The issue of missing essential doses of medicine and vaccines could become a thing of the past, thanks to new technology developed by bioengineers at Rice University. This state-of-the-art technology enables the production of time-release drugs.
“This is a huge problem in the treatment of chronic disease,” said Kevin McHugh, corresponding author of a study about the technology published online in Advanced Materials. “It’s estimated that 50% of people don’t take their medications correctly. With this, you’d give them one shot, and they’d be all set for the next couple of months.”
The consequences of not taking prescription medicine correctly can be devastating, resulting in a staggering annual cost. In the United States alone, it is estimated that the toll includes over 100,000 deaths, as much as 25% of hospitalizations, and a healthcare cost exceeding $100 billion.
Encapsulating medicine in microparticles that dissolve and release drugs over time isn’t a new idea. But McHugh and graduate student Tyler Graf used 21st-century methods to develop next-level encapsulation technology that is far more versatile than its forerunners.
Dubbed PULSED (short for Particles Uniformly Liquified and Sealed to Encapsulate Drugs), the technology employs high-resolution 3D printing and soft lithography to produce arrays of more than 300 nontoxic, biodegradable cylinders that are small enough to be injected with standard hypodermic needles.
The cylinders are made of a polymer called PLGA that’s widely used in clinical medical treatment. McHugh and Graf demonstrated four methods of loading the microcylinders with drugs and showed they could tweak the PLGA recipe to vary how quickly the particles dissolved and released the drugs — from as little as 10 days to almost five weeks. They also developed a fast and easy method for sealing the cylinders, a critical step to demonstrate the technology is both scalable and capable of addressing a major hurdle in time-release drug delivery.
“The thing we’re trying to overcome is ‘first-order release,’” McHugh said, referring to the uneven dosing that’s characteristic with current methods of drug encapsulation. “The common pattern is for a lot of the drug to be released early, on day one. And then on day 10, you might get 10 times less than you got on day one.
“If there’s a huge therapeutic window, then releasing 10 times less on day 10 might still be OK, but that’s rarely the case,” McHugh said. “Most of the time it’s really problematic, either because the day-one dose brings you close to toxicity or because getting 10 times less — or even four or five times less — at later time points isn’t enough to be effective.”
In many cases, it would be ideal for patients to have the same amount of a drug in their systems throughout treatment. McHugh said PULSED can be tailored for that kind of release profile, and it also could be used in other ways.
“Our motivation for this particular project actually came from the vaccine space,” he said. “In vaccination, you often need multiple doses spread out over the course of months. That’s really difficult to do in low- and middle-income countries because of health care accessibility issues. The idea was, ‘What if we made particles that exhibit pulsatile release?’ And we hypothesized that this core-shell structure — where you’d have the vaccine in a pocket inside a biodegradable polymer shell — could both produce that kind of all-or-nothing release event and provide a reliable way to set the delayed timing of the release.”
Though PULSED hasn’t yet been tested for months-long release delays, McHugh said previous studies from other labs have shown PLGA capsules can be formulated to release drugs as much as six months after injection.
In their study, Graf and McHugh showed they could make and load particles with diameters ranging from 400 microns to 100 microns. McHugh said this size enables particles to stay where they are injected until they dissolve, which could be useful for delivering large or continuous doses of one or more drugs at a specific location, like a cancerous tumor.
“For toxic cancer chemotherapies, you’d love to have the poison concentrated in the tumor and not in the rest of the body,” he said. “People have done that experimentally, injecting soluble drugs into tumors. But then the question is how long is it going to take for that to diffuse out.
“Our microparticles will stay where you put them,” McHugh said. “The idea is to make chemotherapy more effective and reduce its side effects by delivering a prolonged, concentrated dose of the drugs exactly where they’re needed.”
A video describing the research. Credit: Rice University
The crucial discovery of the contactless sealing method happened partly by chance. McHugh said previous studies had explored the use of PLGA microparticles for time-released drug encapsulation, but sealing large numbers of particles had proven so difficult that the cost of production was considered impractical for many applications.
While exploring alternative sealing methods, Graf noticed that trying to seal the microparticles by dipping them into different melted polymers was not giving the desired outcome. “Eventually, I questioned whether dipping the microparticles into a liquid polymer was even necessary,” said Graf, who proceeded to suspend the PLGA microparticles above a hot plate, enabling the top of the particles to melt and to self-seal while the bottom of the particles remained intact, “Those first particle batches barely sealed, but seeing the process was possible was very exciting.”Further optimization and experimentation resulted in consistent and robust sealing of the cylinders, which eventually proved to be one of the easier steps in making the time-released drug capsules. Each 22×14 array of cylinders was about the size of a postage stamp, and Graf made them atop glass microscope slides.
After loading an array with drugs, Graf said he would suspend it about a millimeter or so above the hot plate for a short time. “I’d just flip it over and rest it on two other glass slides, one on either end, and set a timer for however long it would take to seal. It just takes a few seconds.”
Reference: “A Scalable Platform for Fabricating Biodegradable Microparticles with Pulsatile Drug Release” by Tyler P. Graf, Sherry Yue Qiu, Dhruv Varshney, Mei-Li Laracuente, Erin M. Euliano, Pujita Munnangi, Brett H. Pogostin, Tsvetelina Baryakova, Arnav Garyali and Kevin J. McHugh, 2 March 2023, Advanced Materials. DOI: 10.1002/adma.202300228
The study was funded by the Cancer Prevention and Research Institute of Texas, the National Institutes of Health, and the National Science Foundation.
Antibiotics help to fight bacterial infections, but they can also harm the helpful microbes living in the gut, which can have long-lasting health consequences.
Now new research being presented at this year’s European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Copenhagen, Denmark (15-18 April) has identified several protective drugs that may lessen the collateral damage caused by antibiotics without compromising their effectiveness against harmful bacteria.
The unique study by Dr Lisa Maier and Dr Camille V. Goemans from the European Molecular Biology Laboratory, Heidelberg, Germany and colleagues, which analyzed the effects of 144 different antibiotics on the abundance of the most common gut bacteria, offers novel insights into reducing the adverse effects of antibiotic treatment on the gut microbiome.
The trillions of microorganisms in the human gut profoundly impact health by aiding digestion, providing nutrients and metabolites, and working with the immune system to fend off harmful bacteria and viruses.
Antibiotics can damage these microbial communities, resulting in an imbalance that can lead to recurrent gastrointestinal problems caused by Clostridioides difficile infections as well as long-term health problems such as obesity, allergies, asthma and other immunological or inflammatory diseases.
Despite this well-known collateral damage, which antibiotics affect which types of bacterial species, and whether these negative side effects be mitigated has not been studied systematically because of technical challenges.
To find out more, researchers systematically analyzed the growth and survival of 27 different bacterial species commonly found in the gut following treatment with 144 different antibiotics. They also assessed the minimal inhibitory concentration (MIC) – the minimal concentration of an antibiotic required to stop bacteria from growing – for over 800 of these antibiotic-bacteria combinations.
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The results revealed that the majority of gut bacteria had slightly higher MICs than disease-causing bacteria, suggesting that at commonly used antibiotic concentrations, most of the tested gut bacteria would not be affected.
However, two widely used antibiotic classes – tetracyclines and macrolides – not only stopped healthy bacteria growing at much lower concentrations than those required to stop the growth of disease-causing bacteria, but they also killed more than half of the gut bacterial species they tested, potentially altering the gut microbiome composition for a long time.
As drugs interact differently across different bacterial species, the researchers investigated whether a second drug could be used to protect the gut microbes. They combined the antibiotics erythromycin (a macrolide) and doxycycline (a tetracycline) with a set of 1,197 pharmaceuticals to identify suitable drugs that would protect two abundant gut bacterial species (Bacteriodes vulgatus and Bacteriodes uniformis) from the antibiotics.
The researchers identified several promising drugs including the anticoagulant dicumarol, the gout medication benzbromarone, and two anti-inflammatory drugs, tolfenamic acid and diflunisal.
Importantly, these drugs did not compromise the effectiveness of the antibiotics against disease-causing bacteria.
Further experiments showed that these antidote drugs also protected natural bacterial communities derived from human stool samples and in living mice.
“This Herculean undertaking by an international team of scientists has identified a novel approach that combines antibiotics with a protective antidote to help keep the gut microbiome healthy and reduce the harmful side effects of antibiotics without compromising their efficiency,” says Dr Ulrike Löber, of the Max-Delbrück-Center for Molecular Medicine in Berlin, Germany who is presenting the research at ECCMID. “Despite our promising findings, further research is needed to identify optimum and personalized combinations of antidote drugs and to exclude any potential long-term effects on the gut microbiome.“
Algorithm calculates how to effectively “repurpose” present-day therapies for future use.
Researchers have developed an algorithmic tool, PHENSIM, which simulates tissue-specific infection of host cells of SARS-CoV-2 to identify existing drugs that could be repurposed to fight future pandemics. The tool could improve disease-specific drug development and offers the possibility of responding more quickly to public health crises.
A global team of researchers has created an algorithmic tool that can identify existing drugs in order to combat future pandemics. The work, reported in the Cell Press journal Heliyon, offers the possibility of responding more quickly to public health crises.
“There is no silver bullet to defeat the Covid pandemic as it takes us over a public-health roller-coaster of deaths and devastation,” explains Naomi Maria, an immunologist, a visiting scientist at New York University’s Courant Institute of Mathematical Sciences, and the paper’s lead author. “However, using this AI tool, coupled with in vitro data and other resources, we’ve been able to model the SARS-CoV-2 infection and identify several COVID-19 drugs currently available as potentially effective in battling the next outbreak.”
“Drug repurposing strategies provide an attractive and effective approach for quickly targeting potential new interventions,” adds Bud Mishra, a professor at NYU’s Courant and one of the paper’s senior authors. “Identifying and selecting ahead of time the best candidates, prior to costly and laborious in vitro and in vivo experiments and ensuing clinical trials, could significantly improve disease-specific drug development.”
COVID-19 has shown to be a daunting challenge over the past three years, even though vaccines and hygienic practices have, over time, lessened its severity. However, despite these tools to combat it, SARS-CoV-2—the virus that causes COVID-19—continues to spread and take lives. This is due, in part, to its ability to rapidly diversify in its target cell types, immune-response pathways, and modes of transmission. These traits make traditional approaches to vaccine and drug design less effective than in the past—and especially when the virus co-infects with other pathogens, such as RSV and influenza.
Recognizing that current methods leave us chasing the virus, the team—which also included researchers from the Feinstein Institutes for Medical Research at Northwell Health in New York, the Red Cross Blood Bank Foundation Curaçao, the Curaçao Biomedical Health and Research Institute, the Netherlands’ University Medical Center Groningen, and Catania University’s Department of Clinical and Experimental Medicine in Sicily—conceived an approach aimed at closing the gap in future pandemics: repurposing existing drugs to fight back.
To do so, they developed a systems biology tool, the PHENotype SIMulator (PHENSIM). PHENSIM simulates tissue-specific infection of host cells of SARS-CoV-2 and then performs, through a series of computer—or in silico—experiments to identify drugs that would be candidates for repurposing. The algorithm computes, taking into account selected cells, cell lines, and tissues and under an array of contexts, by propagating the effects and alterations of biomolecules—such as differentially expressed genes, proteins, and microRNAs—and then calculates antiviral effects. The team confirmed the validity of the tool by comparing its results with recently published in vitro studies, demonstrating PHENSIM’s potential power in aiding effective drug repurposing.
The researchers are part of RxCovea—a multi-disciplinary group of immunologists, biologists, chemists, data scientists, game theorists, geneticists, mathematicians, and physicians, among others, that seeks to develop innovative strategies to address COVID-19.
For the first time, humans with newly diagnosed Type 1 diabetes, or T1D, have received two treatments called GABA and GAD that have shown promise in animal studies and in isolated human pancreas islets. This investigator-initiated clinical trial, published in Nature Communications, focused exclusively on children with recent onset T1D.
Diabetes is a disease affecting two pancreatic hormones -; insulin and glucagon. In healthy people, insulin helps cells take up glucose from the blood when glucose levels are high. In contrast, glucagon helps the liver release glucose into the bloodstream when glucose levels are low. Thus, levels of blood glucose remain steady.
In T1D, autoantibodies destroy the pancreatic beta cells, insulin release is diminished, and glucagon release is excessive relative to the insulin deficiency. This can cause a vicious cycle of escalating blood glucose levels. Strategies to ameliorate or cure T1D, therefore, target the preservation of insulin-secreting beta cells and/or attenuation of the relative excess of alpha cell glucagon. Most importantly, concerning the inhibition of alpha cell glucagon in this trial by GABA/GAD, recent studies in animals made diabetic have shown that inhibition of glucagon leads to expansion of insulin-secreting beta cells and improvements in hyperglycemia.
Researchers in the study, led by University of Alabama at Birmingham physicians, were able to enroll children within the first five weeks of diagnosis, before the near total eradication of beta cells. Forty percent of the study participants were younger than 10 years old. The study -; which was constrained to lower-dose GABA therapy by the United States Food and Drug Administration because it was the first human trial with GABA -; did not achieve its primary outcome, the preservation of insulin production by beta cells. However, it did meet the clinically relevant secondary outcome of reduced serum glucagon. Significantly, the trial confirmed the safety and tolerability of oral GABA. Additionally, in collaboration with the immunology team of Hubert Tse, Ph.D., at the UAB Comprehensive Diabetes Center, a separate manuscript under review will describe a salutary effect of GABA alone and in combination with GAD on cytokine responses in peripheral blood mononuclear cells from trial participants.
GABA is gamma aminobutyric acid, a major inhibitory neurotransmitter. In the endocrine pancreas, GABA participates in paracrine regulation -; meaning a hormone that acts on nearby cells -; on the beta cells that produce insulin and the alpha cells that produce glucagon. In various mouse model studies, GABA was able to delay diabetes onset, and restore normal blood glucose levels after diabetes had already commenced. GABA treatment also led to significant decreases in the inflammatory cytokine expression that participates in the pathogenesis of T1D.
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GAD is glutamic acid decarboxylase, the enzyme that acts on glutamate to form GABA. Animal and pancreatic islet cell studies show that immunization with GAD alone may help preserve beta cells. Both GABA and GAD are highly concentrated in the pancreatic islet, which is the autoimmune target of T1D.
The study, which was conducted between March 2015 and June 2019, screened 350 patients and enrolled 97, whose ages averaged 11 years. Forty-one took oral GABA twice a day; 25 took the oral GABA in combination with two injections of GAD, one at the baseline visit and one at the one-month visit. The remaining 31 children received a placebo treatment. Analysis after one year of treatment included 39 in the GABA group, 22 in the GABA/GAD group and 30 in the placebo group.
Given that GABA reduces immune inflammation at higher doses in several diabetic rodent models, it is plausible that increased GABA doses, or longer-acting preparations, could offer sufficiently prolonged, above-threshold GABA concentrations to preserve islet cells, particularly during stage 1 diabetes.”
Gail Mick, M.D., UAB Professor in the Department of Pediatrics’ Division of Pediatric Endocrinology and Diabetes
Mick and Kenneth McCormick, M.D., who recently retired from UAB Pediatrics, co-led the trial.
Alexandra Martin and Mick, UAB Department of Pediatrics, are co-first authors of the study, “A randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes.”
Other authors are Heather M. Choat, Alison A. Lunsford and Kenneth L. McCormick, UAB Department of Pediatrics; Hubert M. Tse, UAB Department of Microbiology; and Gerald G. McGwin Jr., Department of Epidemiology, UAB School of Public Health.
Martin, A., et al. (2022) A randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes. Nature Communications.doi.org/10.1038/s41467-022-35544-3.
Unique experiments involved ‘mini-organs’, animal research, donated human organs, volunteers, and patients.
Cambridge scientists have identified an off-patent drug that can be repurposed to prevent COVID-19 – and may be capable of protecting against future variants of the virus – in research involving a unique mix of ‘mini-organs’, donor organs, animal studies, and patients.
The research, published recently in the journal Nature, showed that an existing drug used to treat a type of liver disease is able to ‘lock’ the doorway by which SARS-CoV-2 enters our cells, a receptor on the cell surface known as ACE2. Because this drug targets the host cells and not the virus, it should protect against future new variants of the virus as well as other coronaviruses that might emerge.
If confirmed in larger clinical trials, this could provide a vital drug for protecting those individuals for whom vaccines are ineffective or inaccessible as well as individuals at increased risk of infection.
Dr. Fotios Sampaziotis, from the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge and Addenbrooke’s Hospital, led the research in collaboration with Professor Ludovic Vallier from the Berlin Institute of Health at Charité.
Dr. Sampaziotis said: “Vaccines protect us by boosting our immune system so that it can recognize the virus and clear it, or at least weaken it. But vaccines don’t work for everyone – for example patients with a weak immune system – and not everyone has access to them. Also, the virus can mutate into new vaccine-resistant variants.
“We’re interested in finding alternative ways to protect us from SARS-CoV-2 infection that are not dependent on the immune system and could complement vaccination. We’ve discovered a way to close the door to the virus, preventing it from getting into our cells in the first place and protecting us from infection.”
Dr. Sampaziotis had previously been working with organoids – ‘mini-bile ducts’ – to study diseases of the bile ducts. Organoids are clusters of cells that can grow and proliferate in culture, taking on a 3D structure that has the same functions as the part of the organ being studied.
Using these, the researchers found – rather serendipitously – that a molecule known as FXR, which is present in large amounts in these bile duct organoids, directly regulates the viral ‘doorway’ ACE2, effectively opening and closing it. They went on to show that ursodeoxycholic acid (UDCA), an off-patent drug used to treat a form of liver disease known as primary biliary cholangitis, ‘turns down’ FXR and closes the ACE2 doorway.
In this new study, his team showed that they could use the same approach to close the ACE2 doorway in ‘mini-lungs’ and ‘mini-guts’ – representing the two main targets of SARS-CoV-2 – and prevent viral infection.
The next step was to show that the drug could prevent infection not only in lab-grown cells but also in living organisms. For this, they teamed up with Professor Andrew Owen from the University of Liverpool to show that the drug prevented infection in hamsters exposed to the virus, which are used as the ‘gold-standard’ model for pre-clinical testing of drugs against SARS-CoV-2. Importantly, the hamsters treated with UDCA were protected from the delta variant of the virus, which was new at the time and was partially resistant to existing vaccines.
Professor Owen said: “Although we will need properly-controlled randomized trials to confirm these findings, the data provide compelling evidence that UDCA could work as a drug to protect against COVID-19 and complement vaccination programs, particularly in vulnerable population groups. As it targets the ACE2 receptor directly, we hope it may be more resilient to changes resulting from the evolution of the SARS-CoV-2 spike, which result in the rapid emergence of new variants.”
Next, the researchers worked with Professor Andrew Fisher from Newcastle University and Professor Chris Watson from Addenbrooke’s hospital to see if their findings in hamsters held true in human lungs exposed to the virus.
The team took a pair of donated lungs not suitable for transplantation, keeping them breathing outside the body with a ventilator and using a pump to circulate blood-like fluid through them to keep the organs functioning while they could be studied. One lung was given the drug, but both were exposed to SARS-CoV-2. Sure enough, the lung that received the drug did not become infected, while the other lung did.
Professor Fisher said: “This is one of the first studies to test the effect of a drug in a whole human organ while it’s being perfused. This could prove important for organ transplantation – given the risks of passing on COVID-19 through transplanted organs, it could open up the possibility of treating organs with drugs to clear the virus before transplantation.”
Moving next to human volunteers, the Cambridge team collaborated with Professor Ansgar Lohse from the University Medical Centre Hamburg-Eppendorf in Germany.
Professor Lohse explained: “We recruited eight healthy volunteers to receive the drug. When we swabbed the noses of these volunteers, we found lower levels of ACE2, suggesting that the virus would have fewer opportunities to break into and infect their nasal cells – the main gateway for the virus.”
While it wasn’t possible to run a full-scale clinical trial, the researchers did the next best thing: looking at data on COVID-19 outcomes from two independent cohorts of patients, comparing those individuals who were already taking UDCA for their liver conditions against patients not receiving the drug. They found that patients receiving UDCA were less likely to develop severe COVID-19 and be hospitalized.
First author and PhD candidate Teresa Brevini from the University of Cambridge said: “This unique study gave us the opportunity to do really translational science, using a laboratory finding to directly address a clinical need.
“Using almost every approach at our fingertips we showed that an existing drug shuts the door on the virus and can protect us from COVID-19. Importantly, because this drug works on our cells, it is not affected by mutations in the virus and should be effective even as new variants emerge.”
Dr. Sampaziotis said the drug could be an affordable and effective way of protecting those for whom the COVID-19 vaccine is ineffective or inaccessible. “We have used UDCA in clinic for many years, so we know it’s safe and very well tolerated, which makes administering it to individuals with high COVID-19 risk straightforward.
“This tablet costs little, can be produced in large quantities fast and easily stored or shipped, which makes it easy to rapidly deploy during outbreaks – especially against vaccine-resistant variants, when it might be the only line of protection while waiting for new vaccines to be developed. We are optimistic that this drug could become an important weapon in our fight against COVID-19.”
Reference: “FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2” by Teresa Brevini, Mailis Maes, Gwilym J. Webb, Binu V. John, Claudia D. Fuchs, Gustav Buescher, Lu Wang, Chelsea Griffiths, Marnie L. Brown, William E. Scott III, Pehuén Pereyra-Gerber, William T. H. Gelson, Stephanie Brown, Scott Dillon, Daniele Muraro, Jo Sharp, Megan Neary, Helen Box, Lee Tatham, James Stewart, Paul Curley, Henry Pertinez, Sally Forrest, Petra Mlcochova, Sagar S. Varankar, Mahnaz Darvish-Damavandi, Victoria L. Mulcahy, Rhoda E. Kuc, Thomas L. Williams, James A. Heslop, Davide Rossetti, Olivia C. Tysoe, Vasileios Galanakis, Marta Vila-Gonzalez, Thomas W. M. Crozier, Johannes Bargehr, Sanjay Sinha, Sara S. Upponi, Corrina Fear, Lisa Swift, Kourosh Saeb-Parsy, Susan E. Davies, Axel Wester, Hannes Hagström, Espen Melum, Darran Clements, Peter Humphreys, Jo Herriott, Edyta Kijak, Helen Cox, Chloe Bramwell, Anthony Valentijn, Christopher J. R. Illingworth, UK-PBC research consortium, Bassam Dahman, Dustin R. Bastaich, Raphaella D. Ferreira, Thomas Marjot, Eleanor Barnes, Andrew M. Moon, Alfred S. Barritt IV, Ravindra K. Gupta, Stephen Baker, Anthony P. Davenport, Gareth Corbett, Vassilis G. Gorgoulis, Simon J. A. Buczacki, Joo-Hyeon Lee, Nicholas J. Matheson, Michael Trauner, Andrew J. Fisher, Paul Gibbs, Andrew J. Butler, Christopher J. E. Watson, George F. Mells, Gordon Dougan, Andrew Owen, Ansgar W. Lohse, Ludovic Vallier and Fotios Sampaziotis, 5 December 2022, Nature. DOI: 10.1038/s41586-022-05594-0
The research was largely funded by UK Research & Innovation, the European Association for the Study of the Liver, the NIHR Cambridge Biomedical Research Centre and the Evelyn Trust.
Investigational drug works differently than antibody drugs which are losing effectiveness against the COVID-19 virus.
Scientists have developed a drug that potently neutralizes SARS-CoV-2, the COVID-19 coronavirus, and is equally effective against the Omicron variant and every other tested variant. The drug is designed in such a way that natural selection to maintain infectiousness of the virus should also maintain the drug’s activity against future variants.
The investigational drug was developed by researchers at Dana-Farber Cancer Institute. As described in a report published on December 7 in the journal Science Advances, the drug is not an antibody, but a related molecule known as an ACE2 receptor decoy. Unlike antibodies, the ACE2 decoy is far more difficult for the SARS-CoV-2 virus to evade because mutations in the virus that would enable it to avoid the drug would also reduce the virus’s ability to infect cells. The Dana-Farber scientists found a way to make this type of drug neutralize coronaviruses more potently in animals infected with COVID-19 and to make it safe to give to patients.
This report comes at a time when antibody drugs used to treat COVID-19 have lost their effectiveness because the viral spike protein has mutated to escape being targeted by the antibodies.
The researchers, led by first author James Torchia, MD, PhD, and senior author Gordon Freeman, PhD, identified features that make ACE2 decoys especially potent and long-lasting. For example, they found that when they included a piece of the ACE2 protein called the collectrin-like domain, it made the drug stick more tightly to the virus and have a longer life in the body. Their experiments showed that ACE2 decoys have potent activity against the COVID-19 virus because they trigger an irreversible change in the structure of the virus — they “pop” the top off the viral spike protein so it can’t bind to the cell-surface ACE2 receptor and infect cells.
The SARS-CoV-2 virus is covered with projections called spike proteins that enable the virus to infect cells. The spike protein binds to the ACE2 receptor on the cell surface and then refolds, driving the spike into the cell, enabling the virus to enter. ACE2 decoys lure the virus to bind to the decoy instead of the cell, “popping” the spike and inactivating the virus before it can enter cells. This explains the drug’s surprising potency: not only does it function as a competitive inhibitor, but it permanently inactivates the virus. Since binding to ACE2 is required for infection, variants can change but they must continue to bind to ACE2, making the drug persistently active against all variants.
The researchers say that, in addition to treating antibody-resistant variants of SARS-CoV-2, the drug described in this study could be useful to treat new coronaviruses that might emerge in the future to infect humans. This is because many coronaviruses in nature poised to enter the human population also utilize ACE2 to infect cells.
While the drug, called DF-COV-01, has not yet been tested in humans, manufacturing development is nearly complete and preclinical studies needed for regulatory approval are underway, with the goal of advancing the drug to clinical trials.
“Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo” by James A. Torchia, Alexander H. Tavares, Laura S. Carstensen, Da-Yuan Chen, Jessie Huang, Tianshu Xiao, Sonia Mukherjee, Patrick M. Reeves, Hua Tu, Ann E. Sluder, Bing Chen, Darrell N. Kotton, Richard A. Bowen, Mohsan Saeed, Mark C. Poznansky and Gordon J. Freeman, 7 December 2022, Science Advances. DOI: 10.1126/sciadv.abq6527
This work was supported by a Department of Defense CDMRP Peer Reviewed Medical Research Program Technology/Therapeutic Development Award. Additional support was provided by a National Instititutes of Health grant, an Evergrande MassCPR award, and a grant from COVID-19 FastGrants.
The work was performed by a collaborative team including scientists from Dana-Farber Cancer Institute, Massachusetts General Hospital Vaccine and Immunotherapy Center, Boston University Aram V. Chobanian & Edward Avedisian School of Medicine, the National Emerging Infectious Disease Laboratory at Boston University, Colorado State University, and Boston Children’s Hospital.
An interdisciplinary research team led by the University of California, Los Angeles (UCLA) discovered that a drug already approved by the Food and Drug Administration (FDA) for eye disease, verteporfin, stopped the replication of SARS-CoV-2, the virus that causes COVID-19. Their laboratory study identified the Hippo signaling pathway as a potential target for therapies against the coronavirus.
Many important human biological processes are controlled by complicated chain reactions called signaling pathways, in which certain proteins act as messenger molecules that promote or block the signals of other proteins.
The lead researchers were investigating the Hippo pathway, which controls the size of organs in the body, in earlier National Institutes of Health–funded studies of the Zika virus, which can cause undersized brains in infants. Noticing that this pathway also seemed to have virus-fighting effects, they launched the current study investigating SARS-CoV-2.
The scientists performed experiments using tissue samples from people with COVID-19, as well as cultured human heart and lung cells selected to closely reflect how healthy cells respond to SARS-CoV-2 infection. They observed changes in many genes involved with the Hippo signaling pathway after infection. In addition, they examined a protein called YAP, or Yes-associated protein, whose activity is blocked when the Hippo pathway is activated.
The scientists found that in the cultured human cells, both the original strain and Delta variant of SARS-CoV-2 activated the Hippo pathway in the first few days after infection. When they silenced this pathway and increased YAP, the virus replicated itself more. They team also pretreated cells with verteporfin, which blocks YAP in the eye disease known as choroidal neovascularization, and then infected them with SARS-CoV-2. In the verteporfin-treated cells, concentrations of the coronavirus were below detectable levels, compared to more than 60,000 units of the virus per milliliter in an untreated control group.
The results indicate verteporfin may be a candidate to treat COVID-19, and its status as FDA-approved could make it easier to launch clinical trials to verify its safety and effectiveness against the coronavirus. The study showed that the Hippo pathway is activated within days of SARS-CoV-2 infection, suggesting that treatments using the mechanism could be deployed before symptoms arise to reduce the severity of disease.
Reference: “Hippo signaling pathway activation during SARS-CoV-2 infection contributes to host antiviral response” by Gustavo Garcia Jr., Arjit Vijey Jeyachandran, Yijie Wang, Joseph Ignatius Irudayam, Sebastian Castillo Cario, Chandani Sen, Shen Li, Yunfeng Li, Ashok Kumar, Karin Nielsen-Saines, Samuel W. French, Priya S. Shah, Kouki Morizono, Brigitte N. Gomperts, Arjun Deb, Arunachalam Ramaiah, Vaithilingaraja Arumugaswami, 8 November 2022, PLOS Biology. DOI: 10.1371/journal.pbio.3001851
The study’s first author is Gustavo Garcia Jr., a former UCLA staff research associate, and the corresponding authors are Vaithilingaraja Arumugaswami, a UCLA associate professor of molecular and medical pharmacology and a member of the California NanoSystems Institute at UCLA and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, and Arunachalam Ramaiah of the Tata Institute for Genetics and Society in India. Other co-authors are Arjit Jeyachandran, Yijie Wang, Joseph Irudayam, Sebastian Castillo Cario, Chandani Sen, Shen Li, Yunfeng Li, Karin Nielsen-Saines, Samuel French, Kouki Morizono, Brigitte Gomperts, and Arjun Deb, all of UCLA; Ashok Kumar of Wayne State University; and Priya Shah of UC Davis.
The study was funded by the UCLA David Geffen School of Medicine, the Broad Stem Cell Research Center, the UCLA W.M. Keck Foundation COVID-19 Research Award Program, the National Institutes of Health (NIH), and the Tata Institute.
New research findings reveal that a serious condition that can cause the kidneys to suddenly stop working could be treated with existing medicines.
Scientists found that medicines usually used to treat angina and high blood pressure prevented much of the long-term damage to the kidney and cardiovascular system caused by acute kidney injury (AKI). The study, which was conducted in mice, was published on December 14, in the journal Science Translational Medicine.
Experts hope the findings will pave the way for improved treatment of AKI – a common condition that occurs in approximately 20 percent of emergency hospital admissions in the UK.
The condition is usually caused by other illnesses that reduce blood flow to the kidney (such as low blood pressure, blood loss, heart attack, or organ failure), or due to toxicity arising from some medicines.
AKI must be treated quickly to prevent death. Even if the kidneys recover, AKI can cause long-lasting damage to the kidneys and the cardiovascular system.
Of those who survive an episode of AKI, 30 percent are left with chronic kidney disease (CKD). The remaining 70 percent that recover full kidney function are at an almost 30-fold increased risk of developing CKD. In time, CKD can result in kidneys that stop working altogether. This is known as kidney failure, end-stage renal disease (ESRD), or end-stage kidney disease (ESKD).
A team from the University of Edinburgh found that patients with AKI had increased blood levels of endothelin – a protein that activates inflammation and causes blood vessels to constrict. Endothelin levels remained high long after kidney function had recovered.
After finding the same increase in endothelin in mice with AKI, experts treated the animals with medicines that block the endothelin system. The medicines – normally used to treat angina and high blood pressure – work by stopping the production of endothelin or by shutting off endothelin receptors in cells.
The mice were monitored over a four-week period after AKI. Those that were treated with the endothelin-blocking medicines had lower blood pressure, less inflammation and reduced scarring in the kidney.
Their blood vessels were more relaxed and kidney function was also improved, compared with untreated mice.
Dr. Bean Dhaun, Senior Clinical Lecturer and Honorary Consultant Nephrologist at the University of Edinburgh’s Centre for Cardiovascular Science, said: “AKI is a harmful condition, particularly in older people and even with recovery it can have a long-term impact on a person’s health. Our study shows that blocking the endothelin system prevents the long-term damage of AKI in mice. As these medicines are already available for use in humans, I hope that we can move quickly to see if the same beneficial effects are seen in our patients.”
Professor James Leiper, Associate Medical Director at the British Heart Foundation, said: “Impaired kidney function that results from acute kidney injury can also increase a person’s chance of developing and dying from heart and circulatory diseases, so it’s vital we find ways to reduce this risk.
“This promising research suggests that widely available medicines could help to tackle the impact of acute kidney injury before it can cause damage and further complications. While further studies will be needed to demonstrate whether this treatment is safe and effective for patients, this early research is an encouraging first step.”
Reference: “Endothelin blockade prevents the long-term cardiovascular and renal sequelae of acute kidney injury in mice” by Alicja Czopek, Rebecca Moorhouse, Peter J. Gallacher, Dan Pugh, Jessica R. Ivy, Tariq E. Farrah, Emily Godden, Robert W. Hunter, David J. Webb, Pierre-Louis Tharaux, David C. Kluth, James W. Dear, Matthew A. Bailey and Neeraj Dhaun, 14 December 2022, Science Translational Medicine. DOI: 10.1126/scitranslmed.abf5074
The study was published on December 14, 2022, in the journal Science Translational Medicine. It was funded by the Medical Research Council and the British Heart Foundation.
Dr. Benjamin Rotstein and collaborators unveil an operationally simple method to prepare carbon isotope-labeled versions of drugs and diagnostics.
The development of new pharmaceuticals relies on the ability of scientists to design elegantly specific drugs for targeted clinical trials. And the isotopic labeling of drug candidates in research labs is crucial in this overall effort.
In a new study, Dr. Benjamin Rotstein’s lab at the uOttawa Faculty of Medicine has collaborated with colleagues to unveil an operationally simple method to prepare carbon isotope-labeled versions of drugs and diagnostics. They developed a method to exchange a single atom in amino acids – building blocks of proteins that are also used to prepare molecules – for its isotope.
This is really important in drug development because we want to know where the drug goes in the body, how is it metabolized and eliminated so we can plan appropriate dosing and toxicity studies.”
Dr. Benjamin Rotstein, Associate Professor in the Faculty of Medicine’s Department of Biochemistry, Microbiology and Immunology
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The work was described in a paper in Nature Chemistry, a high-impact journal that also published a separate article on the study in which two Danish scientists at Aarhus University described the team’s methods as “important to the field.”
Dr. Rotstein’s lab initially designed their experiments to work like a catalyst that our bodies use: pyridoxal phosphate, which removes the carboxylic acid from amino acids and is the active form of vitamin B-6. But he says they wanted to make it run in reverse, and it turned out the mechanism was a little different than they initially expected.
“We’re actually adding carbon dioxide, then removing the acid. So it’s a different mechanism that allows us to consider even better catalysts and expanding the scope further beyond amino acids,” he says.
The research was done in collaboration with University of Alberta colleagues and chemists at Sanofi, the French pharmaceutical company. Dr. Rotstein’s lab did the carbon-11 studies and worked with these collaborators to unveil the mechanism of the reaction. His lab uses carbon-11 because it’s radioactive in a way that works well for medical imaging.
What are the next steps for his uOttawa lab? Dr. Rotstein and his team are now studying how to make the reaction produce only one “mirror-image” version of amino acids so that researchers won’t need to separate them after the fact.
He says they are especially excited about using carbon-11 amino acids to measure the rate that our bodies are producing proteins because this can be an indicator of disease.
“We’re also using these in imaging studies now to learn about metabolism and protein synthesis rates in different tissues,” says Dr. Rotstein, who is also director of the Molecular Imaging Probes and Radiochemistry Laboratory at the University of Ottawa Heart Institute.
Thought LeadersMatthew DunneDirector for Drug DiscoveryMicreos Pharamceuticals
For World Antimicrobial Awareness Week 2022, we speak to Matthew Dunne, Director for Drug Discovery at Micreos Pharmaceuticals, about the importance of creating new targeted antibacterial products.
Please can you introduce yourself and tell us about your role at Micreos?
My name is Matthew Dunne, and I am a Director for Drug Discovery at Micreos Pharmaceuticals in Switzerland. I provide strategic and technical leadership for R&D and preclinical activities within our newly established Division of Antimicrobial Vector Innovation. I joined Micreos in May of 2022 from the Swiss Federal Institute of Technology Zurich (ETH Zurich) at the same time as Dr. Samuel Kilcher, who sits alongside me as co-Director within the new division, which is developing a new class of medicines we have coined Antimicrobial Vectors.
In my capacity as Director, I work from Micreos’ state-of-the-art research facility in Switzerland, where I analyze data together with our growing team of genetic engineers and biologists. In addition to providing leadership of this new, highly innovative drug discovery division, I provide assistance with developing our regulatory affairs strategy, the management of external innovation development projects with industry partners and academia, as well as dealing with a variety of diverse tasks that are typical for a fast-growing biotech company.
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You are currently a Director of Drug Discovery at Micreos, a company working to develop the world’s first targeted antibacterial products. Can you tell us more about Micreos’ vision and the importance of finding alternatives to antibiotics?
Micreos is working towards providing innovative therapeutic solutions that deliver a profound and transformational impact to improve the standard of care for people living with devastating illnesses.
Antimicrobial resistance, or AMR is a naturally occurring process that cannot be eliminated; it can only be controlled. Unfortunately, decades of overprescribing antibiotics in combination with the use of antibiotics in agriculture and farming, such as growth factors for livestock (that has been banned in the EU since 2006), has driven the spread of antimicrobial resistance genes among bacterial pathogens. AMR is estimated to have caused 1.27 million deaths in 2019, with this number expected to keep on growing. Nevertheless, we are fighting back.
At Micreos, we are developing two classes of antimicrobials: Endolysins and Antimicrobial Vectors. Both have different modes of action compared to antibiotics, making them capable of killing all AMR bacteria. Both technologies provide other important advantages, too, such as their ability to precisely kill a specific pathogenic species while leaving commensal or “good” bacteria unaffected. Also, due to their alternative mechanisms of action, they are able to circumvent some of the harmful side effects of antibiotic use.
The drug discovery sector has seen considerable advances in the last decade, thanks largely to technology and increased collaboration. How do you feel this sector has changed in recent years and what has personally been the most exciting development that you have seen?
Global healthcare is rapidly transitioning towards precision medicine. Personally, I think the most impressive advancements over the last decade have been realized with nucleic acids. For example, antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) that modulate gene expression are being designed for large indications, rare diseases, and even patients with ultrarare, “n-of-1” diseases.
In the last two years, we all witnessed another form of nucleic acid therapy, mRNA. In less than a year, scientists went from sequencing the SARS-CoV-2 virus to designing different mRNA vaccines for global distribution. I am sure there are going to be many more exciting developments within this space in the near future. I am especially interested to see how the mRNA field progresses with regard to gene therapy, where mRNA can be administered to compensate for a faulty gene or protein.
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Micreos has recently launched a new world-class antimicrobial vector engineering team to ramp up the fight against antimicrobial resistance (AMR). Can you tell us more about why this team was created and the work you are carrying out?
Bacteriophages are natural predators of bacteria that, for over 100 years, have sat on the sidelines of modern medicine. They have mostly been applied as an experimental treatment, reserved for patients suffering from chronic infections that are untreatable with conventional antibiotics. As the threat of AMR intensifies, there is a significant demand for developing and enhancing the capabilities of alternative therapeutics to treat bacterial infections, among many other chronic and rare diseases.
At Micreos Pharmaceuticals, we are heavily invested in harnessing the power of genetic information. In the Division of Antimicrobial Vectors, we use the genomes of bacterial viruses or bacteriophages as “blueprints” for engineering using CRISPR-Cas technology as well as various synthetic approaches. First, we isolate and sequence bacteriophages from different environments that are predisposed to target and kill certain pathogenic species. Next, the fun starts, as the team and I get to apply our knowledge and expertise in bacteriophages, biochemistry, and structural biology to reprogram these genetic “blueprints” to generate Antimicrobial Vector libraries.
We can engineer structural genes for improved stability, introduce heterologous payloads for improved potency, remove unneeded elements for better efficiency and safety, and reprogram their targeting capabilities to reach bacteria in niche locations, such as intracellular reservoirs or biofilms. The resulting libraries of Antimicrobial Vectors provide unique and therapeutically important functions when used against bacterial infections.
This new team combines individuals with a variety of knowledge across various sectors, including molecular microbiology, genetic engineering, and phage therapy. Why is having a multidisciplinary team vital when developing new ways to tackle infectious diseases?
We are fortunate to have assembled a multidisciplinary team of experts proficient in all aspects of the Antimicrobial Vector R&D process, from selecting and testing environmental bacteriophages, to designing genetic scaffolds for reprogramming, to early-stage production, efficacy assessment, manufacturing optimization, and preclinical testing.
Our team also works very closely with experts in clinical trial design and regulatory affairs. This not only makes for interesting coffee breaks, where ideas and alternative perspectives are thrown around, but it ensures that we have a drug development pipeline that runs as efficiently as possible. It is important to have frequent input regarding aspects of safety, translatability, and efficacy to ensure our medicines will translate as quickly as possible from bench to bedside.
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How can the technology developed at Micreos help to tackle AMR through the creation of precision antimicrobials?
We are seeing more and more biologics and recombinant protein-based therapies in development to accompany small-molecule antibiotics in the fight against AMR. Micreos has already established itself as the global experts in engineering of endolysins, which has led to an array of precision protein-based antimicrobials capable of targeted killing of harmful S. aureus pathogen while leaving beneficial bacteria intact and without triggering resistance development.
During my PhD studies at EMBL Hamburg, I solved the atomic structures of these cell wall degrading enzymes and witnessed firsthand how miniscule amounts of endolysin could eradicate entire monocultures of specific bacteria in minutes with no off-target effects against “good” bacteria, such as those found on our skin or in our guts. Unlike the development of AMR against antibiotics, scientists do not expect to see similar resistance mechanisms emerge for endolysins due to their targeting of essential cell wall components that are extremely difficult for bacteria to modify.
Currently, our pharmaceutical grade endolysins are being developed for atopic dermatitis, diabetic foot ulcers, cutaneous T-cell lymphoma (based on excessive skin colonization by S. aureus) and bloodstream infections.
At the right time, and following extensive preclinical testing, we are all excited to witness our Antimicrobial Vector technology follow in the footsteps of our endolysins as it translates from discovery to clinical trials and onto improving the standard of care for people suffering from infections and many other devastating disorders.
Every year, the world celebrates World Antimicrobial Awareness Week (WAAW), dedicated to spreading awareness about AMR. The theme for 2022 is ‘Preventing Antimicrobial Resistance Together‘. What does this message mean to you, and how can international collaboration help to tackle this global health threat?
In 2019, nearly 5 million people died from illnesses involving AMR bacteria. Based on the current trajectory, these numbers are only going to keep rising – and at quicker and quicker rates – with predictions estimating AMR will cause 10 million deaths by the year 2050. The solution to controlling antimicrobial resistance is to work together internationally to implement more effective governance surrounding antimicrobials, improve public awareness surrounding antibiotics, and fund the development of new classes of antimicrobials to bolster our arsenal of available medicines.
It is important that drug developers, researchers, health authorities, and academics all play a part, no matter how big (e.g., establishing initiatives and investment funds) or small (e.g., tweets, chats among friends in the pub), to help raise public awareness surrounding AMR. Events such as those taking place during WAAW and their ability to disseminate information about AMR and its threat to our everyday lives are incredibly important. The public needs to know that AMR could impact our normal way of life. We risk reversing nearly a century of progress in public health if we allow normally innocuous infections to again become untreatable.
In addition to WAAW, we are seeing an expansion in other AMR initiatives, the introduction of innovation funds, and a growing number of collaborative organizations providing much-needed platforms for engagement and collaboration between industry, researchers, non-profit organizations, charities, and governments around the world.
Micreos has always focused on forging strong collaborations with other industry partners, clinicians, and academia to help advance the development of our precision antimicrobials. For instance, our proprietary endolysin technology was created together with ETH Zurich, which remains an important partner to us moving forwards with our Antimicrobial Vector technology.
Image Credit: The World Health Organization
Despite AMR being described as one of the top 10 threats to humanity, many people still do not understand its wide-reaching effects. Why is this, and why is it therefore so critical to continue to raise awareness?
I believe this is due to poor public communication and education regarding what antibiotics are, how they work, and what AMR really means. In 2015, when the WHO asked 10,000 people from 12 different countries about antibiotics, 76% of respondents believed that antibiotic resistance happens when the body becomes resistant to antibiotics – rather than bacteria becoming resistant to the antibiotics. Moreover, 44% of people believed they are not at risk of antibiotic-resistant infections if they simply take antibiotics as prescribed and of course, that is not correct.
Governments, academics, drug developers, and health professionals must do better at communicating a clearer message about what antibiotics are and – most importantly – why they are a precious resource that we cannot continue to take for granted.
What do you believe the future of antimicrobials to look like? Is it possible to one day see a world without resistance?
Another imminent threat to human existence is climate change, which shares many similarities, such as urgency, severity, and global effects, as we are seeing with the spread of AMR. What gives me hope for the future of antimicrobials and tackling AMR is witnessing the growth in public conversation and awareness surrounding climate change; the same will happen with AMR.
Improving awareness for AMR is about educating and mobilizing audiences so they are driven to take their own actions and make their own decisions toward confronting this growing crisis. I am hopeful that everyone will play a part through communication, the sharing of novel solutions, and advocating for change that will be shaped by our different experiences, cultures, and underlying values.
Originally from Macclesfield in the Northwest of England, Matthew studied Biochemistry at the University of Birmingham before obtaining a Ph.D. in Biochemistry and Structural Biology from the European Molecular Biology Laboratory (EMBL) in Hamburg and the University College Cork, Ireland, where he characterized the atomic structure and function of endolysins.
For the last eight years, Matthew has worked as a Postdoc and then Senior Scientist at the Swiss Institute of Technology in Zurich (ETH Zurich), where he investigated the molecular-level interactions of bacteriophages against a wide variety of foodborne and clinical pathogens, produced novel bacterial diagnostics, and developed genetic engineering tools that have been used to produce different types of bacteriophage-based therapeutics and diagnostic elements. Matthew maintains a research group within the lab of Prof. Martin Loessner at ETH Zurich, where he is actively involved in using genetic engineering to further explore how bacteriophages interact with their hosts, as well as lead a team of researchers developing bacteriophages to treat urinary tract infections for assessment in future clinical trials.
Matthew lives in Zurich with his wife, Alyssa Hill, also a Senior Scientist in Pharmaceutical Chemistry at ETH Zurich. In his free time, you will find Matthew swimming in the lakes and rivers dotted around the city, coaching and playing field hockey for the Red Sox HC, or skiing, hiking, and exploring Switzerland with Alyssa.
Eichenseher F, Herpers BL, Badoux P, Leyva-Castillo JM, Geha RS, van der Zwart M, McKellar J, Janssen F, de Rooij B, Selvakumar L, Röhrig C, Frieling J, Offerhaus M, Loessner MJ, Schmelcher M. Linker-Improved Chimeric Endolysin Selectively Kills Staphylococcus aureus In Vitro, on Reconstituted Human Epidermis, and in a Murine Model of Skin Infection. Antimicrob Agents Chemother. 2022 May 17;66(5):e0227321. doi: 10.1128/aac.02273-21. Epub 2022 Apr 13. PMID: 35416713; PMCID: PMC9112974.
Microbiome: From Research and Innovation to Market
