̽��ֱ�� of Cambridge - Anthony Davenport

Lab-grown beating heart cells identify potential drug to prevent COVID-19-related heart damage

cjb250 — Thu, 05 Aug 2021 08:35:20 +0000

̽��ֱ��heart is one the major organs damaged by infection with SARS-CoV-2, particularly the heart cells, or ‘cardiomyocytes’, which contract and circulate blood. It is also thought that damage to heart cells may contribute to the symptoms of long COVID.

Patients with underlying heart problems are more than four times as likely to die from COVID-19, the disease caused by SARS-CoV-2 infection. ̽��ֱ��case fatality rate in patients with COVID-19 rises from 2.3% to 10.5% in these individuals.

To gain entry into our cells, SARS-CoV-2 hijacks a protein on the surface of the cells, a receptor known as ACE2. Spike proteins on the surface of SARS-CoV-2 – which give it its characteristic ‘corona’-like appearance – bind to ACE2. Both the spike protein and ACE2 are then cleaved, allowing genetic material from the virus to enter the host cell. ̽��ֱ��virus manipulates the host cell’s machinery to allow itself to replicate and spread.

A team of scientists at the ̽��ֱ�� of Cambridge has used human embryonic stem cells to grow clusters of heart cells in the lab and shown that these cells mimic the behaviour of the cells in the body, beating as if to pump blood. Crucially, these model heart cells also contained the key components necessary for SARS-CoV-2 infection – in particular, the ACE2 receptor.

Working in special biosafety laboratories and using a safer, modified synthetic (‘pseudotyped’) virus decorated with the SARS-CoV-2 spike protein, the team mimicked how the virus infects the heart cells. They then used this model to screen for potential drugs to block infection.

Dr Sanjay Sinha from the Wellcome-MRC Cambridge Stem Cell Institute said: “Using stem cells, we’ve managed to create a model which, in many ways, behaves just like a heart does, beating in rhythm. This has allowed us to look at how the coronavirus infects cells and, importantly, helps us screen possible drugs that might prevent damage to the heart.”

̽��ֱ��team showed that some drugs that targeted the proteins involved in SARS-CoV-2 viral entry signiﬁcantly reduced levels of infection. These included an ACE2 antibody that has been shown previously to neutralise pseudotyped SARS-CoV-2 virus, and DX600, an experimental drug.

DX600 is an ACE2 peptide antagonist – that is, a molecule that specifically targets ACE2 and inhibits the activity of peptides that play a role in allowing the virus to break into the cell.

DX600 was around seven times more effective at preventing infection compared to the antibody, though the researchers say this may be because it was used in higher concentrations. ̽��ֱ��drug did not affect the number of heart cells, implying that it would be unlikely to be toxic.

Professor Anthony Davenport from the Department of Medicine and a fellow at St Catharine’s College, Cambridge said: “ ̽��ֱ��spike protein is like a key that fits into the ‘lock’ on the surface of the cells – the ACE2 receptor – allowing it entry. DX600 acts like gum, jamming the lock’s mechanism, making it much more difficult for the key to turn and unlock the cell door.

“We need to do further research on this drug, but it could provide us with a new treatment to help reduce harm to the heart in patients recently infected with the virus, particularly those who already have underlying heart conditions or who have not been vaccinated. We believe it may also help reduce the symptoms of long COVID.”

̽��ֱ��research was largely supported by Wellcome, Addenbrooke’s Charitable Trust, Rosetrees Trust Charity and British Heart Foundation.

Reference
Williams, TL et al. Human embryonic stem cell-derived cardiomyocyte platform screens inhibitors of SARS-CoV-2 infection. Communications Biology; 29 Jul 2021; DOI: 10.1038/s42003-021-02453-y

Cambridge scientists have grown beating heart cells in the lab and shown how they are vulnerable to SARS-CoV-2 infection. In a study published in Communications Biology, they used this system to show that an experimental peptide drug called DX600 can prevent the virus entering the heart cells.

Using stem cells, we’ve managed to create a model which, in many ways, behaves just like a heart does, beating in rhythm. This has allowed us to look at how the coronavirus infects cells and, importantly, helps us screen possible drugs that might prevent damage to the heart

Sanjay Sinha

Beating heart cells infected with virus

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Heart

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Ageing heart cells offer clues to susceptibility of older people to severe COVID-19

cjb250 — Tue, 18 Aug 2020 13:17:29 +0000

̽��ֱ��findings could help explain why age is major risk factor for dying from COVID-19, with people over 70 years at greatest risk, and why the disease can cause heart complications in severe cases, including heart failure and inflammation of the heart.

“When this novel coronavirus first emerged, we expected it to be primarily a respiratory illness, as the virus usually takes hold first in the lungs,” said Professor Anthony Davenport from the Department of Medicine. “But as the pandemic has progressed, we’ve seen more and more COVID-19 patients – particularly older patients – affected by heart problems. This suggests that the virus is capable of invading and damaging heart cells and that something changes as we age to make this possible.”

Professor Davenport led an international team of researchers from the ̽��ֱ�� of Cambridge, Maastricht ̽��ֱ��, KU Leuven and Karolinska Institute to investigate the link between COVID-19 and heart failure. ̽��ֱ��researchers examined cells known as cardiomyocytes to see how susceptible they were to infection by the coronavirus. Cardiomyocytes make up the heart muscle and are able to contract and relax, enabling the heart to pump blood around the body. Damage to these cells can affect the ability of the heart muscles to perform, leading to heart failure

To cause damage, the virus must first enter the cell. SARS-CoV-2 is a coronavirus – spherical in shape with ‘spike’ proteins on its surface, which it uses to gain entry. ̽��ֱ��spike protein binds to ACE2, a protein receptor found on the surface of certain cells. ̽��ֱ��virus is also able to hijack other proteins and enzymes, including TMPRSS2 and Cathepsins B and L to gain entry.

̽��ֱ��researchers compared cardiomyocytes from five young (19-25 year old) males and five older (63-78 year old) males and found that the genes that give the body instructions to make these proteins were all significantly more active in cardiomyocytes from the older males. This suggests that there is likely to be an increase in the corresponding proteins in aged cardiomyocytes.

“As we age, the cells of our heart muscles produce more of the proteins needed by the coronavirus to break into our cells,” said Dr Emma Robinson from Maastricht ̽��ֱ�� and KU Leuven. “This makes these cells more vulnerable to damage by the virus and could be one reason why age is a major risk factor in patients infected with SARS-CoV-2.”

Some of the proteins encoded by the genes can be inhibited by existing medicines. For example, the anti-inflammatory drug camostat inhibits TMPRSS2 and has been shown to block SARS-CoV-2 entry in cells grown in the laboratory. ̽��ֱ��study also suggests new targets for medicines that could be developed such as compounds blocking binding of the virus to ACE2 that may be beneficial in protecting the heart.

“ ̽��ֱ��more we learn about the virus and its ability to hijack our cells, the better placed we are to block it, either with existing drugs or by developing new treatments,” said Professor Davenport.

̽��ֱ��study was funded by grants including from Wellcome, the British Heart Foundation and Dutch Heart Foundation.

Reference
Robinson, EL et al. Genes Encoding ACE2, TMPRSS2 and Related Proteins Mediating SARS-CoV-2 Viral Entry are Upregulated with Age in Human Cardiomyocytes. Journal of Molecular and Cellular Cardiology; 18 Aug 2020: DOI: 10.1016/j.yjmcc.2020.08.009

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Genes that play an important role in allowing SARS-CoV-2 to invade heart cells become more active with age, according to research published today in the Journal of Molecular and Cellular Cardiology.

̽��ֱ��more we learn about the virus and its ability to hijack our cells, the better placed we are to block it, either with existing drugs or by developing new treatments

Anthony Davenport

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Repurposing existing drugs for COVID-19 a more rapid alternative to a vaccine, say researchers

cjb250 — Thu, 07 May 2020 08:25:58 +0000

Since the emergence of the SARS-CoV-2 virus in late 2019, more than 3.5 million people are known to have been infected, leading to over 240,000 deaths worldwide from COVID-19, the disease caused by the novel coronavirus. ̽��ֱ��race is on to find new drugs to treat COVID-19 patients and to develop a vaccine to prevent infection in the first place.

A team of researchers representing the International Union of Basic and Clinical Pharmacology today say there will be no ‘magic bullet’ to treat the disease and argue that a multi-pronged approach is needed to find new drugs. They caution that an effective and scalable vaccine is likely to take over a year before it can used to tackle the global pandemic.

When a virus enters our body, unless we have already developed immunity from previous infection or vaccination, it will break into our cells, hijacking their machinery and using it to replicate and spread throughout the body. Often, the symptoms we see are a result of our immune system fighting back in an attempt to clear the infection. In severe cases, this immune response can become overactive, potentially leading to a so-called cytokine storm, causing collateral damage to organs along the way.

“Any drug to treat COVID-19 will need to focus on the three key stages of infection: preventing the virus entering our cells in the first place, stopping it replicating if it gets inside the cells, and reducing the damage that occurs to our tissues, in this case, the lungs and heart,” said Professor Anthony Davenport from the ̽��ֱ�� of Cambridge, one of the authors of the review.

̽��ֱ��review looks at potential therapeutic drug targets – the cracks in the virus’s own armour or weak spots in the body’s defences. Two key targets appear to be proteins on the surface of our cells, to which SARS-CoV-2 binds allowing it entry – ACE2 and TMPRSS2. TMPRSS2 appears to be very common on cells, whereas ACE2 is usually present at low levels that increase depending on sex, age, and smoking history.

“As we know these two proteins play a role in this coronavirus infection, we can focus on repurposing drugs that already have regulatory approval or are in the late stages of clinical trials,” said Professor Davenport. “These treatments will have already been shown to be safe and so, if they can now be shown to be effective in COVID-19, they could be brought to clinical use relatively quickly.”

One promising candidate is remdesivir, a drug originally developed for Ebola. Although clinical trials found it to be insufficiently effective at treating Ebola, clinical trials in the USA have suggested the drug may be beneficial for treating patients hospitalised with COVID-19, and the FDA has now approved it for emergency use. There have also been promising findings from studies of monoclonal antibodies, but this type of drug is expensive to produce and therefore less likely to be scalable.

“While we're waiting for a vaccine, drugs currently being used to treat other illnesses can be investigated as treatments for COVID-19 – in other words repurposed,” said Dr Steve Alexander from the ̽��ֱ�� of Nottingham.

“There’s unlikely to be a single magic bullet – we will probably need several drugs in our armoury, some that will need be used in combination with others. ̽��ֱ��important thing is that these drugs are cheap to produce and easy to manufacture. That way, we can ensure access to affordable drugs across the globe, not just for wealthier nations.”

̽��ֱ��team say that we need to move quickly to identify existing drugs that are effective in clinical trials so that we can begin treating patients as rapidly as possible, but also because cases are likely to fall during the summer meaning there will be fewer people who can be recruited to clinical trials ahead of an anticipated second wave of the disease in autumn. They estimate there are currently more than 300 clinical trials taking place worldwide, though many of these investigational drugs are unlikely to be effective for widespread use because either it is not clear which part of the disease pathway they are targeting or they cause unpleasant side-effects.

They also advise patience for the promise of developing an effective vaccine against the virus anytime soon. Even after a new vaccine candidate has been shown to offer immunity against the coronavirus in humans, it needs to be tested in larger numbers of people to ensure it is safe to use. Manufacturing and distributing a vaccine at the scale needed to tackle this pandemic will also present significant challenges.

“Although there are a lot of vaccines being developed around the world, which we hope will be successful, it's still going to take a long time before those vaccines are shown to be effective and can be manufactured at the scale needed to make an impact,” said Dr Steve Alexander.

“Some of the vaccines may not work, so the more drugs that can be tested and the more we know about the targets, the more likely we are to get something which is effective. ̽��ֱ��very specificity of vaccines means they are limited in which viruses they can neutralise. ̽��ֱ��lessons we learn and the drugs we generate will hopefully provide a greater degree of protection, not just against the COVID-19 virus, but also against the next viral threat.”

Professor Davenport is a member of the Department of Medicine, ̽��ֱ�� of Cambridge, and a Fellow at St Catharine’s College.

Reference
Alexander, SPH, et al. A rational roadmap for SARS-CoV-2/COVID-19 pharmacotherapeutic research and development. British Journal of Pharmacology; 1 May 2020; DOI: 10.1111/bph.15094

Repurposing existing medicines focused on known drug targets is likely to offer a more rapid hope of tackling COVID-19 than developing and manufacturing a vaccine, argue an international team of scientists in the British Journal of Pharmacology.

"[Repurposed drugs] will have already been shown to be safe and so, if they can now be shown to be effective in COVID-19, they could be brought to clinical use relatively quickly"

Anthony Davenport

PIRO4D

Coronavirus

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New research allows doctors to image dangerous ‘hardening’ of the arteries

cjb250 — Fri, 10 Jul 2015 08:21:49 +0000

̽��ֱ��technique, reported in the journal Nature Communications, could help in the diagnosis of these conditions in at-risk patients and in the development of new medicines.

Atherosclerosis – hardening of the arteries – is a potentially serious condition where arteries become clogged by a build-up of fatty deposits known as ‘plaques’. One of the key constituents in these deposits is calcium. In some people, pieces from the calcified artery can break away – if the artery supplies the brain or heart with blood, this can lead to stroke or heart attack.

“Hardening, or ‘furring’, of the arteries can lead to very serious disease, but it’s not clear why the plaques are stable in some people but unstable in others,” explains Professor David Newby, the BHF John Wheatley Professor of Cardiology at the Centre for Cardiovascular Science, ̽��ֱ�� of Edinburgh. “We need to find new methods of identifying those patients at greatest risk from unstable plaques.”

̽��ֱ��researchers injected patients with sodium fluoride that had been tagged with a tiny amount of a radioactive tracer. Using a combination of scanning techniques (positron emission tomography (PET) and computed tomography (CT)), the researchers were able to track the progress of the tracer as it moved around the body.

“Sodium fluoride is commonly found in toothpaste as it binds to calcium compounds in our teeth’s enamel,” says Dr Anthony Davenport from the Department of Experimental Medicine and Immunotherapeutics at the ̽��ֱ�� of Cambridge, who led the study. “In a similar way, it also binds to unstable areas of calcification in arteries and so we’re able to see, by measuring the levels of radioactivity, exactly where the deposits are building up. In fact, this new emerging technique is the only imaging platform that can non-invasively detect the early stages of calcification in unstable atherosclerosis.”

Following their sodium fluoride scans, the patients had surgery to remove calcified plaques and the extracted tissue was imaged, this time at higher resolution, using a laboratory PET/CT scanner and an electron microscope. This confirmed that the radiotracer accumulates in areas of active, unstable calcification whilst avoiding surrounding tissue.

Dr James Rudd, a cardiologist and researcher from the Department of Cardiovascular Medicine at the ̽��ֱ�� of Cambridge adds: “Sodium fluoride is a simple and inexpensive radiotracer that should revolutionise our ability to detect dangerous calcium in the arteries of the heart and brain. This will allow us to use current treatments more effectively, by giving them to those patients at highest risk. In addition, after further work, it may be possible to use this technique to test how well new medicines perform at preventing the development of atherosclerosis.”

̽��ֱ��Wellcome Trust provided the majority of support for this study, with additional contributions from the British Heart Foundation, Cancer Research UK and the Cambridge NIHR Biomedical Research Centre.

Reference
Irkle, A et al. Identifying active vascular microcalcification by 18F-sodium fluoride positron emission tomography. Nature Communications; 7 July 2015.

Researchers at the ̽��ֱ�� of Cambridge, in collaboration with the ̽��ֱ�� of Edinburgh, have shown how a radioactive agent developed in the 1960s to detect bone cancer can be re-purposed to highlight the build-up of unstable calcium deposits in arteries, a process that can cause heart attack and stroke.

Sodium fluoride is a simple and inexpensive radiotracer that should revolutionise our ability to detect dangerous calcium in the arteries of the heart and brain

James Rudd

̽��ֱ�� of Cambridge

Imaging atherosclerotic calcification or ‘hardening of the arteries’ using positron emission tomography

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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