Dr. Ron Davis of Stanford - Research Update - Drug Screening. Video from Emerge Symposium March 2019, Australia

jamari

jamari

Established Member (Voting Rights)
Moderator note: There is a thread on the symposium here
https://www.s4me.info/threads/me-cfs-international-research-symposium-march-2019-australia.6914/


Dr. Ron Davis of Stanford Presents an ME/CFS Research Update.
25/04/2019
Drug Screening Using NanoNeedle Technology

Source: Here

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Summary

Two drugs have shown to be effective at reducing the stress response in CFS/ME cells when measured with Nanoneedle biosensors.
  • Copaxone. Used in treating MS relapses.
  • SS31. New unapproved drug which target mitochondria.
Detail

Dr Ron Davis of Standford University and his team have developed a NanoNeedle technology with the intentions of using it as a diagnostic tool for ME/CFS.

The idea is that the patients' cells are unable to cope with stress. So a sample of the patient's blood is dropped onto the NanoNeedle sensor and mixed with sodium chloride (salt), triggering a stress response.

20 severe patients have been tested against controls and show a clear difference in behavior. (see below). The result is repeatable.

ye1g91fqb9p11.png


The team are also using this for drug screening and both Copaxone and SS31 (when added to the blood sample) both normalize the signal. Dr Ron Davis stated that he does not understand why.

This could be optimistic data and a early sign of potential treatments. A more conservative idea would be that the drugs are interfering/blocking the signal.

I found this finding particularly interesting and I look forward to hearing more from the researchers.
 
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Elamipretide (also known as SS-31, , MTP-131 and Bendavia)[1][2] is a small mitochondrially-targeted tetrapeptide (D-Arg-dimethylTyr-Lys-Phe-NH2) that appears to reduce the production of toxic reactive oxygen species and stabilize cardiolipin.[3]

Stealth Peptides, a privately held company, was founded in 2006 to develop intellectual property licensed from several universities including elamipretide; it subsequently changed its name to Stealth BioTherapeutics.[4][5]

As of November 2017 Stealth had obtained an orphan designation in the US for use in mitochondrial myopathy and had started a Phase III trial in that indication.
Click to expand...
https://en.wikipedia.org/wiki/Elamipretide

Glatiramer acetate (also known as Copolymer 1, Cop-1, or Copaxone) is an immunomodulator medication currently used to treat multiple sclerosis. Glatiramer acetate is approved in the United States to reduce the frequency of relapses, but not for reducing the progression of disability. Observational studies, but not randomized controlled trials, suggest that it may reduce progression of disability. While a conclusive diagnosis of multiple sclerosis requires a history of two or more episodes of symptoms and signs, glatiramer acetate is approved to treat a first episode anticipating a diagnosis. It is also used to treat relapsing-remitting multiple sclerosis. It is administered by subcutaneous injection.

It is a mixture of random-sized peptides that are composed of the four amino acids found in myelin basic protein, namely glutamic acid, lysine, alanine, and tyrosine. Myelin basic protein is the antigen in the myelin sheaths of the neurons that stimulates an autoimmune reaction in people with MS, so the peptide may work as a decoy for the attacking immune cells.
Click to expand...
https://en.wikipedia.org/wiki/Glatiramer_acetate
 
jamari said:
Dr. Ron Davis of Stanford Presents an ME/CFS Research Update.
25/04/2019
Drug Screening Using NanoNeedle Technology

Source: Here

==========================================================

Summary

Two drugs have shown to be effective at reducing the stress response in CFS/ME cells when measured with Nanoneedle biosensors.
  • Copaxone. Used in treating MS relapses.
  • SS31. New unapproved drug which target mitochondria.
Detail

Dr Ron Davis of Standford University and his team have developed a NanoNeedle technology with the intentions of using it as a diagnostic tool for ME/CFS.

The idea is that the patients' cells are unable to cope with stress. So a sample of the patient's blood is dropped onto the NanoNeedle sensor and mixed with sodium chloride (salt), triggering a stress response.

20 severe patients have been tested against controls and show a clear difference in behavior. (see below). The result is repeatable.

ye1g91fqb9p11.png


The team are also using this for drug screening and both Copaxone and SS31 (when added to the blood sample) both normalize the signal. Dr Ron Davis stated that he does not understand why.

This could be optimistic data and a early sign of potential treatments. A more conservative idea would be that the drugs are interfering/blocking the signal.

I found this finding particularly interesting and I look forward to hearing more from the researchers.
Click to expand...

Just checking (apologies if I’m just not reading it right): what is the y-scale measuring? Stress response in what substance/unit/process?
What are they specifically measuring, do you know?
 
Subtropical Island said:
Just checking (apologies if I’m just not reading it right): what is the y-scale measuring? Stress response in what substance/unit/process?
What are they specifically measuring, do you know?
Click to expand...

My understanding is that this test measures impedance, i.e. the resistance to the flow of electrical current in the nano-needle.

ETA: In Dr. Davis' presentation, it looks like the healthy control values are normalized to 1 and all the ME/CFS values are higher than that.

The chart below is more clear. The baseline of normal is 1 and one of the ME/CFS cases is as high as 5.

123a.jpg
 
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Alvin said:
The why really matters. They need to identify the molecule which might help answer this question or may lead in a direction of preventing its release in the first place.
Click to expand...
sure.
and in the meantime, if some things may help would be great.
unfortunately, the meds are very expensive and may be needed long term.

what symptoms did the drugs change in "severe mecfs" patients?
was any patient of the test group willing to try ?
 
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is there a graph, showing the signal difference after
- elamipretide
- copaxone

(except the signal is then the same as "healthy", is it?)
 
what symptoms may the signal-normalization fix in mecfs ?

muscles ?
brain fog ?

also, would be interesting to know if the MS patients have a similar signal deviation ? since copaxone helps them.
does copaxone in MS help for the same reason (signal improvement) ?
 
roller* said:
sure.
and in the meantime, if some things may help would be great.
unfortunately, the meds are very expensive and may be needed long term.

what symptoms did the drugs change in "severe mecfs" patients?
was any patient of the test group willing to try ?
Click to expand...
None of this has been tested in patients so far, so we don't what symptoms, if any, might change.

roller* said:
is there a graph, showing the signal difference after
- elamipretide
- copaxone

(except the signal is then the same as "healthy", is it?)
Click to expand...
No, I don't believe there is a publicly available graph.

roller* said:
what symptoms may the signal-normalization fix in mecfs ?

muscles ?
brain fog ?

also, would be interesting to know if the MS patients have a similar signal deviation ? since copaxone helps them.
does copaxone in MS help for the same reason (signal improvement) ?
Click to expand...
Again, we don't know what symptoms will be helped yet, if any.

I don't believe Ron has said whether he has used the nano needle on MS cells, either treated or not.
 
Very interesting indeed. Delving more into the two compounds :

Copaxone : It is a mixture of random-sized peptides that are composed of the four amino acids found in myelin basic protein, namely glutamic acid, lysine, alanine, and tyrosine.

and

SS-31 aka Elamipretide


Elamipretide (also known as SS-31, , MTP-131 and Bendavia)[1][2] is a small mitochondrially-targeted tetrapeptide (D-Arg-dimethylTyr-Lys-Phe-NH2) that appears to reduce the production of toxic reactive oxygen species and stabilize cardiolipin.[3]



Some thoughts :

- It appears that both compounds contain Lysine and tyrosine (can someone confirm for elamipretide?)

-Robert Phair is looking for a trap in tyrosine metabolism. I also confirm that tyrosine should be further researched previously, based on the output of Machine Learning system.

- Here is one idea. I used my collected pubmed data to try to identify which medical topics (out of a total of 592) mention all of the terms that we have seen in ME/CFS research (e.g cardiolipin, sepsis, MAIT cells,pyruvate, lactate, leptin, TRAIL, etc - list not inclusive). This is the output from the run :

find . -type f -exec grep -q thyroid {} \; -exec grep -q exosome {} \; -exec grep -q hypoxia {} \; -exec grep -q sepsis {} \; -exec grep -q MAIT {} \; -exec grep -q leptin {} \; -exec grep -q pyruvate {} \; -exec grep -q lactate {} \; -exec grep -q virus {} \; -exec grep -q "bile acid" {} \; -exec grep -q acetylation {} \; -exec grep -q TRAIL {} \; -exec grep -q "creatine kinase" {} \; -exec grep -q DAMPs {} \; -exec grep -q "beta oxidation" {} \; -exec grep -q lysine {} \; -exec grep -q tyrosine {} \; -exec grep -l cardiolipin {} \;

./albumin.csv
./cd36.csv
./ckd.csv
./er.csv
./fatty_acid.csv
./glutamate.csv
./glycolysis.csv
./glycoproteins.csv
./gut.csv
./hepatocytes.csv
./il_6.csv
./inflammatory_cytokines.csv
./leptin.csv
./liver_disease.csv
./liver_injury.csv
./macrophage.csv
./p53.csv
./proteasome.csv
./retinoic_acid.csv
./ros.csv
./sepsis.csv
./tnf_alpha.csv
Click to expand...

I won't discuss about Liver injury, that's a promise ;-)

ckd = chronic kidney disease, er = endoplasmic reticulum stress.

Finally a paper -study in rats- i found on using SS-31 for CKD (CKD, TNF-a, ROS also shown in the results listed above )

SS-31 (also known as elamipretide) is a synthetic tetrapeptide (D-Arg-2′6′-dimethylTyr-Lys-Phe-NH2) that selectively targets cardiolipin on the inner mitochondrial membrane to protect cristae curvature, stabilizes mitochondrial structure, facilitates electron transport, and minimizes ROS production.26–28 SS-31 is very effective in minimizing ischemic AKI and preventing the development of interstitial fibrosis and glomerulosclerosis
------
Our results suggest that persistent mitochondrial damage underlies the progression of CKD, and this was confirmed with the mitoprotective agent SS-31. Treatment with SS-31 before ischemia protected endothelial and epithelial mitochondria, preserved peritubular and glomerular capillaries, and prevented inflammation and fibrosis.29 Here we show that SS-31, started 1 month after ischemia, can repair mitochondria in endothelial cells, podocytes, and tubular cells. This led to restoration of peritubular and glomerular capillaries, preservation of podocyte architecture, suppression of inflammation, and fibrosis. SS-31 abolished the increase in TNF-α and TGF-β over the 6-week treatment interval.
-----
Click to expand...

DAMPs are also mentioned in the paper : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407729/

Very promising compounds !
 
these "tests" dont seem overly complicated to me.
the implications of the signalling seem important. so much is going "wrong".
 
123a.jpg

FWIW, what I think is going on in this chart is that sodium has been added to the samples prior to any of the measurements shown. Sodium is a conductor, so it has lowered the resistance to the flow of electricity (the impedance) in the serum to the level of about "1" in all the samples.

As time goes by, the cells in all the samples start to absorb the sodium.

The healthy cells are able to quickly pump the sodium back out into the serum, which keeps the serum's sodium level high and its impedance low (around "1").

For some reason, the ME/CFS cells can't pump the sodium back out into the serum efficiently, so the level of the sodium in the serum drops as more and more of it is absorbed into the ME/CFS cells. As the level of sodium in the ME/CFS serum drops, the serum becomes a poorer conductor of electricity, and so the impedance (resistance to the flow of electricity) of the serum - as measured by the nano-needle - rises by as much as 5 times the baseline (as shown by the red lines).

The question is: Why can't the ME/CFS blood cells pump the sodium back out into the serum as efficiently as the healthy cells?

[ETA: This was just my guess as to what is going on based on the chart and what I'd heard about the test. In light of the subsequently released paper, I'm less confident about my guess. For instance, measurements seem to have been taken before the sodium chloride was added. The addition of salt may be represented by the slight drop in impedance seen at 0.0. It's also not clear to me if they are measuring the impedance of the serum, the cells, or both.]
 
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lansbergen said:
Not enough ATP production?
Click to expand...

Na+/K+ ATPase actively transports potassium into the cell and sodium to the extra-cellular space according to the general scheme depicted below
Click to expand...

we may produce endogenous Ouabain in the Hypothalamus

if this is caused by such a process of endogenous production, then an antagonist could be Rostafuroxin (german wiki again only) ?

.. am just wondering, since so much has been tried already... perhaps this one too ?
 
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Copaxone and EAE worth searching
Can you get these amino acids in a health food store to work together in the same way
 
mariovitali said:
Very interesting indeed. Delving more into the two compounds :

Copaxone : It is a mixture of random-sized peptides that are composed of the four amino acids found in myelin basic protein, namely glutamic acid, lysine, alanine, and tyrosine.

and

SS-31 aka Elamipretide


Elamipretide (also known as SS-31, , MTP-131 and Bendavia)[1][2] is a small mitochondrially-targeted tetrapeptide (D-Arg-dimethylTyr-Lys-Phe-NH2) that appears to reduce the production of toxic reactive oxygen species and stabilize cardiolipin.[3]

Very promising compounds !
Click to expand...


It appears that Copaxone is hepatotoxic and is also listed on LiverTox database :

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528838/


A member on PR has tried it out -unfortunately- with a negative outcome :

https://forums.phoenixrising.me/threads/starting-copaxone.62406/

There are no entries for suramin and SS-31 on LiverTox database.
 
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