drug screening
Exploring Drug Repurposing for COVID-19 Treatment
Posted on by Dr. Francis Collins
It usually takes more than a decade to develop a safe, effective anti-viral therapy. But, when it comes to coronavirus disease 2019 (COVID-19), we don’t have that kind of time. One way to speed the process may be to put some old drugs to work against this new disease threat. This is generally referred to as “drug repurposing.”
NIH has been doing everything possible to encourage screens of existing drugs that have been shown safe for human use. In a recent NIH-funded study in the journal Nature, researchers screened a chemical “library” that contained nearly 12,000 existing drug compounds for their potential activity against SARS-CoV-2, the novel coronavirus that causes COVID-19 [1]. The results? In tests in both non-human primate and human cell lines grown in laboratory conditions, 21 of these existing drugs showed potential for repurposing to thwart the novel coronavirus—13 of them at doses that likely could be safely given to people. The majority of these drugs have been tested in clinical trials for use in HIV, autoimmune diseases, osteoporosis, and other conditions.
These latest findings come from an international team led by Sumit Chanda, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA. The researchers took advantage of a small-molecule drug library called ReFRAME [2], which was created in 2018 by Calibr, a non-profit drug discovery division of Scripps Research, La Jolla, CA.
In collaboration with Yuen Kwok-Yung’s team at the University of Hong Kong, the researchers first developed a high-throughput method that enabled them to screen rapidly each of the 11,987 drug compounds in the ReFRAME library for their potential to block SARS-CoV-2 in cells grown in the lab. The first round of testing narrowed the list of possible COVID-19 drugs to about 300. Next, using lower concentrations of the drugs in cells exposed to a second strain of SARS-CoV-2, they further narrowed the list to 100 compounds that could reliably limit growth of the coronavirus by at least 40 percent.
Generally speaking, an effective anti-viral drug is expected to show greater activity as its concentration is increased. So, Chanda’s team then tested those 100 drugs for evidence of such a dose-response relationship. Twenty-one of them passed this test. This group included remdesivir, a drug originally developed for Ebola virus disease and recently authorized by the U.S. Food and Drug Administration (FDA) for emergency use in the treatment of COVID-19. Remdesivir could now be considered a positive control.
These findings raised another intriguing question: Could any of the other drugs with a dose-response relationship work well in combination with remdesivir to block SARS-CoV-2 infection? Indeed, the researchers found that four of them could.
Further study showed that some of the most promising drugs on the list reduced the number of SARS-CoV-2 infected cells by 65 to 85 percent. The most potent of these was apilimod, a drug that has been evaluated in clinical trials for treating Crohn’s disease, rheumatoid arthritis, and other autoimmune conditions. Apilimod is now being evaluated in the clinic for its ability to prevent the progression of COVID-19. Another potential antiviral to emerge from the study is clofazimine, a 70-year old FDA-approved drug that is on the World Health Organization’s list of essential medicines for the treatment of leprosy.
Overall, the findings suggest that there may be quite a few existing drugs and/or experimental drugs fairly far along in the development pipeline that have potential to be repurposed for treating COVID-19. What’s more, some of them might also work well in combination with remdesivir, or perhaps other drugs, as treatment “cocktails,” such as those used to successfully treat HIV and hepatitis C.
This is just one of a wide variety of drug screening efforts that are underway, using different libraries and different assays to detect activity against SARS-CoV-2. The NIH’s National Center for Advancing Translational Sciences has established an open data portal to collect all of these data as quickly and openly as possible. As NIH continues its efforts to use the power of science to end the COVID-19 pandemic, it is critically important that we explore as many avenues as possible for developing diagnostics, treatments, and vaccines.
References:
[1] Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Riva L, Yuan S, Yin X, et al. Nature. 2020 Jul 24 [published online ahead of print]
[2] The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis. Janes J, Young ME, Chen E, et al. Proc Natl Acad Sci USA. 2018;115(42):10750-10755.
Links:
Coronavirus (COVID-19) (NIH)
ReFRAMEdb (Scripps Research, La Jolla, CA)
The Chanda Lab (Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA)
Yuen Kwok-Yung (University of Hong Kong)
OpenData|Covid-19 (National Center for Advancing Translational Sciences/NIH)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences
Body-on-a-Chip Device Predicts Cancer Drug Responses
Posted on by Dr. Francis Collins
Researchers continue to produce impressive miniature human tissues that resemble the structure of a range of human organs, including the livers, kidneys, hearts, and even the brain. In fact, some researchers are now building on this success to take the next big technological step: placing key components of several miniature organs on a chip at once.
These body-on-a-chip (BOC) devices place each tissue type in its own pea-sized chamber and connect them via fluid-filled microchannels into living, integrated biological systems on a laboratory plate. In the photo above, the BOC chip is filled with green fluid to make it easier to see the various chambers. For example, this easy-to-reconfigure system can make it possible to culture liver cells (chamber 1) along with two cancer cell lines (chambers 3, 5) and cardiac function chips (chambers 2, 4).
Researchers circulate blood-mimicking fluid through the chip, along with chemotherapy drugs. This allows them to test the agents’ potential to fight human cancer cells, while simultaneously gathering evidence for potential adverse effects on tissues placed in the other chambers.
This BOC comes from a team of NIH-supported researchers, including James Hickman and Christopher McAleer, Hesperos Inc., Orlando, FL. The two were challenged by their Swiss colleagues at Roche Pharmaceuticals to create a leukemia-on-a-chip model. The challenge was to see whether it was possible to reproduce on the chip the known effects and toxicities of diclofenac and imatinib in people.
As published in Science Translational Medicine, they more than met the challenge. The researchers showed as expected that imatinib did not harm liver cells [1]. But, when treated with diclofenac, liver cells on the chip were reduced in number by about 30 percent, an observation consistent with the drug’s known liver toxicity profile.
As a second and more challenging test, the researchers reconfigured the BOC by placing a multi-drug resistant vulva cancer cell line in one chamber and, in another, a breast cancer cell line that responded to drug treatment. To explore side effects, the system also incorporated a chamber with human liver cells and two others containing beating human heart cells, along with devices to measure the cells’ electrical and mechanical activity separately.
These studies showed that tamoxifen, commonly used to treat breast cancer, indeed killed a significant number of the breast cancer cells on the BOC. But, it only did so after liver cells on the chip processed the tamoxifen to produce its more active metabolite!
Meanwhile, tamoxifen alone didn’t affect the drug-resistant vulva cancer cells on the chip, whether or not liver cells were present. This type of cancer cell has previously been shown to pump the drug out through a specific channel. Studies on the chip showed that this form of drug resistance could be overcome by adding a second drug called verapamil, which blocks the channel.
Both tamoxifen alone and the combination treatment showed some off-target effects on heart cells. While the heart cells survived the treatment, they contracted more slowly and with less force. The encouraging news was that the heart cells bounced back from the tamoxifen-only treatment within three days. But when the drug-drug combination was tested, the cardiac cells did not recover their function during the same time period.
What makes advances like this especially important is that only 1 in 10 drug candidates entering human clinical trials ultimately receives approval from the Food and Drug Administration (FDA) [2]. Often, drug candidates fail because they prove toxic to the human brain, liver, kidneys, or other organs in ways that preclinical studies in animals didn’t predict.
As BOCs are put to work in testing new drug candidates and especially treatment combinations, the hope is that we can do a better job of predicting early on which chemical compounds will prove safe and effective in humans. For those drug candidates that are ultimately doomed, “failing early” is key to reducing drug development costs. By culturing an individual patient’s cells in the chambers, BOCs also may be used to help doctors select the best treatment option for that particular patient. The ultimate goal is to accelerate the translation of basic discoveries into clinical breakthroughs. For more information about tissue chips, take a look at NIH’s Tissue Chip for Drug Screening program.
References:
[1] Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics. McAleer CW, Long CJ, Elbrecht D, Sasserath T, Bridges LR, Rumsey JW, Martin C, Schnepper M, Wang Y, Schuler F, Roth AB, Funk C, Shuler ML, Hickman JJ. Sci Transl Med. 2019 Jun 19;11(497).
[2] Clinical development success rates for investigational drugs. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Nat Biotechnol. 2014 Jan;32(1):40-51.
Links:
Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)
James Hickman (Hesperos, Inc., Orlando, FL)
NIH Support: National Center for Advancing Translational Sciences
Progress Toward 3D Printed Human Organs
Posted on by Dr. Francis Collins
There’s considerable excitement that 3D printing technology might one day allow scientists to produce fully functional replacement organs from one’s own cells. While there’s still a lot to learn, this video shows just some of the amazing progress that’s now being made.
The video comes from a bioengineering team at Rice University, Houston, that has learned to bioprint the small air sacs in the lungs. When hooked up to a machine that pulsed air in and out of the air sacs, the rhythmic movement helped to mix red blood cells traveling through an associated blood vessel network. Those red cells also took up oxygen in much the way that blood vessels do when surrounding the hundreds of millions of air sacs in our lungs.
As mentioned in the video, one of the biggest technical hurdles in growing fully functional replacement tissues and organs is to find a way to feed the growing tissues with a blood supply and to remove waste products. In this study recently published in Science [1], the NIH-supported team cleared this hurdle by creating an open-source bioprinting technology they call SLATE, which is short for “stereo-lithography apparatus for tissue engineering.”
The SLATE system “grows” soft hydrogel scaffolds one layer at a time. Each layer is printed using a liquid pre-hydrogel solution that solidifies when exposed to blue light. By also projecting light into the hydrogel as a pixelated 3D shape, it’s possible to print complex 3D structures within minutes.
When the researchers first started, their printouts lacked the high resolution, submillimeter-scale channels needed to generate intricate vascular networks. In other manufacturing arenas, light-absorbing chemicals have helped control the conversion from liquid to solid in a very fine polymer layer. But these industrial light-absorbing chemicals are highly toxic and therefore unsuitable for scaffolds that grow living tissues and organs.
The researchers, including Bagrat Grigoryan, Jordan Miller, and Kelly Stevens, wondered whether they could swap out those noxious ingredients with synthetic and natural food dyes widely used in the food industry. These dyes include curcumin, anthocyanin, and tartrazine (yellow dye #5). Their studies showed that those fully biocompatible dyes worked as effective light absorbers, allowing the scientists to recreate the complex architectures of human vasculature. Importantly, the living cells survived within the soft scaffold!
These models are already yielding intriguing new insights into the vascular structures found within our organs and how those architectures may influence function in ways that hadn’t been well understood. In the near term, tissues and organs grown on such scaffolds might also find use as sophisticated, 3D tissue “chips,” with potential for use in studies to predict whether drugs will be safe in humans.
In the long term, this technology may allow production of replacement organs from those needing them. More than 100,000 men, women, and children are on the national transplant waiting list in the United States alone and 20 people die each day waiting for a transplant [2]. Ultimately, with the aid of bioprinting advances like this one, perhaps one day we’ll have a ready supply of perfectly matched and fully functional organs.
References:
[1] Multivascular networks and functional intravascular topologies within biocompatible hydrogels. Grigoryan B, Paulsen SJ, Corbett DC, Sazer DW, Fortin CL, Zaita AJ, Greenfield PT, Calafat NJ, Gounley JP, Ta AH, Johansson F, Randles A, Rosenkrantz JE, Louis-Rosenberg JD, Galie PA, Stevens KR, Miller JS. Science. 2019 May 3;364(6439):458-464.
[2] Organ Donor Statistics, Health Resources & Services Administration, October 2018.
Links:
Tissue Engineering and Regenerative Medicine (National Institute of Biomedical Imaging and Bioengineering/NIH)
Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)
Miller Lab (Rice University, Houston)
NIH Support: National Heart, Lung, and Blood Institute; National Institute of Biomedical Imaging and Bioengineering; National Institute of General Medical Sciences; Common Fund
Treating Zika Infection: Repurposed Drugs Show Promise
Posted on by Dr. Francis Collins
Credit: National Center for Advancing Translational Sciences, NIH
In response to the health threat posed by the recent outbreak of Zika virus in Latin America and its recent spread to Puerto Rico and Florida, researchers have been working at a furious pace to learn more about the mosquito-borne virus. Considerable progress has been made in understanding how Zika might cause babies to be born with unusually small heads and other abnormalities and in developing vaccines that may guard against Zika infection.
Still, there remains an urgent need to find drugs that can be used to treat people already infected with the Zika virus. A team that includes scientists at NIH’s National Center for Advancing Translational Sciences (NCATS) now has some encouraging news on this front. By testing 6,000 FDA-approved drugs and experimental chemical compounds on Zika-infected human cells in the lab, they’ve shown that some existing drugs might be repurposed to fight Zika infection and prevent the virus from harming the developing brain [1]. While additional research is needed, the new findings suggest it may be possible to speed development and approval of new treatments for Zika infection.
DNA Barcodes Could Streamline Search for New Drugs to Combat Cancer
Posted on by Dr. Francis Collins
A little more than a decade ago, researchers began adapting a familiar commercial concept to genomics: the barcode. Instead of the black, printed stripes of the Universal Product Codes (UPCs) that we see on everything from package deliveries to clothing tags, they used short, unique snippets of DNA to label cells. These biological “barcodes” enable scientists to distinguish one cell type from another, in much the same way that a supermarket scanner recognizes different brands of cereal.
DNA barcoding has already empowered single-cell analysis, including for nerve cells in the brain. Now, in a new NIH-supported study, DNA barcoding helps in the development of a new method that could greatly streamline an increasingly complex and labor-intensive process: screening for drugs to combat cancer.
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