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Trius Therapeutics, Inc. (TSRX) Message Board

posgost67 73 posts  |  Last Activity: Jul 18, 2014 9:52 PM Member since: May 30, 2013
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  • Reply to

    Gerald

    by wikidsnoboarder2000 Jun 28, 2014 12:24 AM
    posgost67 posgost67 Jun 28, 2014 7:43 PM Flag

    Got it. Thanks. I agree, less Wolfram's patients likely means less patients to enroll in the study. The only issue is with power analysis (getting enough patients to be able to detect statistically significant differences in the treatment. I wouldn't want to underpower the study.

  • Reply to

    Gerald

    by wikidsnoboarder2000 Jun 28, 2014 12:24 AM
    posgost67 posgost67 Jun 28, 2014 5:21 PM Flag

    I don't know what you mean by "A Wolfram's trial will use less MANF than an RP trial". Both are chronic diseases, so both will require repeated doses (after MANF is proven to be safe, etc). The pathogenesis of eye disease in Wolfram's is similar but not the same as RP, ZB.

    RP is heterogeneous and many different mutations can cause RP. Its thought that the retina degenerates because of toxic accumulation of proteins and other things from degenerated rods and cones in the retinal pigmented epithelial (RPE) cells. It causes blindness because the retina becomes completely dysfunctional.
    Wolfram's is caused by a defect in WFS1 gene (encoding wolframin). Loss of WFS1 causes blindness because the optic nerve atrophies. The retina is fine. Also, even though the Wolfram's patients have diabetes, they don't seem to get diabetic retinopathy.

    I do concur that if they treat Wolfram's with MANF, it will be local eye treatment first, but not for retinitis pigmentosa. They will be treating the optic nerve dysfunction. If that is successful, they may try targeted therapy to the beta cells of the pancreas, or systemic therapy.

    It will be like the Biomarin approach... Treat rare diseases because nobody else is doing it.

    The only difference is, if MANF can treat retinitis pigmentosa, it may be a useful therapy for other forms or retinopathy. If it helps with retina degeneration, it may help with neuron degeneration in Parkinson's, Alzheimer's, and Huntington's. Also, if it can help with Wolfram's associated diabetes, it may help with protecting beta cells in type 1 or type 2 diabetes.

  • Reply to

    Huge deal

    by posgost67 Jun 20, 2014 10:37 AM
    posgost67 posgost67 Jun 20, 2014 10:58 AM Flag

    All gene therapy approaches thus far to correct a mutation/gene deletion have targeted the mutant protein. Urano thinks supplying MANF via gene therapy is better than supplying wolframin to patients with mutated wolframin. Do you see that yet? I do not know of one instance where a scientist has tried to do that yet. For instance, boys with SCID by mutation of adenosine deaminase. People give them adenosine deaminase gene therapy to fix their lymphocytes. Not MANF. That's why it's a huge deal. Urano has stated he is testing different proteins in his wolframin mice. He had to like what he saw with MANF

  • posgost67 by posgost67 Jun 20, 2014 10:37 AM Flag

    For Urano, a scientist to go after MANF, a similar but unrelated protein, as a GENETIC therapy TO CORRECT cells in a genetic disease where the DISEASE IS CAUSED BY A MUTATION IN ANOTHER I REPEAT ANOTHER protein, wolframin, means the data with replacement therapy/treatment in animal models is better than replacing the mutant protein. It could be a dominant negative (scientists, you know what I am talking about) effect of mutant wolframin which would make any additional wolframin useless because of the dominant effect of the mutant protein.
    Last part about the dominant negative is speculation on my part. First part with all caps for emphasis is speculation from Urano... Or is it... He said he had data coming out which would help him choose/decide between replacement therapy with wolframin or treatment with MANF for Wolfram's syndrome.

    Looks like he chose.

  • Reply to

    So tempting to flip this right now

    by youenj0ymyself Jun 2, 2014 3:55 PM
    posgost67 posgost67 Jun 2, 2014 5:51 PM Flag

    Enjoy your luxury tax on the $400 profit.

  • posgost67 posgost67 Jun 2, 2014 5:49 PM Flag

    Isn't that an insider violation if you do it within a certain amount of time before a binary event?

    Just curious

  • Reply to

    Yesssssssss

    by porschetarga55 May 28, 2014 4:00 PM
    posgost67 posgost67 Jun 1, 2014 11:33 PM Flag

    Good luck bball. I enjoyed some of your posts on the INO board as well. I typically go there and search for markbuti, or kyleramer. Even some of the pumper'/investor's bickering is intolerable there. Kyle has good info, though and does good DD. Mark has some good comments as well.

  • Reply to

    Yesssssssss

    by porschetarga55 May 28, 2014 4:00 PM
    posgost67 posgost67 May 28, 2014 8:21 PM Flag

    Yes, of course. I really can't take that message board. The bashers say the same 30 year #$%$, same posts rehashed. Still long and strong.

    Although the reverse split is very annoying. I over-doubled, sold half when it hit ~$4 (sold at 3.97), and am holding free shares through the binary event that is upcoming. Even if it doesn't meet primary endpoint, they can always go back and redo same trials with IL-12 plasmid or IL-33 plasmid which will, IMO, lead to approval. Still bullish on VGX alone (without plasmid).

  • Reply to

    Yesssssssss

    by porschetarga55 May 28, 2014 4:00 PM
    posgost67 posgost67 May 28, 2014 6:12 PM Flag

    Praying is generally not a good investment strategy. But I agree with your sentiments (and my DD agrees too) wholeheartedly.

  • Reply to

    More Wolframs Data is Coming!

    by riskreturn168 May 20, 2014 1:02 PM
    posgost67 posgost67 May 26, 2014 5:28 AM Flag

    Local delivery of a drug like MANF is where it's at. Eye is easiest choice. That's why ISIS went after CMV retinitis in AIDS patients as their first antisense candidate, and that's why the local antisense therapy worked, and got approved by the FDA. If I were working for AMBS I would tell the go after the low hanging fruit: RP. If it succeeds, you can go after other eye indications next, diabetic retinopathy, for instance, or go after another local therapy: Parkinson's in the substantial nigra. Then go for the systemic therapy, like diabetes.... Wolfram's a genetic mutation, so it is systemic, even though the clinical manifestations are local (eye, brain, pancreas problem). So far, I don't know any way to locally deliver a medication to the pancreas

  • Reply to

    DR. URANO is getting CLOSE...

    by paismanolo1 May 24, 2014 6:54 AM
    posgost67 posgost67 May 25, 2014 12:39 AM Flag

    The important thing is that once the ER stress pathway or unfolded protein response (remember proteins are made and folded in the ER) is triggered, MANF is one of three mechanisms that the cells use to protect themselves against death. The cytoprotective mechanisms are 1) phosphorylation of eIF2-alpha by PERK (protein kinase RNA like ER stress kinase) which stops translation (mRNA to protein) of new proteins to prevent continued production of toxic, misfolded proteins, 2) activation of XBP-1 and ATF6 transcription factor which causes the production of molecular chaperones such as Grp78 that help refold the misfolded proteins, and 3) MANF

    Type in google browser: unfolded protein response (UPR) and Alzheimer's, or UPR and Huntington's, or UPR and myotonic dystrophy, or UPR and retinitis pigmentosa, or UPR and diabetes, or UPR and cardiac ischemia, or UPR and heart failure.

    That is the big picture.

  • Reply to

    DR. URANO is getting CLOSE...

    by paismanolo1 May 24, 2014 6:54 AM
    posgost67 posgost67 May 25, 2014 12:26 AM Flag

    You guys are missing the big picture. This is a review in Circulation Research about ER stress in disesasefrom a few years ago summarizing ER stress. The important thing is that calcium homeostasis is one of many cellular problems that can trigger the ER stress response leading to the broader cellular protective mechanism, the unfolded protein response. Low oxygen from ischemia (heart attacks, stroke, arterial occlusion, organ preservation for organ transplantation), misfolding of proteins (hello Alzheimer's disease, Huntington's disease), Calcium homeostasis (Wolfram's, retinitis pigmentosa), are triggers of the ER stress pathway/unfolded protein response. You can trigger the ER stress pathway in the absence of calcium influx/efflux issues.
    Endoplasmic Reticulum Stress As a Therapeutic Target in Cardiovascular Disease
    Tetsuo Minamino, Issei Komuro, Masafumi Kitakaze
    "Cardiovascular disease constitutes a major and increasing health burden in developed countries. Although treatments have progressed, the development of novel treatments for patients with cardiovascular diseases remains a major research goal. The endoplasmic reticulum (ER) is the cellular organelle in which protein folding, calcium homeostasis, and lipid biosynthesis occur. Stimuli such as oxidative stress, ischemic insult, disturbances in calcium homeostasis, and enhanced expression of normal and/or folding-defective proteins lead to the accumulation of unfolded proteins, a condition referred to as ER stress. ER stress triggers the unfolded protein response (UPR) to maintain ER homeostasis. The UPR involves a group of signal transduction pathways that ameliorate the accumulation of unfolded protein by increasing ER-resident chaperones, inhibiting protein translation and accelerating the degradation of unfolded proteins. The UPR is initially an adaptive response but, if unresolved, can lead to apoptotic cell death. Thus, the ER is now recognized as an important organelle in deciding cell life and death"

  • Reply to

    More Wolframs Data is Coming!

    by riskreturn168 May 20, 2014 1:02 PM
    posgost67 posgost67 May 25, 2014 12:04 AM Flag

    No. I am just saying with the gene therapy/gene editing approach (which is very difficult and hasn't really worked yet to a degree that we want it in humans), targeting wolframin seems like the more logical candidate.
    Remember though, from a treatment perspective, MANF also acts as a growth factor/cytokine and has an extracellular receptor (the receptor has not been identified yet) making it a good druggable candidate. I don't think wolframin has ever been tested for signaling effects. That's why I think MANF replacement therapy (in Wolfram's or other diseases) makes sense.

  • Reply to

    What do y'all think of this article out today?

    by jegfsu May 24, 2014 5:35 PM
    posgost67 posgost67 May 24, 2014 11:55 PM Flag

    Not much. I am going to take a scientific realist approach.

    They used a genetic Alzheimer's like mouse strain that overexpresses mutant amyloid precursor protein, which mimics several aspects of Alzhemier's because they get amyloid plaques.

    However human Alzheimer's is more complex, and drugs that have targeted amyloid precursor protein or the processing of amyloid precursor protein by beta secretase (BACE-1) or gamma secretase (the proteins that cleave and modify amyloid precursor protein to form beta-amyloid plaques) have either led to no improvement in phase II trials, stoppage due to severe liver toxicity, or actual worsening of Alzheimer's when compared to doing nothing.

    So why would using an antisense therapy to the RNA of amyloid precursor protein have an effect in human disease? Well obviously in an animal model where the disease phenotype depends on the over expression of amyloid precursor protein, knocking down the protein with antisense will improve the disease.

    But in all actuality, the human disease is caused by many problems acting in concert, that we don't quite fully understand.

    That's why the paper is published in Journal of Alzheimer's Research and not Nature or Science. It is an incremental advance at best, and likely won't amount to much.

    I hope I am wrong for the patients' sake, but I am not getting my hopes up yet.

  • Reply to

    More Wolframs Data is Coming!

    by riskreturn168 May 20, 2014 1:02 PM
    posgost67 posgost67 May 22, 2014 11:00 PM Flag

    Ok guys. Wolfram's is caused by a defect in the protein wolframin, the protein encoded by the gene WFS1. It is an endoplasmic reticulum stress protein just like MANF. Most of Urano's work is on wolframin, not MANF. A lot of what he is talking about with gene therapy is with regards to wolframin not MANF. I'm not saying that Urano isn't interested in MANF or isn't looking into MANF as a treatment for diabetes, he is... All I'm saying is he has other projects he refers to that are not MANF related

  • posgost67 by posgost67 May 22, 2014 10:52 PM Flag

    He posted it on twitter. Very good read and discusses the new IP just licensed. Didn't know about this but he also talks about a trial that is suspended using the new updated Lympro IP in 40 something patients that data should be out in July on.
    Very good read especially on the new financial position of the company

  • posgost67 posgost67 May 21, 2014 6:06 PM Flag

    I don't know what the IP entails. The press release didn't say exactly what they were licensing.
    My guess is that the new data leading to the new IP came out after the original test was already licensed. I have not seen any new publications with regards to LymPro, so it has to be unpublished data from the original inventors.

  • posgost67 posgost67 May 21, 2014 5:52 PM Flag

    All flow cytometers go cell by cell. The machine they got is a typical CLIA certified flow cytometer. They need flow cytometry to run Lympro. That is why BD (the masters of flow cytometry) are validating their results for Lympro. Everything, the cytometer, the antibodies, are from BD biosciences. Read the original and follow up Lympro papers. They use BD equipment.

  • posgost67 posgost67 May 21, 2014 5:46 PM Flag

    Guys: I've said this before. Lympro is a flow cytometry based test. They stimulate peripheral blood mononuclear cells with pokeweed mitogen and they look for the increase of CD69, a marker of very early activation, on the cell surface of B cells and T cells by flow cytometry. Then they calculate an index of activation (The fold increase of CD69 expression in stimulated divided by unstimulated T cells or B cells). Cells from Alzheimer's and possibly TBI patients have an impaired stimulation index compared to healthy people. That is the basis of the test.

    Without a flow cytometer, you cannot do the lympro assay. My hypothesis is that they are going to try to validate the new IP they were just licensed in regards to the LymPro test (the "upgraded" test that they just PRed a couple weeks ago) to see how much more sensitive and specific the test is compared to the old method, or maybe even just see if the new IP is feasible compared to the old methodology.

    Provista sells used laboratory equipment, including flow cytometers. I don't know what type of flow cytometer they bought, but 20K can buy you a pretty good used machine. They, in theory, only need a 3-color flow cytometer (CD3, CD20, and CD69), but clinical grade flow cytometers are typically more expensive than for research only flow cytometers, because they need to be CLIA certified.

    FYI

  • Reply to

    MANF - in retinal transplantation

    by zoombboom May 20, 2014 6:40 PM
    posgost67 posgost67 May 21, 2014 2:55 PM Flag

    it should say reperfusion... Sorry spell check on my phone... Lol

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