A promising therapeutic solution to COVID-19 - using ACE2 decoy

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In summary: So if production is scaled up, it shouldn't be an issue. However, as mentioned, the demand for a COVID-19 anti-viral treatment would be much less, so the price would be lower.
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The SARS-CoV-2 virus enters cells through the ACE2 surface protein, which is expressed mainly in cells of the lung and of the small intestine. Using recombinant technology, researchers have created a protein that mimics ACE2. The SARS-CoV-2 virus cannot distinguish the human recombinant soluble ACE2 (hrsACE2) from the ACE2 protein on cell surfaces so the hrsACE2 acts as a decoy diverting the virus from infecting cells.
I came across this article about a promising COVID 19 therapy developed by an international team led by researchers from the University of British Columbia.

Since the SARS-CoV-2 virus that causes COVID-19 gets into cells by attaching to the ACE2 surface protein (which is expressed mainly in epithelial cells of the lung and cells in the lining of the small intestine but also in blood vessels and kidneys and other organs), the idea is to create a molecule that mimics ACE2 but is not attached to a cell to draw the virus away from cells. This very clever idea appears to work:

"The team’s study reveals that clinical grade human recombinant soluble ACE2 (hrsACE2) reduces SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5,000. ... Based on this and other findings, the team declared that hrsACE2 can materially block early stages of SARS-CoV-2 infections. "

The drug that has been developed to deliver hrsACE2 is APN01 or APN001. It will be interesting to see what comes of this approach.

[P.S. - Here is published paper in Cell that is referred to in the cited article]

AM
 
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Here's a link to the paper, published in the journal Cell: https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00739.pdf

Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2
Abstract:
We have previously provided the first genetic evidence that Angiotensin converting enzyme 2 (ACE2) is the critical receptor for SARS-CoV and that ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growthof SARS-CoV-2. Here we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5 ,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.

The soluble ACE2 has gone through phase I and II clinical trials for other indications (e.g. see https://link.springer.com/article/10.1007/s40262-013-0072-7 and https://ccforum.biomedcentral.com/articles/10.1186/s13054-017-1823-x), and although it did not seem effective as a cardiovascular drug or treatment for acute respiratory distress syndrome, it was well tolerated by people in the trials, suggesting that it can be administered safely to people. It definitely seems like a promising candidate for further testing as a COVID-19 treatment.

However, because the drug is a biologic, it could be difficult to manufacture large quantities and cost could be an issue.
 
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Ygggdrasil said:
However, because the drug is a biologic, it could be difficult to manufacture large quantities and cost could be an issue.
Yes, it would likely take a bit of time to ramp up production. I expect that it would be produced by growing it in some fast-replicating bacteria such as E.coli or a yeast into which the hrsACE2 gene has been inserted. That kind of manufacturing system supplies insulin users which are somewhere around .02-.05% of the population of western countries. The demand for a COVID-19 anti-viral treatment would be much less, I would expect, because it would be for short-term use by a patient and there would be many fewer patients than insulin users (we hope...). If it worked, I don't think cost would be a concern.

AM
 
  • #4
Andrew Mason said:
Yes, it would likely take a bit of time to ramp up production. I expect that it would be produced by growing it in some fast-replicating bacteria such as E.coli or a yeast into which the hrsACE2 gene has been inserted. That kind of manufacturing system supplies insulin users which are somewhere around .02-.05% of the population of western countries. The demand for a COVID-19 anti-viral treatment would be much less, I would expect, because it would be for short-term use by a patient and there would be many fewer patients than insulin users (we hope...). If it worked, I don't think cost would be a concern.

AM
According to the Cell paper, they produced the drug in CHO cells (Chinese hamster ovary), which is a common cell line used for the manufacture of biologic drugs.
 
  • #5
Ygggdrasil said:
According to the Cell paper, they produced the drug in CHO cells (Chinese hamster ovary), which is a common cell line used for the manufacture of biologic drugs.
Yes. Thanks for pointing that out. From what I can gather CHO cells reproduce very quickly. Would there be anything to prevent scaling up production to a sufficient level, other than cost?

AM
 
  • #6
I looked CHO cells up last night.

I was concerned that they might only grow as adherent cells (stuck on the substrate).
Apparently they can be grown in suspension which makes production much easier in many ways (I used to grow non-adherent hybridomas to make monoclonal antibodies).
What I don't know is if the CHO cells will produce their product as non-adherent cells.

In graduate school, it was quite easy for me to make decent quantities of hybridoma produced antibody in large non-aggitated TC flasks (in a primitive TC room I set-up, when I was using my DIY plywood hood).
A modern lab should be able to do much better.
 
  • #7
Now commercial biopharmaceutical manufacturing utilizes bioreactors 10,000 – 25,000 liters and larger in size. Media and nutrients for the cells are monitored continuously as well as oxygen levels, CO2 levels, and waste product. This constant information about cell health has led to more efficient and productive culture with average production yields from 1-6 grams/liter.
https://cellculturedish.com/cho-cells-the-top-expression-system-of-best-selling-biologic-drugs/ (though note that this article is from 2012)

I don't know much about the time needed or cost to scale to these levels of production. Potentially, existing capacity could be diverted toward production of a COVID-19 treatment, but I am not familiar with the logistics here.
 
  • #8
This may help to explain why significantly more men than women experience severe outcomes from COVID19: they seem to have more ACE2 receptors:

“When we found that one of the strongest biomarkers, ACE2, was much higher in men than in women, I realized that this had the potential to explain why men were more likely to die from COVID-19 than women,” said Iziah Sama, a doctor at UMC Groningen who co-led the study.

This follows from earlier studies such as this one from researchers in Wuhan Province, China that:

"the distribution of ACE2 is also more widespread in male donors than females: at least 5 different types of cells in male lung express this receptor, while only 2~4 types of cells in female lung express the receptor. This result is highly consistent with the epidemic investigation showing that most of the confirmed 2019-nCov infected patients were men (30 vs. 11, by Jan 2, 2020)."

That suggests that limiting virus access to cells expressing ACE2 receptors may be a key to limiting the damage.

AM
 
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Andrew Mason said:
This may help to explain why significantly more men than women experience severe outcomes from COVID19: they seem to have more ACE2 receptors:

“When we found that one of the strongest biomarkers, ACE2, was much higher in men than in women, I realized that this had the potential to explain why men were more likely to die from COVID-19 than women,” said Iziah Sama, a doctor at UMC Groningen who co-led the study.

This follows from earlier studies such as this one from researchers in Wuhan Province, China that:

"the distribution of ACE2 is also more widespread in male donors than females: at least 5 different types of cells in male lung express this receptor, while only 2~4 types of cells in female lung express the receptor. This result is highly consistent with the epidemic investigation showing that most of the confirmed 2019-nCov infected patients were men (30 vs. 11, by Jan 2, 2020)."

That suggests that limiting virus access to cells expressing ACE2 receptors may be a key to limiting the damage.

AM

I think there are other plausible reasons that could explain the differences in the responses of men and women. Some are behavioral (e.g. smoking is more common in men than women) and some are biological (men tend to have weaker immune responses than women). See https://www.nytimes.com/2020/02/20/health/coronavirus-men-women.html for a good discussion.

I am skeptical of the ACE2 explanation because of other data that suggests relative expression of ACE2 is not a major risk factor for the disease. For example, ACE inhibitors are commonly prescribed to treat high blood pressure. While the drug affects only the ACE enzyme and not ACE2, treatment with the drug was observed increase the expression of ACE2 in animal studies. A similar effect was seen in animal studies of angiotensin II receptor blockers, another class of drugs to treat hypertension. However, despite these drugs promoting higher expression of ACE2, observational studies have found slightly decreased mortality among those taking these drugs. If increased ACE2 expression were a major risk factor, one would expect to have seen worse outcomes among those taking these drugs.
 
  • #10
Ygggdrasil said:
I am skeptical of the ACE2 explanation because of other data that suggests relative expression of ACE2 is not a major risk factor for the disease. For example, ACE inhibitors are commonly prescribed to treat high blood pressure. While the drug affects only the ACE enzyme and not ACE2, treatment with the drug was observed increase the expression of ACE2 in animal studies. A similar effect was seen in animal studies of angiotensin II receptor blockers, another class of drugs to treat hypertension. However, despite these drugs promoting higher expression of ACE2, observational studies have found slightly decreased mortality among those taking these drugs. If increased ACE2 expression were a major risk factor, one would expect to have seen worse outcomes among those taking these drugs.
There may be explanations for the apparent slightly decreased mortality among COVID19 patients using ACE inhibitors such as the one offered in this report.

As that report explains, ACE2 breaks down the Angiontensin II enzyme (ANG II) and ACE stimulates production of ANG II. Although they act in different ways, ACE inhibitors and ACE2 both serve a similar function in regulating the amount of ANG II (ACE inhibitors slow production of ANG II while ACE2 breaks it down). If not regulated, ANG II can produce excessive inflammatory response to injury and lead to severe tissue and organ damage, which is what appears to be occurring in COVID patients.

The Conversation: Canadian edition said:
"Of greatest relevance to COVID-19, ANG II can increase inflammation and the death of cells in the alveoli which are critical for bringing oxygen into the body; these harmful effects of ANG II are reduced by ACE2.

When the SARS-CoV-2 virus binds to ACE2, it prevents ACE2 from performing its normal function to regulate ANG II signaling. Thus, ACE2 action is “inhibited,” removing the brakes from ANG II signaling and making more ANG II available to injure tissues. This “decreased braking” likely contributes to injury, especially to the lungs and heart, in COVID-19 patients.
...
When the amount of ACE2 is reduced because the virus is occupying the receptor, individuals may be more susceptible to severe illness from COVID-19. That is because enough ACE2 is available to facilitate viral entry but the decrease in available ACE2 contributes to more ANG II-mediated injury. In particular, reducing ACE2 will increase susceptibility to inflammation, cell death and organ failure, especially in the heart and the lung.

AM
 
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hello : a small question about the ACE2 decoy , would that decoy bind also with blood plasma chemicals?

best regards
hagop
 
  • #12
Andrew Mason said:
As that report explains, ACE2 breaks down the Angiontensin II enzyme (ANG II) and ACE stimulates production of ANG II. Although they act in different ways, ACE inhibitors and ACE2 both serve a similar function in regulating the amount of ANG II (ACE inhibitors slow production of ANG II while ACE2 breaks it down). If not regulated, ANG II can produce excessive inflammatory response to injury and lead to severe tissue and organ damage, which is what appears to be occurring in COVID patients.

In the The Conversation article you cite, the authors argue that lower amounts of ACE2 would lead to more severe disease:
When the amount of ACE2 is reduced because the virus is occupying the receptor, individuals may be more susceptible to severe illness from COVID-19. That is because enough ACE2 is available to facilitate viral entry but the decrease in available ACE2 contributes to more ANG II-mediated injury. In particular, reducing ACE2 will increase susceptibility to inflammation, cell death and organ failure, especially in the heart and the lung.

However, the Reuters piece you cited earlier reports on a study that shows that men have higher levels of ACE2 (also relevant to our discussion, it notes that people taking ACE inhibitors or angiotensin receptor blockers don't have elevated levels of ACE2). If the ACE2 hypothesis is correct, higher levels of ACE2 should be protective against COVID-19, yet this is opposite of the observed poorer outcomes for men vs women. Similarly, the results showing no changes to ACE2 expression when taking ACEi or ARB drugs suggests that changes to ACE2 expression do not underlie the mild protective effect of these drugs on COVID-19. One caveat of the study is that the researchers measured the levels of circulating ACE2 in blood plasma, which may not reflect the changes in lung, which would be most relevant to COVID-19.
 
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Ygggdrasil said:
In the The Conversation article you cite, the authors argue that lower amounts of ACE2 would lead to more severe disease:

However, the Reuters piece you cited earlier reports on a study that shows that men have higher levels of ACE2 (also relevant to our discussion, it notes that people taking ACE inhibitors or angiotensin receptor blockers don't have elevated levels of ACE2). If the ACE2 hypothesis is correct, higher levels of ACE2 should be protective against COVID-19, yet this is opposite of the observed poorer outcomes for men vs women. Similarly, the results showing no changes to ACE2 expression when taking ACEi or ARB drugs suggests that changes to ACE2 expression do not underlie the mild protective effect of these drugs on COVID-19. One caveat of the study is that the researchers measured the levels of circulating ACE2 in blood plasma, which may not reflect the changes in lung, which would be most relevant to COVID-19.

According to this paper from 2009 dealing with the SARS-CoV virus, which operates in a similar way to SARS-CoV-2, it seems that the virus knocks out the ACE2 function when it gains entry via the ACE2 receptor.

Jia et al (Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia-July 2009) said:
"Additional data indicate that SARS-CoV S protein or SARS virus infection directly downregulates pulmonary ACE2 expression. Together these studies indicate that loss of ACE2 catalytic function perturbs the pulmonary renin-angiotensin system, enhancing inflammation and vascular permeability. In addition to loss of ACE2 cleavage of renin-angiotensin system components, the failure to inactivate other ACE2 targets such as bradykinin metabolites and other vasoactive peptides might also contribute to SARS lung disease."

If I understand it correctly, for ACE2 to function it must be expressed on the cell surface. Since the virus gains entry to the cell by receptor-mediated endocytosis, the virus entry removes both the ACE2 extra-cellular and cytoplasmic domains. So, the more cells expressing ACE2 receptors leads to more cells being infected by the virus, which results in more initial tissue damage, which ramps up production of ANG II, which is unregulated because of the loss of ACE2 function, which leads to catastrophic tissue damage.

AM
 
  • #14
hagopbul said:
a small question about the ACE2 decoy , would that decoy bind also with blood plasma chemicals?
The ability of a protein to bind with other molecules is highly specific to the shape of the protein. It so happens that the spikes on the SARS-CoV-2 virus are complementary to the ACE2 receptor protein so those spikes fit into it and bind to ACE2.

Presumably, the ANG II enzyme also has a similar ability to bind with the ACE2 receptor. I am not sure if that means that hrsACE2 (i.e. present in the blood, unattached to a cell) would bind to ANG II enzymes. I don't know enough to comment further, but it is a good question.

AM
 
  • #15
This report in Nature May 15:
https://www.nature.com/articles/d41587-020-00013-z
updates the progress of trials for several antiviral drug candidates that show promise in thwarting SARS-Cov-2, including hrsACE2 (APN01).

The various approaches taken are quite ingenious. It would not surprise me at all if one or more of these drug candidates should end up being effective in neutralizing the virus long before an effective vaccine is found.

AM
 
  • #16
This paper:
https://www.sciencedirect.com/science/article/pii/S2329050120301005
looks at differences in COVID19 susceptibility in the population. The amount of ACE2 expression seems to be key. It offers this as an explanation for the fact that children are less susceptible to SARS-Cov-2 infection. The authors comment:
Airways Expression of SARS-CoV-2 Receptor ACE2 said:
However, interestingly, the expression levels of both ACE2 and TMPRSS2 were significantly lower in nasal as well as bronchial epithelial tissue of children compared with those of adults (p < 0.0001; Figure 1B). Notably, these receptors were found to be differentially expressed between upper and lower airways. In children, the expression levels of ACE2 (p = 0.032) and TMPRSS2 (p = 0.002) were both significantly higher in upper respiratory nasal tissue compared with the bronchial epithelial brushing (Figure 1C). Similarly, in adults, we found significantly higher expression of these genes in upper nasal epithelial tissue compared with bronchial and small airway epithelial brushings (p < 0.0001; Figure 1D). Moreover, the expression of these two genes was found to be significantly higher in nasal compared with blood or saliva of adult subjects (p < 0.0001; Figure S2D). This significant differential expression of both ACE2 and TMPRSS2 between children and adults could contribute to the lower infectivity and disease severity observed in younger populations.
...
Therefore, the reduced airway tissue expression of ACE2 and TMPRSS2 reported here may contribute to the lower risk for infection14,15 and the reduced disease severity observed in the younger population."
AM
 
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  • #17
Here is an explanation of how APN01 is intended to work published by Apeiron Biologics, the company doing the Phase II clinical trial. According to Apeiron:

Apeiron Biologics said:
"APN01 therefore provides the best scientific rationale for a specific treatment of COVID-19 that surpasses other suggested strategies by acting at all relevant stages of this disorder. "

However, it occurred to me that if the hrsACE2 protein is blocking all the virus spikes as shown, antibodies against the virus that target those spikes will not function, leaving the virus intact (but unable to enter cells). Could that be a potential a problem?

AM
 
  • #18
[Edited as per Ygggdrasil's comment below]
This report [paper] in the Journal Signal Transduction and Targeted Therapy [Nature] last month
provides an interesting report on a COVID patient who was doing very poorly until they received hrsACE2 by intravenous injection and recovered very quickly afterward. At this point it is simply one anecdote - but a promising one at that.

Here is a link to the original paper [another report] on the same patient which contains a bit more data. It appears that the human recombinant ACE2 not only reduces infection rate but it also seems to work like the cellular trans-membrane ACE2 receptor: it lowers Angiotensin II and increases Angiotensin (1-7):
The Lancet 1Nov20 said:
Our named patient use in a patient with COVID-19 now shows that hrsACE2 is highly active in cleaving angiotensin II into angiotensin 1–7, as well as cleaving angiotensin I into angiotensin 1–9, starting with the first infusion, and that hrsACE2 remains active throughout the course of the 7-day treatment.
...
Therefore, hrsACE2 treatment was associated with a marked decrease in concentrations of critical cytokines implicated in COVID-19 pathology, and hrsACE2 remains catalytically active in the scenario of severe COVID-19.

AM
 
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  • #19
Andrew Mason said:

Small correction. The piece you link to is neither a research paper nor published in the journal Nature. Instead, it is a research highlight (a non-peer reviewed commentary piece commissioned by the journal to summarize a research paper) published in the journal Signal Transduction and Targeted Therapy. This journal is published by the same company that published the journal Nature, but it is not as prestigious as Nature.

Another note: the research highlight summarizes the paper published in The Lancet Respiartory Medicine that you link to below, so it is not really correct to refer to that as "another report" since both the research highlight and research paper are commenting on the same set of data within the research paper.
 
  • #20
Ok. I found it interesting that they would be a publishing report about a single patient. That strikes me as rather unusual. What is quite striking about the data is that it indicates that extracellular hrsACE2 seems to function the same as cellular ACE2.

AM
 
  • #21
Here is a link to a report in EMBO Molecular Medicine that found that in-vitro treatment of human kidney and liver tissue with hrsACE2 and remdesivir is more effective than just remdesivir in reducing viral load. It does not appear to me that they compared their results of combining remdesivir with hrsACE2 to just using hrsACE2 alone.

Of significance the absence of liver and kidney toxicity from the hrsACE2:
Human soluble ACE2 improves the effect of remdesivir in SARS‐CoV‐2 infection - EMBO Press 12Nov20 said:
These data show, that remdesivir, but not hrsACE2, exhibits liver and kidney toxicity, as determined by engineered human tissues, at doses that are required to effectively control the SARS-CoV-2 infection.

AM
 
  • #22
This was announced a few days ago with a press release from Apeiron Biologics, the privately held Austrian company that is conducting Phase II testing of the drug APN01 (hrsACE2):

PharmaWeb 4Dec20 said:
"APN01 is one of the most advanced COVID-19 drug candidates and the only clinical stage treatment specifically targeting SARS-CoV-2. We have seen clear results in preclinical studies and named patient use confirming the mode of action and clinical benefit of APN01 in COVID-19 patients and feel encouraged to confirm efficacy with this clinical phase II trial," said Peter Llewellyn-Davies, Chief Executive Officer of APEIRON Biologics AG. "Currently, we are defining with the European Medicines Agency (EMA) a potential rolling Marketing Authorization Application (MAA) submission to make this drug candidate available for severely suffering patients as fast as possible, subject to positive clinical results."

[The press release refers to the paper in the journal Cell that is referred to in the original post at the top of this thread]

It looks promising that this drug may be approved quickly and become a widely used therapy for severe COVID19 patients. If it is as effective as its proponents suggest and COVID19 can be readily cured, this drug may be more effective than vaccines in ending the pandemic.

AM
 
  • #23
It sounds promising, but it also sounds like a pharma press release hype too. The paper was from early 2020 (April?). Now, about 8 months later, they are starting phase II trials with "results expected in Q1 2021".

So, is it not exciting enough to attract big money to speed it up? Is the company holding on too tight to prevent rapid development?

It looks like we should have a pretty effective vaccine being widely deployed before this drug is ready for widespread use. But SARS-CoV-2 will be around for a long while, it would be great to have therapeutic agents to deal with infections in the endemic phase.
 
  • #24
I imagine this would face the same problems seen with other drugs, to have much of an effect, any antiviral needs to be given at the time the viral load is increasing rapidly, that is early in the course of the illness. This would mean that we would need to be able to predict who is likely to become seriously ill, it wouldn't be practical to admit everyone to hospital to give the IV drugs. This is a current problem with monoclonal antibodies, a treatment that was supposed to prevent serious illness and keep people out of hospital, some people are now being admitted just to get the infusion.
It usually takes 7-8 days after symptom onset for sever disease to be recognised and at that time the main problems are not really the viraemia, its the bodies own immune responses and reactions to damage, particularly to blood vessels, lungs, heart and kidneys. Really we need a drug that can be given orally, that's cheap and relatively free from side effects, to have an impact implies treating a large number of people many of which wouldn't need it as soon as they got any symptoms.
 
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Laroxe said:
I imagine this would face the same problems seen with other drugs, to have much of an effect, any antiviral needs to be given at the time the viral load is increasing rapidly, that is early in the course of the illness. This would mean that we would need to be able to predict who is likely to become seriously ill, it wouldn't be practical to admit everyone to hospital to give the IV drugs.

This is a current problem with monoclonal antibodies, a treatment that was supposed to prevent serious illness and keep people out of hospital, some people are now being admitted just to get the infusion.
It usually takes 7-8 days after symptom onset for sever disease to be recognised and at that time the main problems are not really the viraemia, its the bodies own immune responses and reactions to damage, particularly to blood vessels, lungs, heart and kidneys. Really we need a drug that can be given orally, that's cheap and relatively free from side effects, to have an impact implies treating a large number of people many of which wouldn't need it as soon as they got any symptoms.
The difference between hrsACE2 and other anti-virals, such as remdesivir, is that not only does it prevent entry of the virus (and, therefore, viral replication) but it also appears to replace the ACE2 function. It is the loss of ACE2 function that seems to be the major cause of respiratory disease. The lung damage (clotting in the lung tissue) is strongly correlated to elevated levels of Angiotensin II (vasoconstrictor) and reduced levels of Angiotensin (1-7) (a vasodilator). ACE2 down-regulates Angiotensin II and up-regulates Angiotensin (1-7).

In the reported case (my post #18) it was given to a patient with severe respiratory COVID and appears to have not only reduced the viral load but it reduced Angiotensin II levels and increased Angiotensin (1-7) markedly, leading to patient recovery.

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  • #26
Andrew Mason said:
The difference between hrsACE2 and other anti-virals, such as remdesivir, is that not only does it prevent entry of the virus (and, therefore, viral replication) but it also appears to replace the ACE2 function. It is the loss of ACE2 function that seems to be the major cause of respiratory disease. The lung damage (clotting in the lung tissue) is strongly correlated to elevated levels of Angiotensin II (vasoconstrictor) and reduced levels of Angiotensin (1-7) (a vasodilator). ACE2 down-regulates Angiotensin II and up-regulates Angiotensin (1-7).

In the reported case (my post #18) it was given to a patient with severe respiratory COVID and appears to have not only reduced the viral load but it reduced Angiotensin II levels and increased Angiotensin (1-7) markedly, leading to patient recovery.

AM
Its certainly an interesting idea and given your comments I had a look around at anything available, I have to say even though I'd love to be wrong about this, I think there are serious problems. The links to Covid 19, while presenting a credible rational, really appear to be opportunistic, ACE2 is involved in a range of important physiological functions. They were in fact already looking at using these drugs to manage chronic lung disease, arterial and cardiovascular diseases and kidney diseases and ACE2 seems to have an impact on hypertension, diabetes, ageing, and the control of regional blood flow. This was all before Covid 19 become known and the evidence of an antiviral effect is based on in vitro work.
I found the published study interesting, the lady was admitted after being symptomatic for 7 days and was started on hydroxychloroquine, she was intubated on the following day and began treatment with the hrsACE2 the day after, day 9 after the onset of symptoms. Normally the adaptive immune response gets going at day 8 following initial exposure, its likely that she was already clearing the virus before this treatment and its possible the hydroxychloroquine might have helped. This is in fact what is commonly found in the people that become severely ill, its usually not caused by a viraemia. The lady was treated for 7 days and there are extensive reports of improvements in biological indicators and recovery being complicated by a bacterial infection she remained intubated for a further 6 days and remained in hospital for 57 days. This is really less than impressive and the drugs are still being tested in phase 1 & 2 trials, the trials being planned seem unlikely to be useful in providing evidence for a Covid treatment.
There just seems no sense of urgency and the funding supporting the work is not Covid related, I know you talked about the case study but I'll repeat the link & I've linked to the Clinical trials site. Its interesting.
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30418-5/fulltext
https://clinicaltrials.gov/ct2/show/NCT00886353
 
  • #27
Laroxe said:
Its certainly an interesting idea and given your comments I had a look around at anything available, I have to say even though I'd love to be wrong about this, I think there are serious problems. The links to Covid 19, while presenting a credible rational, really appear to be opportunistic, ACE2 is involved in a range of important physiological functions. They were in fact already looking at using these drugs to manage chronic lung disease, arterial and cardiovascular diseases and kidney diseases and ACE2 seems to have an impact on hypertension, diabetes, ageing, and the control of regional blood flow. This was all before Covid 19 become known and the evidence of an antiviral effect is based on in vitro work.
I found the published study interesting, the lady was admitted after being symptomatic for 7 days and was started on hydroxychloroquine, she was intubated on the following day and began treatment with the hrsACE2 the day after, day 9 after the onset of symptoms. Normally the adaptive immune response gets going at day 8 following initial exposure, its likely that she was already clearing the virus before this treatment and its possible the hydroxychloroquine might have helped. This is in fact what is commonly found in the people that become severely ill, its usually not caused by a viraemia. The lady was treated for 7 days and there are extensive reports of improvements in biological indicators and recovery being complicated by a bacterial infection she remained intubated for a further 6 days and remained in hospital for 57 days. This is really less than impressive and the drugs are still being tested in phase 1 & 2 trials, the trials being planned seem unlikely to be useful in providing evidence for a Covid treatment.
One aspect of the SARS-CoV, SARS-CoV-2 and MERS-CoV viruses that distinguishes them from other viruses that cause respiratory disease is the mechanism of cell entry. They access cells through the ACE2 receptor. In doing so, the virus takes the ACE2 receptor with it, thereby disabling the ACE2 function. There are a number of very good videos on Youtube that explain the connection between COVID and the loss of ACE2 function such as this one.

A report from the University of Cincinnati published in September refers to their study of data collected in Ohio which indicates that COVID patients had very low levels of Ang-(1,7). Ang-(1-7) is produced by the ACE2 receptor cleaving the Angiotensin II enzyme.

University of Cincinnati said:
“This is among the first substantial evidence supporting the hypothesis of a potential inhibition of ACE2 activity due to virus binding,” Henry stated. “As angiotensin (1-7) is anti-inflammatory peptide that also dilates the vessels, low levels of this peptide due to [the coronavirus] may promote ARDS. As such, supplementation with synthetic angiotensin (1-7) may be a potential therapeutic target for treating COVID-19.”
Laroxe said:
There just seems no sense of urgency and the funding supporting the work is not Covid related, I know you talked about the case study but I'll repeat the link & I've linked to the Clinical trials site. Its interesting.
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30418-5/fulltext
https://clinicaltrials.gov/ct2/show/NCT00886353
You are referring to 2009 trials of APN01. The current trials are definitely COVID related and are due to be completed this month. They are being conducted in Europe by Apeiron Biologics. There is also a trial being conducted in Egypt using bacterial ACE2

AM
 
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  • #28
Andrew Mason said:
One aspect of the SARS-CoV, SARS-CoV-2 and MERS-CoV viruses that distinguishes them from other viruses that cause respiratory disease is the mechanism of cell entry. They access cells through the ACE2 receptor. In doing so, the virus takes the ACE2 receptor with it, thereby disabling the ACE2 function. There are a number of very good videos on Youtube that explain the connection between COVID and the loss of ACE2 function such as this one.
Human Coronavirus NL63 also uses ACE2 as a receptor, but it is generally associated only with mild respiratory symptoms (and much less deadly than the SARS-family coronaviruses): https://en.m.wikipedia.org/wiki/Human_coronavirus_NL63

A report from the University of Cincinnati published in September refers to their study of data collected in Ohio which indicates that COVID patients had very low levels of Ang-(1,7). Ang-(1-7) is produced by the ACE2 receptor cleaving the Angiotensin II enzyme.
This is just correlation. It's possible that these changes are a result of the disease rather than a cause.
 
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  • #29
Ygggdrasil said:
Human Coronavirus NL63 also uses ACE2 as a receptor, but it is generally associated only with mild respiratory symptoms (and much less deadly than the SARS-family coronaviruses): https://en.m.wikipedia.org/wiki/Human_coronavirus_NL63
Good point ... and thanks for the link to the HCoV-NL63. Of course, the difference may be in how effective the virus is in gaining entry to the cell entry or how efficiently it reproduces once it enters the cell. The effectiveness of the virus in gaining entry could depend, for example, on the strength of the bond that the viral spike makes with the ACE2 receptor, which would then affect replication efficiency. If that bond is not strong, viral effectiveness in gaining entry and replicating would decrease with higher temperatures. This is what an article from 2012 found: an inverse correlation between ACE2 expression and viral replication efficiency and that the efficiency of HCoV-NL63 replication was very sensitive to temperature:
Replication-dependent downregulation of ACE2 expression by HCoV-NL63 said:
" A specific decrease for ACE2 protein level was observed when HCoV-NL63 was cultured at 34 °C. Culturing the virus at the suboptimal temperature of 37 °C resulted in low replication of the virus and the effect on ACE2 expression was lost. We conclude that the decline of ACE2 expression is dependent on the efficiency of HCoV-NL63 replication, and that HCoV-NL63 and SARS-CoV both affect cellular ACE2 expression during infection."
What is interesting, though, is the impact of HCoV-NL63 on young children as well as on immune compromised patients and elderly people. This suggests that a mature and healthy immune system will prevent serious infection of HCoV-NL63. That does not appear to be the case for SARS-CoV.
This is just correlation. It's possible that these changes are a result of the disease rather than a cause.
Yes. Or it may be both a result and a cause. I expect we will have a much better understanding of these Coronavirus diseases fairly soon.

AM
 
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  • #30
Just a footnote to my earlier post (#27 above) apropos the logistics and cost of producing hrsACE2 (see posts 2-7 above). In the material filed with regard to the bacterial ACE2 trial that is being conducted in Egypt, this interesting comment appears in the study description:
Clinical Trials summary NCT04375046 for Recombinant Bacterial ACE2 Receptors Like Enzyme of B38-CAP said:
"Despite its beneficial effects, rhACE2 is a glycosylated protein and thus its preparation requires time- and cost-consuming protein expression system with mammalian or insect cells, which may not be advantageous in drug development and medical economy. ... B38-CAP is easily prepared with E. coli expression system and is cost effective.

The hrsACE2 being used in the APN01 trial by Apeiron Biologics is produced in a mammalian cell line (Ovarian cells of Chinese hamsters that reproduce well in vitro) whereas the very similar therapeutic ACE2 protein B38-CAP is a bacterial protein can be produced in e.coli - one of the fastest reproducing cells known.

AM
 
  • #31
Andrew Mason said:
One aspect of the SARS-CoV, SARS-CoV-2 and MERS-CoV viruses that distinguishes them from other viruses that cause respiratory disease is the mechanism of cell entry. They access cells through the ACE2 receptor. In doing so, the virus takes the ACE2 receptor with it, thereby disabling the ACE2 function. There are a number of very good videos on Youtube that explain the connection between COVID and the loss of ACE2 function such as this one.

A report from the University of Cincinnati published in September refers to their study of data collected in Ohio which indicates that COVID patients had very low levels of Ang-(1,7). Ang-(1-7) is produced by the ACE2 receptor cleaving the Angiotensin II enzyme.
You are referring to 2009 trials of APN01. The current trials are definitely COVID related and are due to be completed this month. They are being conducted in Europe by Apeiron Biologics. There is also a trial being conducted in Egypt using bacterial ACE2

AM
I'm familiar with the role of the ACE2 receptor as the binding site for SARs-Cov2 and was considering the original interest in the commonly used ACE and Angiotensin II receptor blockers. There were very similar rationals used in the investigations into whether they increased risk or reduced risk, apparently they don't really do much of either.
One of the key themes in current treatment research is the timing of the interventions, it seems almost pointless to be using antivirals at the point that people are already seriously ill. This is considered to be one of the main reasons that treatment trials have been failing. Even with oseltamivir one of the newer influenza treatments it needs to be started within 48 hours of symptom onset, it seems that decisions about when drugs should be used can be as important as the drug itself.
I am aware of drugs in development, that have only just become public knowledge and have almost immediately started clinical evaluation trials, the pandemic is considered a very serious problem and has attracted huge sums of money to promote developments. Research into these hrsACE2's has been pottering along for well over a decade and I see no evidence of it picking up - now call me an old cynic but ... :)
 
  • #32
Laroxe said:
I'm familiar with the role of the ACE2 receptor as the binding site for SARs-Cov2 and was considering the original interest in the commonly used ACE and Angiotensin II receptor blockers. There were very similar rationals used in the investigations into whether they increased risk or reduced risk, apparently they don't really do much of either.
A number of independent sources indicate that use of ACE inhibitors and ACE2 receptor blockers is correlated with better Covid19 outcomes as this recent British report based on data of almost 20,000 Covid19 patients shows.

One of the key themes in current treatment research is the timing of the interventions, it seems almost pointless to be using antivirals at the point that people are already seriously ill. This is considered to be one of the main reasons that treatment trials have been failing. Even with oseltamivir one of the newer influenza treatments it needs to be started within 48 hours of symptom onset, it seems that decisions about when drugs should be used can be as important as the drug itself.

I am aware of drugs in development, that have only just become public knowledge and have almost immediately started clinical evaluation trials, the pandemic is considered a very serious problem and has attracted huge sums of money to promote developments. Research into these hrsACE2's has been pottering along for well over a decade and I see no evidence of it picking up - now call me an old cynic but ... :)
I guess I have to call you an old cynic then,... :).

The use of hrsACE2 to treat COVID-19 is new and has attracted widespread interest. Apeiron Biologics' financing was oversubscribed. They raised 17.5 million Euros in June.

Whether it will amount to anything depends on the cause(s) of COVID-19 - in particular, it depends on whether the loss of the ACE2 function plays a significant role in the the progress of the disease. If so, the success of hrsACE2 will depend on :
1. whether hrsACE2 is effective in blocking entry of SARS-CoV-2 into epithelial cells expressing the ACE2 receptor; and
2. whether hrsACE2 is effective in carrying out the function of the ACE2 receptor in converting Ang II to Ang (1-7).

AM
 
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  • #33
I see that Apeiron Biologics has provided a recent update on the progress of its Phase 2 trials for its drug APN01 (hrsACE2).

The results are somewhat disappointing, at least for severely ill Covid patients:
  • The data showed that fewer patients treated with APN01 (n=9) died or received invasive ventilation compared to placebo (n=12),although statistical significance was not achieved due to the low total number of events.
While it does not appear to be a miracle cure for Covid, it does appear to provide some benefit in both in reducing viral load and in correcting the imbalance in the renin-angiotensin system that results and which may be a significant contributing factor to the severity of the disease:
  • "A reduction in viral RNA load over time was observed in the APN01 treatment group. Viral RNA levels over time compared to baseline showed a statistically significant improvement with APN01treatmenton day 3 and 5 compared to placebo. "
  • "Throughout the trial, plasma levels of Ang II were significantly reduced under APN01 treatment compared to control. APN01 treatment was shown to significantly increase Ang1-7 and Ang1-5 levels while no increase in these anti-inflammatory factors was seen in the placebo group. "
One advantage of a drug therapy to ameliorate the effects of COVID rather than just attack the virus is the prospect that it will still work even if the virus mutates:
  • “We are encouraged to continue the development of this promising therapeutic candidate. Importantly, with the recent emergence of virus variants that can escape antibody drugs and even vaccines but cannot escape binding to its receptor and entry door ACE2, APN01 could become a critical drug in the global therapy repertoire against virus variants, even against variants that might emerge in the future.”
aM
 
  • #34
Related - Nano-sized vesicles with ACE2 receptor could prevent, treat infection from current and future strains of SARS-CoV-2
https://phys.org/news/2022-01-nano-sized-vesicles-ace2-receptor-infection.html

Scientists at The University of Texas MD Anderson Cancer Center and Northwestern Medicine have identified natural extracellular vesicles containing the ACE2 protein (evACE2) in the blood of COVID-19 patients that can block infection from broad strains of SARS-CoV-2 virus in preclinical studies. The study was published today in Nature Communications.

The evACE2 act as decoys in the body and can serve as a therapeutic to be developed for prevention and treatment for current and future strains of SARS-CoV-2 and subsequent coronaviruses, the scientists report. Once developed as a therapeutic product, evACE2 have the potential to benefit humans as a biological treatment with minimal toxicities.
 
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  • #35
Astronuc said:
Related - Nano-sized vesicles with ACE2 receptor could prevent, treat infection from current and future strains of SARS-CoV-2
https://phys.org/news/2022-01-nano-sized-vesicles-ace2-receptor-infection.html
As noted in this thread, I have been following the development of APN01 (hrsACE2) by Apeiron. How does the nano-particle capsule improve delivery of the ACE2 decoy molecule over the human recombinant soluble version, hrsACE2?

The evACE2 contents appears to be essentially the same molecule (presumably without the part that makes hrsACE2 soluble) but with a different delivery system. The nano particle delivery system is used to allow intra-cellular delivery e.g. they are used by mRNA vaccines to allow the vaccine particles to pass through human cell membranes and deliver the mRNA contents into the cell. But, as I understand it, the decoy molecule remains in the extra-cellular environment to attach to the spike proteins of the virus and prevent attachment of the virus to the ACE2 receptor which is essential for the virus to gain entry to the cell. Perhaps @Ygggdrasil may wish to comment.

AM
 
<h2>1. What is ACE2 decoy and how does it work?</h2><p>ACE2 decoy is a potential therapeutic solution for COVID-19, which involves using a genetically engineered version of the ACE2 protein. This protein acts as a decoy for the virus, binding to it instead of the ACE2 receptors on human cells. This prevents the virus from entering and infecting cells, ultimately reducing the severity of the infection.</p><h2>2. What are the potential benefits of using ACE2 decoy for COVID-19 treatment?</h2><p>The use of ACE2 decoy has several potential benefits for COVID-19 treatment. It can reduce the severity of the infection, prevent the virus from entering and infecting cells, and potentially decrease the risk of complications and death. Additionally, ACE2 decoy has shown to be effective against different variants of the virus, making it a promising solution for the ongoing pandemic.</p><h2>3. Are there any potential risks or side effects associated with ACE2 decoy treatment?</h2><p>As with any new treatment, there are potential risks and side effects associated with using ACE2 decoy for COVID-19. These may include allergic reactions, interactions with other medications, and potential long-term effects that are not yet known. Further research and clinical trials are needed to fully understand the safety and efficacy of this treatment.</p><h2>4. How far along is the development of ACE2 decoy as a COVID-19 treatment?</h2><p>Currently, ACE2 decoy is still in the early stages of development. While initial studies have shown promising results, further research and clinical trials are needed to determine its effectiveness and safety. It is important to note that the development and approval process for new treatments can take several years.</p><h2>5. Is ACE2 decoy a potential cure for COVID-19?</h2><p>While ACE2 decoy shows promise as a potential therapeutic solution for COVID-19, it is not a cure for the virus. It may help reduce the severity of the infection and prevent complications, but it cannot completely eliminate the virus from the body. It should be used in conjunction with other preventive measures, such as vaccines and mask-wearing, to effectively control the spread of COVID-19.</p>

1. What is ACE2 decoy and how does it work?

ACE2 decoy is a potential therapeutic solution for COVID-19, which involves using a genetically engineered version of the ACE2 protein. This protein acts as a decoy for the virus, binding to it instead of the ACE2 receptors on human cells. This prevents the virus from entering and infecting cells, ultimately reducing the severity of the infection.

2. What are the potential benefits of using ACE2 decoy for COVID-19 treatment?

The use of ACE2 decoy has several potential benefits for COVID-19 treatment. It can reduce the severity of the infection, prevent the virus from entering and infecting cells, and potentially decrease the risk of complications and death. Additionally, ACE2 decoy has shown to be effective against different variants of the virus, making it a promising solution for the ongoing pandemic.

3. Are there any potential risks or side effects associated with ACE2 decoy treatment?

As with any new treatment, there are potential risks and side effects associated with using ACE2 decoy for COVID-19. These may include allergic reactions, interactions with other medications, and potential long-term effects that are not yet known. Further research and clinical trials are needed to fully understand the safety and efficacy of this treatment.

4. How far along is the development of ACE2 decoy as a COVID-19 treatment?

Currently, ACE2 decoy is still in the early stages of development. While initial studies have shown promising results, further research and clinical trials are needed to determine its effectiveness and safety. It is important to note that the development and approval process for new treatments can take several years.

5. Is ACE2 decoy a potential cure for COVID-19?

While ACE2 decoy shows promise as a potential therapeutic solution for COVID-19, it is not a cure for the virus. It may help reduce the severity of the infection and prevent complications, but it cannot completely eliminate the virus from the body. It should be used in conjunction with other preventive measures, such as vaccines and mask-wearing, to effectively control the spread of COVID-19.

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