Posted on NIH. 9 July, 2020
The National Institutes of Health (NIH) is our nation’s medical research agency and strives to make 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 ground-breaking NIH research.
Pandemic Brings All Hands on Deck
In December of 2019, the CDC first became aware of a “mysterious respiratory illness” spreading in Wuhan, China. By January 20th, the first known case of this disease in the US was reported in Washington State originating from a traveler returning from a trip to Wuhan. Within days, more cases were reported in Chicago and southern California. Almost immediately following the spread of COVID-19 in the US, IRP Researchers began studying the mode of transmission and characterization of the virus.
With the disease spreading at an unprecedented rate, the NIH has adopted an “all hands on deck” approach to combating this deadly virus and bringing this global pandemic under control. To date, nearly 300 new intramural research projects relating to COVID-19 are underway. Current studies include testing therapies for the virus and the impact of genetics and the impact of pre-existing health conditions on the spread and severity of the disease.
IRP Research Take Aim at COVID-19
With further understanding of the COVID-19 virus and factors surround the resulting illness, the IRP research teams have focused efforts on the development of treatments for COVID-19 disease. IRP senior investigator Avindra Nath, M.D., is studying DNA-like molecules called anti-sense oligonucleotides (ASOs) that show promise in the treatment of the disease. These molecules bind to specific sequences found on the virus’s genome and trigger the infected cell to destroy them, thereby preventing further replication of the virus.
Immediate efforts are also underway to investigate how existing therapies for related ailments could prove effective in the fight against COVID-19. NIH researcher Dr. Wei Zheng is conducting a large scale screening project to determine the ability of current FDA approved medications as well as investigational drug candidates to prevent the virus from infecting cells. The coronavirus utilizes spike proteins to invade human cells. One of the target areas of Dr. Zheng’s study is to identify compounds that prevent the virus’ spike protein from binding to ACE2 receptors in human cells, potentially eliminating the pathway of infection.
A third angle of attack against COVID-19 is present within the animal kingdom. Nanobodies, which are smaller than human antibodies, allow them to bind to sites on the coronavirus that the larger antibodies cannot. The small size and high stability of the nanobodies would enable them to be administered to patients through the use of an inhaler as a potential therapeutic for COVID-19 related respiratory infections. IRP senior investigator Dr. Mitchell Ho is leading a group of researchers in the search for nanobodies from camels and sharks that have potential to be combined to target multiple binding sites on the coronavirus as a promising antiviral therapy.
Boosting the Immune Response
An alternative approach to combating COVID-19 focused on promoting the natural defensives of the immune to ward off the virus. Research conducted by IRP senior investigator Thomas Waldmann, M.D. has shown that interleukin IL-15, whose function is to naturally produce an immune response to kill virally infected cells, can be incorporated into COVID-19 vaccines to boost the immune response that is stimulated by the vaccine to prevent infection. In cases where infection has already occurred, IL-15 can be administered alongside other therapies to bolster the production of natural killer cells to help fight off the disease.
Diminishing the impact of COVID-19 infection
Patients with COVID-19 infection will exhibit a wide range of response to the disease depending on a variety of factors including genetic and pre-existing medical conditions. While COVID-19 may have a lower mortality rate than many other infectious diseases, a large number of patients will experience severe or life-threatening symptoms. In some patients, the coronavirus will trigger an elevated immune system response known as a ‘cytokine storm,’ which can result in coronavirus related fatalities.
A team led by IRP senior investigator Robert Star, M.D., is testing strategies to mitigate cytokine storms in an animal model. Sepsis is an illness that can occur when an infection spurs a similar out-of-control immune response. Dr. Star’s group is examining the effects of a wide array of medications and investigational drug candidates targeting toll-like receptor seven (TLR7) protein which plays an important role in pathogen recognition. TLR7 triggers a natural immune response that may help control the negative effects resulting from a cytokine storm. The team is also exploring a novel therapy that utilizes capsules of chemicals called exosomes that are released by mesenchymal stromal cells that have the potential to diminish the immune system’s overreaction to the coronavirus.
COVID-19 infection can result in serious lung complications such as pneumonia or acute respiratory distress syndrome (ARDS). An IRP team led by senior investigator Edward Lakatta, M.D., is exploring the hypothesis that interventions affecting the body’s renin-angiotensin system could help stop the virus from critically injuring patients’ lungs. This system controls numerous bodily functions, including regulating inflammation in the lungs, and is influenced in part by the ACE2 protein that the virus utilizes to infect cells. Binding of the virus to ACE2 on the exterior of cells reduces their production of ACE2, thereby limiting ACE2’s ability to decrease inflammation that is triggered by the renin-angiotensin system. The results of these studies could confirm the potential of targeting the renin-angiotensin system to reduce COVID-19 related lung damage.
The NIH has played a vital role in the battle against infectious diseases over the course of history, dating back to the late 1800’s. IRP researchers have already made important scientific contributions in the quest for effective treatments, preventative measures and ultimately a cure for COVID-19. With the wide range of expertise within the Intramural Research Program along with collaborative efforts extending throughout the research community we are certain to win the fight against COVID-19.
The landscape of coronavirus testing capabilities is changing at an accelerated pace in the wake of the COVID-19 pandemic. The ability to determine if an individual is actively infected with coronavirus is of critical importance in controlling the spread of COVID-19. While numerous efforts are underway to develop rapid and reliable diagnostic testing methods, many of the methods that are currently available lack the requirements needed for the widespread point of care testing for presence of the coronavirus.
NIH Director Dr. Francis Collins recently spoke via videoconference with Dr. Bruce Tromberg, director of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), to discuss the latest developments in new technologies for the diagnostic testing of the coronavirus. Dr. Tromberg also plays a key role in the recently launched Rapid Acceleration of Diagnostics (RADx) initiative to bring together innovative ideas for novel COVID-19 testing strategies. The charter of the RADx organization is to speed the development, commercialization and implementation of new technologies for widespread COVID-19 testing.
An estimated 400,000 to 900,000 COVID-19 tests are performed on a daily basis in the United States, a substantial increase over the April rate of approximately 150,000 test per day. However, the majority of the testing is still being performed in laboratories or complex facilities. Results from those tests can take hours to days to obtain. One of the goals of the RADx initiative is to develop a point of care test that can be performed easily and conveniently home or in the workplace, with immediate results.
Abbott ID Now is a lightweight, portable rapid molecular testing unit able to deliver a result in 13 minutes, thereby providing a solution to safe screenings in non-traditional settings such as the home or workplace. While the unit shows promise as a point of care tests for COVID-19, Dr. Tromberg has indicated that additional testing may be required for individuals needing to know with absolute certainty if the virus is present or not in their system.
The goal of RADx-tech is to identify exciting new technologies for the diagnostic testing of COVID-19 and help scale them up quickly. As efforts move towards the ability to provide rapid testing in large populations, a greater testing capacity is required to help optimize the management of each individual.
One general class of technologies is called a lateral flow assay. These tests are small enough to fit in your hand and come in a convenient container. A sample from an oral swab is placed on one of the pads and a solution is added. The actual assay itself has a membrane inside of a little plastic container. The fluid flows across the membrane, and there’s chemistry that goes on inside the container to detect genetic material from the coronavirus. The assay is very quick and straightforward. A line will “light up” if the virus is present.
Another type of lateral flow assay, also small enough to hold in your hand, looks for proteins on the surface of the virus. An aptamer, which is similar to an antibody but made from nucleic acid, captures and binds tightly to the virus within a membrane. Using this device to analyze a saliva sample, you will see a line appear if the presence of the coronavirus is detected, making this an attractive alternative to sampling via a nasal swab.
Mobile device technologies such as a tablet offer another unique type of a lateral flow assay test using an apparatus which resembles an elongated zip drive that slides into the tablet itself. A light inside of the tablet alerts you to when the result is ready, while another color of light that comes directly from the lateral flow strip will indicate if the virus is present. The test is very easy to use and can be performed at home.
One last example is a nucleic acid test. A hand-held device reminiscent of a computer disc, looks inside the virus to amplify small traces of its nucleic acid to detectable levels. It is completely self-contained. The technology today is used in complex laboratory settings that require big machines and multi-step procedures. Efforts are underway to reduce the size and complexity of these devices to enable point of care testing without compromising the level of performance that is expected from a laboratory-based system.
Other considerations in developing rapid, reliable point of care COVID-19 testing surround the total cost of testing and the ability to provide low cost disposable technology. The current business model for the RADx initiatives is to develop testing technology that can be scaled up very quickly to make tens of millions of tests, using inexpensive components. Right now, if you go to a laboratory for a nucleic acid test, the cost may be on the order of $40 or so. With the transfer of this technology to these one-time-use nucleic acid tests, the aim is to scale up the manufacturing to produce larger volumes that will bring the cost down, estimating an average of about $60 per one-time use test.
In the months ahead, the need to provide testing for millions of people on a frequent basis for the presence of the coronavirus will necessitate the need to have a diverse offering of tests available on the market depending the accuracy, performance and convenience that may be required. Tests that are more easily accessible and inexpensive may have a higher false negative rate. Dr. Tromberg envisions that every test that comes out of the RADx innovation funnel will have documentation about its best-use case.
The RADx innovation funnel, often referred to as a “shark tank” began 13 years ago with the Point of Care Technology Research Network (POCTRN). It now focuses almost exclusively on COVID-19 testing efforts. They have 5 sites across the US, with more than 200 people that are working day and night to provide independent validation of tests, facilitate clinical studies, and determine manufacturing and scale-up requirements while creating a roadmap for every project team to follow. They have also made funding available for the development of novel COVID-19 test ideas through the POCTRN website. Applications are reviewed by a panel of 30 experts within a day and, if approved, will move to the next stage of the shark tank. The strengths and weaknesses of the test from a technical, clinical and commercial perspective will be evaluated by a team of experts and a detailed proposal will be presented to a steering committee, then sent to the NIH. If the project is approved, it will enter phase one, with considerable financial support and the expectation that the company will hit its validation milestones within a month.
Since the inception of RADx on April 29, 2020, almost 60 projects have entered or emerged from the shark-tank stage with the expectation that at least 15 projects of those projects will be in the phase one stage this month. If they can reach their validation milestones in that first month, they will be eligible to move to phase two which provides substantial funding to allow companies to move into manufacturing and scale up for distribution. Dr. Tromberg is hopeful to have between 5 and 10 companies emerge over time from this innovation funnel, resulting in at least two viable products by the end of the summer.
The guidance, support and funding provided by RADx may allow companies to fast-track their progress by giving them the surge that they need, plus the additional support with regulatory issues, commercialization, and manufacturing, in a short period of time to go to market.
Dr.Tromberg is confident that they are engaging the innovation and entrepreneurial community in such a way that a lot of these ideas will move out and give us better performing tests and more of them. With estimates that they will have the capacity to test roughly 2 percent of the population, around 6 million people per day that they will achieve their target by the end of the year. He would also like to see testing technologies move away from being based predominantly in laboratories, making them more accessible to people as technologies that they can use in their homes. By applying the venture capitalist strategy to RADx of trying to discover what’s out there, while not being afraid to invest in risky endeavors, they are helping promising COVID-19 testing technologies take their best shot and fail early, if they’re going to fail. And for technologies that are further along, providing the needed resources to advance to commercialization.
A research team led by Drs. Wyndham H. Wilson, Louis M. Staudt, and Mark Roschewski at NIH’s National Cancer Institute (NCI) and Mihalis Lionakis at NIH’s National Institute of Allergy and Infection Diseases (NIAID) conducted a study on the ability of a cancer drug called acalabrutinib to treat COVID-19 disease.
The immune system normally protects your body from bacterial and viral infections by detecting and attacking the infection. However, an exaggerated immune response, called a cytokine storm, can damage the function of your organs, such as the lungs. Cytokines act as chemical messengers that help to stimulate and direct the immune response. But when large amounts of cytokines are released in the body, it can cause a dangerous hyperinflammatory state. Currently, there are no proven treatment strategies for COVID-19 patients exhibiting these symptoms.
Early data has shown that acalabrutinib, which is a Bruton tyrosine kinase (BTK) inhibitor, reduced respiratory distress and over-reactive immune responses in patients with COVID-19. Based on these results, researchers have designed a clinical trial to test whether the drug can be used as a safe and effective treatment for patients with COVID-19. The BTK protein plays an important role in the immune system response. Macrophages, a type of immune cell, use BTK to produce cytokines and inflammation. BTK inhibitors are approved to treat certain cancers, but they have not been approved as a treatment for COVID-19.
The research team carried out a clinical study of 19 patients with a confirmed COVID-19 diagnosis who required hospitalization and had low blood-oxygen levels along with evidence of inflammation. Of these, 11 had been receiving supplemental oxygen for an average of two days, and eight others had been on ventilators for an average of 1.5 days.
Within one to three days after receiving acalabrutinib, the majority of patients receiving supplemental oxygen experienced a substantial drop in inflammation, and their breathing improved. Eight of these 11 patients were able to come off supplemental oxygen and were discharged from the hospital. Four of the eight patients who were on a ventilator were able to come off it, while two recovered and were eventually discharged. Two of the patients in this group died.
Blood samples from the patients showed that levels of interleukin-6 (IL-6), a major cytokine associated with hyperinflammation in severe COVID-19, decreased after treatment with acalabrutinib. Counts of lymphocytes, a type of white blood cell, also rapidly improved in most patients. Low lymphocyte counts have been associated with worse outcome for patients with severe COVID-19. Patients with COVID-19 showed higher activity of the BTK protein along with an increased product of IL-6 when compared with blood cells from healthy volunteers.
If the results of this study are confirmed within a controlled clinical trial, acalabrutinib may play an important role as a new therapy to control severe cases of COVID-19. Clinical trials are currently underway to further investigate the drug’s safety and efficacy.
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