COVID-19 Therapeutics Accelerator
gatesfoundation.org
gatesfoundation.org
If anyone is reading this with connections to the Gates Foundation: Please contact Dr. Robert Kruse at John Hopkins. https://twitter.com/RobertLKruse. I have been trying to get in touch with people at Gates. This announcement unfortunately features no contact email address :(
Dr. Kruse is developing an extremely promising therapeutic, ACE2-fc, which will both neutralize the virus and treat the symptoms of the disease. It has been shown to work in vitro; variants have been tested in animals models; and its been through Phase II human trials for a different indication. A variant of the therapy, soluble ACE2, is being trialed in humans now in China.
Details on the approach can be found in his paper here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029759/ see "ACE2 immunoadhesin strategy"
1. lungs are highly vascularised areas with a large amount of vascular endothelium, making them a great location to express ACE if you want to convert as much angiotensin I as you can in the space of a heartbeat (which you'd like to do if your blood pressure dropped, for example).
2. ACE is not specific for angiotensin, it acts on a variety of peptides. Bradykinin is a good example as it can provide more perspective on why ACE is expressed mainly in lung tissue. Bradykinin acts to contract smooth muscle in your airways. Thus, degrading bradykinin via ACE is a good way to improve your breathing.
https://www.dpz.eu/en/home/single-view/news/die-vermehrung-v...
>The largest Chinese study with 44,672 confirmed cases of Covid-19 shows a high overall case fatality rate (CFR) of 2.3% [2]. Important co-morbidities are hypertension (CFR 6.0%), diabetes (CFR 7.3%), cardiovascular disease (CFR 10.5%) and age >70 (CFR 10.2%) [2]. Similar co-morbidities were noted for the SARS outbreak in 2003.
> ...
>On the one hand, it has been shown that the Covid-19 agent (also known as SARS-CoV-2), uses the SARS-COV receptor angiotensin converting enzyme (ACE) 2 for entry into target cells [4]. The interface between ACE2 and the viral spike protein SARS-S has been elucidated and the efficiency of ACE2 usage was found to be a key determinant of SARS-CoV transmissibility [4].
>
>On the other hand, it could be shown in animal experiments that both the ACE-inhibitor lisinopril and the angiotensin-receptor blocker losartan can significantly increase mRNA expression of cardiac ACE2 (5-fold and 3-fold, respectively) [5]. Further, losartan also significantly increases cardiac ACE2 activity [5].
Edit: thank you philipn for your twitter link.
https://twitter.com/__philipn__/status/1235756671852589056
It may be the other way around: ACEi/ARB may be protective. HTN without ACEi/ARB would be non-protective, potentially so much so that it skews the group fatality numbers. This is because people with HTN have a different renin-angiotensin system profile: more AT1R, less AT2R, more ACE, potentially less ACE2.
This is being looked at now. But the key is that in every study ever done on viral lung disease, etc, AT1R blockade was highly beneficial, and we know that ACE2-knockout basically screws up lungs, makes viral lung disease way worse, etc. Please see my twitter posts.
The virus eats up ACE2, downregulating it as it binds. This would have delirious effects. Check out the linked "essential reading" twitter post.
Will be posting a summary to my twitter soon.
It's only the scientists who didn't start studying Coronaviruses until two weeks ago who seem to think that having ACE2 receptors is dangerous.
Which country are you in?
Edit: Luckily I own several acres of Hawthorn bushes.
I'm not 100% sure on the mechanism of action on Hawthorn. I've read that it's an ACE inhibitor, but I don't have a good source. But I can see at the very least that it's an elastase inhibitor, which is supposed to be protective against ARDS.
edit: I think proanthocyanidin is the component that is supposed to be an ACE inhibitor.
Sources:
https://www.ncbi.nlm.nih.gov/pubmed/12866623
https://www.phcogj.com/sites/default/files/PharmacognJ-10-25...
Do you take them like some herbal remedies (grind it, add honey etc.etc) or do you process it in a lab?
People make their own hawthorn jam and jelly though, so it isn't excessively dangerous, but on principle it's probably better to take a conservative approach, or at least one that's commensurate with the initial risk.
Because I'm in NYC we actually have them growing everywhere because they are one of a handful of approved small-sized street trees, and they're in all the parks, but regardless it's easier just to buy as a supplement.
I'm taking a low dose though, in part to hedge my bets, and in part because I don't want to bleed out if I get into a bike accident.
As per the paper, you want to either block the receptor or down regulate it.
There are also many other ways you can block the virus from entering your lungs that don't involve downregulating your ACE2 receptors.
https://www.nejm.org/doi/full/10.1056/NEJMoa2002032
86.9% of non severe cases had never smoked 77.9% of severe cases had never smoked
Contrasted with 1.3% and 5.2% in former smokers and 11.8% and 16.9% in current smokers.
For instance, there are 137 current smokers. 108 are listed as non-severe. 29 are listed as severe. This means 108/137 = 79% non-severe, 29/137 21% severe.
Never smoked: 927 total, 793/927 non-severe (86%), 134/927 severe (14%).
Hope that makes sense. That table confused me too. Don't start smoking!
When this came up for discussion on HN a few days ago, I was initially confused, as some of what I read seemed to suggest that taking e.g. lisinopril could possibly increase the risk of an infection because it seems to increase the expression of ACE2 receptors that are used by the virus to infect cells.
On the other hand, some of what I read seemed to suggest that ACE inhibitors (e.g. lisinopril) could have a therapeutic benefit. The virus is going to inactivate a bunch of ACE2 receptors through the course of infection. Since ACE2 receptors inactivate angiotensin, that would leave a lot of active angiotensin floating around, which is potentially very bad. ACE inhibitors would seem to help here because they inhibit the active form of angiotensin from being created in the first place.
Now I'm wondering: Is it possible that taking lisinopril could increase the risk of serious infection for those of us not yet infected, but also could reduce the severity of an active infection?
Elderly people are usually on BP meds. Diabetics are frequently prescribed Losartan to protect their kidneys. I know. I am a diabetic, and was prescribed it for that reason and also for high BP.
As a diabetic over 50 with high BP I have a greater interest than most. Especially since my wife was exposed to coronavirus, is sick, and I am starting to feel unwell.
Stopped taking losartan yesterday. Have some tenofovir lying around and might start taking it. It's the only antiviral I was able to get my hands on. Hopefully my chloroquine arrives in the mail soon.
Review of small molecule therapies (not comprehensive): https://blogs.sciencemag.org/pipeline/archives/2020/03/06/co...
I think this is the best thing i achieved all year.
Is this the soluble ACE2 mentioned?
https://www.clinicaltrialsarena.com/news/ubc-apeiron-biologi...
https://pipelinereview.com/index.php/2020022673884/Proteins-...
https://connect.myesr.org/course/novel-coronavirus-outbreak-...
It was initially discovered and developed during the SARS epidemic - https://www.nature.com/articles/nm1267
https://www.theatlantic.com/ideas/archive/2020/03/coronaviru...
This work is based on B-cell epitope mapping of SARS patients and subsequent identification of ACE2 binding peptides like: https://www.sciencedirect.com/science/article/pii/S016635421...
I'm the "dry lab" side of this project -- looking for peptide candidates. My other collaborators at UNC are going to do formulate the aerosol and test for safety in mice.
Normally this would be a very early stage in drug development, but it seems like we have to move quickly.
So similar shout out to the Gates Foundation folks -- if you're interested in this approach email alex.rubinsteyn@unc.edu
To avoid side effects, a therapy ought to be as orthogonal as possible to natural systems. A high dose of a hormone activator smushed together with an immune activator is definitely not orthogonal to natural systems.
More useful to focus on genomic smart bombs like CRISPR Cas13 ( cough, https://github.com/bionicles/coronavirus ) or RNAi because they’re way, way, way, less likely to have side effects, they can last forever, can easily be retargeted to future germs hella quick, etc etc
https://www.gatesfoundation.org/Media-Center/Press-Releases/...
https://www.gatesfoundation.org/Media-Center/Press-Releases/...
>The foundation will provide up to $100 million to improve detection, isolation and treatment efforts; protect at-risk populations in Africa and South Asia; and accelerate the development of vaccines, drugs and diagnostics.
That early investment is going to be so valuable. It's not so easy to get those six weeks back by spending 10x the amount the later.
The article says nothing about shortening the time from in vitro discovery to first use in humans. As far as I can tell, it just promises $125 million for early stage work. That's a lot of money, but a drop in the bucket by drug development standards.
Good to know the effort is being made, just keep some perspective.
[1]https://www.sciencedirect.com/science/article/pii/S016635422...
“At least ten clinical trials are testing chloroquine, approved as an antimalarial and autoimmune disease drug. In vitro, the endosomal acidification fusion inhibitor blocked infection of a clinical isolate of SARS-CoV-2.” https://www.nature.com/articles/d41587-020-00003-1
Choloroquine is also used for autoimmune disease, which also doesn't make sense. Of course none of any of this makes sense to me because i don't know anything about it.
For instance:
Here are the Netherlands treatment guidelines (in Dutch): https://lci.rivm.nl/covid-19/bijlage/medicamenteuze-behandel...
Here are the Italy treatment guidelines (in Italian): http://www.simit.org/medias/1555-covid19-linee-guida-trattam...
I think the anecdote on how they found out about the effectiveness of chloroquine in China is fascinating and has nothing to do with the in vitro efficiency study nor with the malaria usage but solely with the immunomodulator effect. They just noticed that there were no lupus patients infected with Covid19. And after investigating with the dermatology dept, they confirmed that indeed there were no reported lupus patients of that hospital infected with covid19.
Their common treatment was chloroquine...
Source: https://www.jqknews.com/news/388543-The_novel_coronavirus_pn...
It should be noted that as far as the Chinese are concerned, it doesn't seem like there is any debate about chloroquine usefulness for COVID19.
Sources:
https://pubmed.ncbi.nlm.nih.gov/32075365-expert-consensus-on...
and https://pubmed.ncbi.nlm.nih.gov/32074550-breakthrough-chloro...
The bad part of the answer: Overseas testing (e.g. the testing needed for EU approvals) usually does not count for this purpose for bureaucracy reasons.
[1]- I am not affiliated with them in any way, have no specific nonpublic information, and I don't know if they are looking at this specific treatment.
There is "on label" and "off label" usage of drugs. Just because this existing medication is being used in the EU, or has made its way into guidelines, does not mean that it would even make it through EU approvals. It's being used "off label" if it's used for a new condition.
I've personally been treated "off label" for a condition using a drug developed and FDA approved for a serious condition that you wouldn't immediately associate with my condition. It was weird being unable to find any substantive literature on that medication and my condition, but that's the nature of uncommon conditions, or being at the edge like we are with COVID-19.
US doctors will, based on the evidence available, make their own decision on whether to follow the treatments used by their colleagues in the EU and China. They are not going to be held up by FDA approval for off-label use, but they may find things that warrant FDA review and approval because they feel the outcome is not worth the risk. The impact on the US is trailing China and EU to some degree. This buys a little time for some very smart people to do some level of analyses of what's happening elsewhere. It'd be a little different if the early waves hit here first.
From the doctor's perspective, at minimum this is a cover-your-ass move because they don't want to get blamed for an adverse event. The administration needs to manage the risk too, and find other experts to review the situation. They may also need to manage supplies, or costs. This is really no different from the usual medical bureaucracy in the US.
One item that I'll end with is that approval processes (FDA, EU, etc.) provide no guarantees. There are many drugs that have been approved and then removed from general use based on additional experience, or long-term clinical trials. It's obviously good to do more trials and get approvals, but patients and doctors really want the best possible outcome given the situation.
it's said that many covid death are related to cytokine storm, hence why anti rhumatism drugs help, they tame the storm even if they dont touch the originating virus.
maybe, and plausibly, cquine has a similar purpose.
Take SSRIs (selective serotonin uptake inhibitors) used for depression. If you dig up the data, they also hit (at a lower level) acetylcholine, dopamine, histamine, and other receptors. Those off target effects are often responsible for side effects.
So chloroquine could very easily be doing something different for Coronavirus than what it does for malaria.
Essentially it opens some ion gates that allows Zinc to inhibit the virus.
https://blogs.sciencemag.org/pipeline/archives/2020/03/06/co...
Personal anecdote, I was looking up whether to stop occasional cannabis usage as a precaution for a while because it has been labelled an immunosuppressant and an immunomodulator. I don't understand enough of the science to decide, so I'm stopping, but what I saw in those papers suggested that it is good at preventing autoimmune diseases from getting out of hand. Any expert knowledge/opinion very welcome, as many people have access to this drug already.
Definitely avoid combustion with shared bongs. If we might get sick with something that’s gonna impair our lungs, we ought to take action to increase lung function e.g. VO2Max (lactate threshold training / HIIT / Lung muscle exercises with incentive spirometers OR IMST devices) Not sure about the viral implications of systems biology of immune effects of cannabis, but it’s an interesting topic
The above may yield a pill that patients can take at home, reducing further spread of infections that can easily occur in clinical settings. Without such a pill, hospital overflow will occur in any area with more than a few thousand cases. And there will be 100s-1000s of cities worldwide that medical resources could be overwhelmed within a few months.
We need to explore all avenues now. In only 3-4 months, there will be 100,000s of deaths worldwide, if an effective treatment that can be administered outside of hospital settings is not available.
A scientist recently presented at the AHA meeting with these bullet points:
“- 4.8 million hospitalizations associated with the novel coronavirus
- 96 million cases overall in the US
- 480,000 deaths
- Overall, the slide points out that hospitals should prepare for an impact to the system that's 10 times a severe flu season.”
The figures are just for the US, not the world.
https://www.businessinsider.com/presentation-us-hospitals-pr...
If I understand correctly there are many strains of influenza and they mutate. That's why new vaccines are needed.
What about SARS/MERS? Did they mutate too?
We should talk about the test error intervals.
With that small amount of secondary cases, maybe it was a false positive the first time. No procedure is 100% failsafe and this is a price that we pay for being in the real world. Maybe the test was not applied correctly, was not stored accurately or was triggered by some artifact.
From my understanding (I.e. someone who wasn't a doctor or biologist once told me), the flu virus is special in that it is very big for a virus and has something akin to primitive sexual reproduction: it is made of six(?) parts and if two strains of flu infect the same cell, the cell will give birth to viruses that have each part chosen at random from one of the two strains (e.g. aBCdEF or AbcdEf etc').
That's why there are so many strains of flu and the vaccine changes every year.
Apart from that, every virus mutates, and from what I've read there are already at least two known functionally different strains of nCov-2019 (one more aggressive than the other). However, I'd wager the same vaccines and medicines would work for both - to get resistance you need selection pressure or the amount of variance you get from sexual reproduction.
Edit: oh, and nCov-2019 attacks the immune system in a way that seems to lower or prevent acquiring immunity from reinfection.
The study that suggested ADE for this virus showed a very mild effect in vitro. However, antibodies still prevented infection. More crucially yet, a high number of viruses exhibit ADE in vitro, yet only two exhibit ADE in vivo. Moreover, even in vitro, infection of immune cells by the virus did not lead to viral replication. It's therefore unlikely that it shows ADE in humans, especially since its far less severe than viruses that do.
You might notice that for critical cases, lymphocytes counts are down. The issue is that lymphocyte counts are low, yet those patients show very high cytokine levels, and lymphocytes also exhibit exhaustion. Studies in a clinical setting have shown that indeed cytokine levels are a good predictor of lower lymphocyte counts. Thus this seems better explained by the cytokine storm.
Another thing that's good to know is that this coronavirus seems to have a very good exoribonuclease, which is an error checking enzyme. Mutation rates are also quite low, empirically. It is thus probable that this virus will not evolve too much.
Finally, the study that suggests that there are two lineages is deeply flawed. When you take into account the founder effect of international dissemination right before border controls are implemented, and the low mutation rate, you will find that the observation that led to the conclusions that there are two strains is not significantly more likely than the null hypothesis that this is simply a coincidence. Therefore it is not possible to make conclusions about the existence of strains, and certainly not possible to suggest they would behave differently in any way.
(One of which was that biologists have a more specific definition of "virus attacks X system" than computer security researchers, so my wording seems to have been off there. I was trying to say "seems to do something against its effectiveness, because we see cases of reinfection after a short time")
Actemra is a biologic approved in 2010 in the US for rheumatoid arthritis and tones down immune responses by inhibiting interleukin 6 (IL-6).
Basically it turns down the effect called a cytokine storm which causes your own immune system to attack your lungs. This kills a lot of people.
Also take Vitamin D3 (1000 IU a day) it's proven to help lessen respiratory illness if you catch the virus.
It mostly seems to be just dropbox equivalents that let you drag and drop test results and PDFs into shareable folders.
Though specific discussion of essential useful features and shortcomings of the basic concept might be helpful.
Such a shame that the US is not on that list of countries.
That’s not what a paradox is... sigh.
Not trying to nitpick, but isn't the virus called SARS-CoV-2 and COVID-19 is the illness?
https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndr... https://en.wikipedia.org/wiki/Coronavirus_disease_2019
https://ais.badische-zeitung.de/piece/0a/f1/b2/8f/183612047-...
https://ais.badische-zeitung.de/piece/0a/f1/b2/8a/183612042-...
https://arxiv.org/pdf/2002.09334.pdf
https://www.medrxiv.org/content/10.1101/2020.02.25.20021568v...
https://slatestarcodex.com/2020/03/02/coronavirus-links-spec...
(UVC is a specific wavelength of light of the UV band - think UV lights in clubs - it kills bacteria and is now used in hospitals to sterilize equipment ) ...to cleanse the colon of both good and bad bacteria in the intestines in order to immediately cure patients with IBS (Irritable Bowel Syndrome) and Chrons, which are both caused by harmful gut bacteria that even the best probiotics unfortunately do not successfully treat. (Which lead me down the rabbit hole...) If you want to be as sick to your stomach as I am, here is the truth and I am happy to source over 8 case studies out of dozens on the subject which all say the same thing, UVC kills cancer cells as well as COVID-19 and also strong ionized oxygen can kill any virus on contact instantly. Those tiny tentacles of Covid 19 virus will be neutralized in a fraction of a second in contact with the ionized oxygen.
It kills any cell, it's not discriminatory. Oh, and UV-C is carcinogenic. Once you understand that you might appreciate why we don't just shove a UV light up a colon.