remain in the bloodstream for an extended amount of time.
Following a successful study of CIS43LS for the prevention of malaria in animals, a Phase 1 clinical trial of the experimental antibody was launched voluntarily with 40 healthy adults ages 18 to 50 years who had never had malaria or been vaccinated for the disease. The trial, led by Dr. Martin Gaudinski, medical director of the VRC Clinical Trials Program, was conducted at the NIH Clinical Center, and the Walter Reed Army Institute of Research (WRAIR).
During the first half of the trial, the study team gave 21 participants one dose of CIS43LS by either an intravenous infusion or an injection under the skin. Investigators followed the participants for 6 months to learn whether the infusions and subcutaneous injections of the various doses of the experimental antibody were safe and well tolerated and the amount of CIS43LS in the blood was measured to determine its durability over time.
In the second half of the trial, nine participants who had received CIS43LS and six participants who served as controls voluntarily underwent controlled human malaria infection (CHMI) and were closely monitored for 21 days. Within that period, none of the nine participants who had received CIS43LS developed malaria, but five of the six controls did. The participants with malaria received standard therapy to eliminate the infection.
The results of the study indicate that just one dose of the experimental antibody can prevent malaria for 1 to 9 months after infusion. Collectively, these data provide the first evidence that administration of an anti-malaria monoclonal antibody is safe and can prevent malaria infection in humans. A larger NIAID Phase 2 clinical trial is underway in Mali to evaluate the safety and efficacy of CIS43LS at preventing malaria infection in adults during the six-month malaria season with results expected in early 2022.
NIH scientists develop faster COVID-19 test
Diagnostic testing is of vital importance in the fight against the COVID-19 pandemic. Standard tests for detection of SARS-CoV-2, the virus responsible for causing COVID-19, involve the amplification of viral RNA to detectable levels using a technique called real-time quantitative reverse transcription PCR (RT-qPCR). But first, the RNA must be extracted from the patient sample. Manufacturers of RNA extraction kits have had difficulty keeping up with the high demand during the COVID-19 pandemic, hindering testing capacity worldwide. With new virus variants emerging, the need for better, faster COVID-19 diagnostics tests is greater than ever.
To address this critical issue, research teams from the National Eye Institute (NEI), the NIH Clinical Center (CC), and the National Institute of Dental and Craniofacial Research (NIDCR) collaborated to develop a rapid sample preparation method to aid in the detection of SARS-Cov-2. This novel method eliminates the need for the extraction of the viral RNA, streamlining the testing process while decreasing the test time and the overall cost.
The IRP research team, led by Dr. Robert Hufnagel, chief of the NEI Medical Genetics and Ophthalmic Genomics Unit, and Dr. Bin Guan, a fellow at the NEI Ophthalmic Genomics Laboratory, used Bio-Rad’s Chelex 100 chelating resin to preserve SARS-CoV-2 RNA in samples for detection by RT-qPCR. The team made their discovery by testing a variety of chemicals using synthetic and human samples to identify those that could preserve the RNA in samples with minimal degradation while allowing direct detection of the virus by RT-qPCR.
“We used nasopharyngeal and saliva samples with various virion concentrations to evaluate whether they could be used for direct RNA detection,” said Dr. Guan, “The answer was yes, with markedly high sensitivity. Also, this preparation inactivated the virus, making it safer for lab personnel to handle positive samples.” In addition to the significant increase in sensitivity and RNA stability, this novel methodology will provide a reduction in cost and time for COVID-19 diagnostic testing.
Explosive Blasts Wreak Havoc in Inner Ear
The war on terrorism has increased the exposure of both military personnel and civilians to explosive blasts that can lead to long-term or permanent hearing and balance difficulties, among other adverse health effects. In a recent collaborative IRP study, research teams at the National Institute on Deafness and Other Communication Disorders (NIDCD) and the Walter Reed Army Institute of Research (WRAIR) have gained important insights into the biological basis of those disabilities, which could eventually lead to more effective approaches to the prevention and treatment of concussive blast disorders.
During the wars in Afghanistan and Iraq, nearly half of American military deaths and 80 percent of injuries incurred have been related to home-made bombs called ‘improvised explosive devices’ (IEDs). Even when the heat and debris released by an IED doesn’t cause apparent bodily harm, the detonation can still produce a fast-moving wall of pressurized air, known as a ‘blast wave’, capable of causing damage to the brain and the delicate biological structures inside the ear involved in hearing and balance.
Despite the prevalence of the problem, little is known about exactly how blast waves lead to hearing and balance disorders. One reason is that much of the research surrounding how these forces affect the body rely on small, home-made ‘blast simulators’ that are often made from plastic PVC pipe, which are highly variable and generally do a poor job of approximating real-world explosions.
To solve this problem, NIDCD senior investigator, Dr. Matthew Kelley and his
lab teamed up with researchers at WRAIR who had access to a more advanced blast simulator that was carefully designed by engineers to produce more consistent blast waves that closely resemble those produced by real-life explosions. This new method was tested by exposing mice to simulated blasts either once or three times, and the effects on their hearing was assessed over a six month period. All the mice showed initial signs of severe hearing loss, and mice exposed to three blasts showed only minimal signs of recovery six months later.
To further explore the underlying cause of hearing loss, researchers examined the sensory hair cells located on the cochlea, the part of the inner ear responsible for converting sounds into electrical signals the brain can interpret. The inner hair cells did not show a decrease in number after the mice were exposed to blast waves. However, a decrease the number of connections between the inner hair cells and the spiral ganglion neurons that serve as the first stop for auditory signals traveling from the inner hair cells to the brain was observed. In humans, this change could contribute to a phenomenon called ‘hidden hearing loss’, which has been reported by many service members who have encountered explosions. This form of hearing loss causes difficulty hearing in noisy environments but does not show up on traditional hearing tests that rely on simple, pure tones produced in quiet surroundings.
“Hidden hearing loss is a relatively recent discovery,” says Dr. Beatrice Mao, the study’s first author and a postdoctoral fellow in Dr. Kelley’s lab. “It has to do not with a loss of cells, but a loss of the cells’ ability to transmit signals. It’s only identified when someone is given a test where they need to detect a specific sound amongst noise.”
The research team further observed a significant decrease in the number of outer hair cells, which assist in the pre-amplification of sounds before they reach the inner hair cells, and once lost they cannot grow back. Additionally, all mice in the study incurred damage to their eardrums, which help transfer sound energy to the hair cells in the inner ear.
The study results indicate that extremely loud sounds can damage the inner ear even without passing through the ear drum, such as by sending powerful vibrations to the inner ear through the skull. If this is the case, it would mean that in-ear hearing protection like earplugs may not be enough to protect hearing in these situations. Furthermore, since none of the mice showed obvious behavioral signs of balance problems nor changes to the vestibular hair cells in the inner ear that send balance-related information to the brain, the team hypothesized that the balance problems some people experience after encountering explosive blasts might be caused by traumatic brain injury or other mechanisms rather than damage to vestibular hair cells.
The findings of this study suggest that researchers working on treatments for blast-induced hearing loss might want to focus their efforts on preventing the loss of the outer hair cells or stimulating their regeneration.
NIH hamster study evaluates airborne and fomite transmission of SARS-CoV-2
In a new study, researchers from the National Institute of Allergy and Infectious Diseases (NIAID) Rocky Mountain Laboratories analyzed how different routes of exposure to SARS-CoV-2, the virus that causes COVID-19, are linked to disease severity.
To investigate how the various routes of exposure affected the development of COVID-19 disease, the team of researchers exposed Syrian hamsters to SARS-CoV-2 via both aerosols and contact with contaminated surfaces, called fomites. For aerosol exposure, the scientists used equipment that controlled the size of virus-loaded droplets. For fomite exposure, they placed a dish contaminated with SARS-CoV-2 in the animal cages.
The scientists determined that aerosol exposure directly deposited SARS-CoV-2 deep into the lungs, whereas fomite exposure resulted in initial virus replication in the nose. In both cases, the mice had SARS-CoV-2 replicating in the lungs, but lung damage was more severe in aerosol-exposed mice as compared to the fomite group.
The team also compared animal-to-animal transmission of the virus through the air and in contaminated cage environments (fomites). Airborne transmission was significantly more efficient than the fomite transmission, suggesting that airborne droplets are a key route of SARS-CoV-2 transmission. Additional testing, using air flowing from infected to uninfected mice, supported the finding. Reversing the airflow from uninfected to infected mice greatly reduced transmission efficiency. The study concluded that exposure from contaminated surface contact is markedly less efficient than airborne transmission but does occur.
The findings of this study support public health guidance focused on interventions to reduce indoor airborne transmission of SARS-CoV-2. These recommendations include masking, increasing air filtration and social distancing, as well as handwashing and regular surface disinfection, particularly in clinical settings.
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