Pipeline Therapeutics

Discussion in 'Research News' started by FGG, Nov 14, 2019.

    1. xyz
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      xyz Member

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      I just read that PIPE-505 uses a gamma secretase inhibitor. Isn't that the same thing Audion/Regain has tested? So if Pipeline Therapeutics hasn't got some great reformulation of this drug, this looks not very promising.
       
    2. AUTHOR
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      FGG
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      FGG Member Podcast Patron Benefactor Ambassador Hall of Fame Advocate

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      They do but it seems to have minimal effect on hair cell regrowth and mostly on synapses so my guess is it is a much weaker inhibitor. I did ask them ages ago about support cell depletion and they said for their drug it wasn't a significant amount.

      But I would like to know if it is not significant because it does a minimal amount of OHC regeneration and/or if their method produces less support cell depletion. Maybe we can get them on the Tinnitus Talk Podcast at some point and ask them these things.
       
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    3. wwtsai
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      wwtsai Member Podcast Patron Benefactor

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      Pipeline Therapeutics announced the initiation of their Phase 1 clinical trial for PIPE-307, a drug targeting remyelination. At the bottom of the press release under their About, they state that they're still currently enrolling for their PIPE-505 Phase 1/2 which seems kinda... weird? Based on the last update back in November, the estimated completion date was pushed to this month. If they haven't even finished recruitment then they definitely aren't making that deadline.

      Pipeline Therapeutics Initiates Phase 1 Clinical Trial of PIPE-307
       
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    4. Aaron91
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      Aaron91 Member Podcast Patron Benefactor Ambassador Advocate

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      So with FX-322 news imminent, I thought I'd go down the rabbithole a bit with this question in the event Frequency Therapeutics do drop a bombshell on us.

      I think most are already aware of this, but PIPE have a transdifferentiation approach when it comes to regenerating hair cells:

      Pipeline.png

      Transdifferentiation.png

      To put it simply, FX-322 causes asymmetric division where you end up with a hair cell and a new progenitor, whereas with PIPE the progenitor turns into a hair cell and the progenitor is depleted. Of course people are confused because PIPE are saying they are not seeing much depletion of the support cells, but as @FGG has pointed out this could be down to the fact that they're not getting much regeneration in the first place.

      So I did a bit more digging, and found an interesting slide from one of Frequency Therapeutics' presentations. Before I get to that though, here's just a reminder of what Carl LeBel had to say on this:

      "What those [transdifferentation] programmes have tried to do is take a progenitor cell and – it’s a process we call transdifferentiation – you’re taking a supporting cell, a progenitor cell, and turning it into a hair cell, you’re making it want to become a hair cell. The problem is, it can’t be a fully functional hair cell, because you haven’t turned the right genes on. And the other problem is, you have now exhausted now your progenitor pool".​

      PIPE use one small molecule, whereas Frequency Therapeutics use two. Again, this is what Carl LeBel had to say:

      "The other molecule is a proprietary molecule, and this is a molecule that goes after a specific pathway, and as I said earlier, it’s the combination of these two agents that we think is important"​

      So far, I don't think I've said anything new, but I just wanted to bring people up to speed in any case. But now, here's the slide from Frequency Therapeutics that I think is interesting and backs up the above:

      Notch inhibition.png

      So what we are looking at here are the differences in cell proliferation when using the two Frequency Therapeutics molecules individually and then together. As I don't have a medical background, the first thing I was interested to know was whether valproic acid (sodium valproate), as a HDAC Inhibitor, is comparable to other notch inhibitor approaches companies such as PIPE have. After a bit of research I came across this paper, which looks at transdifferentiation of pancreatic cells using HDAC. Indeed, it seems to confirm that "HDAC1 regulates retinal neurogenesis by suppressing Wnt and Notch signalling pathways". Obviously we are talking about ears and not eyes here, but I'm assuming the science remains largely relevant.

      So one could argue that what we are looking at in the 3rd graph is something close to what one might see when using PIPE's drug, as that too is a notch inhibitor. If anything, it may be even worse in reality, because HDAC seems to also have Wnt inhibition properties as well. What's interesting about the last graph though is that although the red area is more than double, if you look at the x-axis, which indicates the number of green-fluorescent progenitors observed, the numbers are logarithmic. Using Frequency Therapeutics' approach, we are seeing 10x more progenitors compared to single-molecule approaches.

      I can only then infer that the reason why there isn't much cell support depletion observed is because there probably isn't much regeneration going on in the first place, at least compared to that observed when using a drug like FX-322.
       
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    5. AUTHOR
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      FGG
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      FGG Member Podcast Patron Benefactor Ambassador Hall of Fame Advocate

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      That's an awesome, well reasoned and well explained deep dig.

      Pipeline Therapeutics knew pre-clinically they didn't grow many hair cells but grew synapses well but I think this is obviously preferable when you are dealing with a transducing drug that depletes support cells.

      I think what you suggest is part of the picture, however, Audion's drug, if I recall right is also a single molecule (and also a gamma secretase inhibitor like Pipeline Therapeutics' drug) and transduced a non insignificant amount of support cells into "hair cells" as a single molecule.

      There has to also be something about the strength of the inhibition, too imo. I.e. maybe a partial or competitive inhibitor doesn't transduce support cells well but stimulates synapse connection.
       
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    6. Tezcatlipoca

      Tezcatlipoca Member

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      Wow, that's amazing, looks like FREQ may be sitting on the holy grail of regenerative medicine.
       
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    7. Lucifer

      Lucifer Member Podcast Patron Benefactor Hall of Fame

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      FX-322 is going to change the hearing industry for life.
       
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    8. Matchbox

      Matchbox Member

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      Auditory nerves at the hair cell base are unmyelinated. This might help MS patients though.
       
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    9. Tezcatlipoca

      Tezcatlipoca Member

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      It is for MS.
       
    10. Aaron91
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      Aaron91 Member Podcast Patron Benefactor Ambassador Advocate

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      I've had a few more thoughts.

      There's been a lot of discussion recently on the FX-322 thread about the pharmacokinetics/dynamics of the two small molecules. Specifically, there has been some concern about VPA, the HDAC inhibitor, being depleted a lot more quickly compared to CHIR99021 in that it does not go as deep into the cochlea, the implication being some regeneration potential goes to waste because Frequency have "undershot" the amount of VPA required. See graph below:

      VPA.png

      I'm now wondering whether this is actually somewhat intentional.

      Given my post yesterday, we can infer that VPA alone, given its inhibition properties, causes progenitors to transduce into hair cells, not divide asymmetrically. The paper I posted yesterday, in paraphrasing another paper, supports this:

      "A study recently reported the usefulness of VPA in transdifferentiation of BMSSCs into hepatocytes in vitro."​

      So it would appear this is why the two-molecule approach is key, because it is the presence of CHIR99021, the proprietary molecule, that ensures we have asymmetric division and not transdifferentiation, although it's unclear whether the prevention of transdifferentiation is synergetic i.e. either drug alone causes transdifferentiation but together we have asymmetric division.

      My point though is this: assuming transdifferentiation is limited to VPA, I'm wondering whether Frequency Therapeutics have purposefully "capped" the amount of VPA relative to CHIR in order to prevent a case transdifferentiation in places where there is not enough CHIR, as an excess of VPA could lead to FX-322 causing unintended support cell depletion.

      Thoughts?

      Also, do you guys think I should perhaps share this on the Frequency Therapeutics thread?
       
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    11. AUTHOR
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      FGG
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      FGG Member Podcast Patron Benefactor Ambassador Hall of Fame Advocate

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      I'm still thinking about this, lol. I have some reading to do. Yeah post it on the Frequency Therapeutics thread...
       
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    12. Diesel

      Diesel Member Benefactor Ambassador Hall of Fame Advocate

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      Interesting thought. If that's the case, then perhaps in additional doses, the VPA would flow past the already OHC/IHC that have asymmetrically divided, and be absorbed by LGR5+ cells deeper in the cochlea. There would likely already be CHIR present. I may re-post this in the Frequency Therapeutics thread...
       
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    13. Aaron91
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      Aaron91 Member Podcast Patron Benefactor Ambassador Advocate

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      Just working on a draft now compiling all posts.
       
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    14. Zugzug

      Zugzug Member Podcast Patron Benefactor Ambassador Hall of Fame Advocate

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      Extremely nice write up (even going back a couple posts). I've been studying this process to death, but never really took the time to understand the roles of VPA and CHIR -- I just assumed it was out of reach. Whether or not your theory is correct, you explained the science like a high-level ELI5 post. I also now know more about PIPE-505 and even their remyelinating drug program. Good stuff.

      As far as your theory, and obviously I'm speculating from a place of total ignorance, I find it unlikely that CHIR has anything to do with HDAC inhibition or transdifferentiation. As even just a layman, it seems like the risk is too high of depleting LGR5+, which would be a major mistake for a company that devised such beautiful synergy.

      Something I'm wondering about with those 2 graphs is why the z-axis has different scaling. Is it just a matter of molecular weight differences mostly? I must say, on the math end, it's strange to me that the axes are such perfect numbers like powers of 10. The logarithmic scaling makes sense, but I wonder if they could have produced a more informative VPA graph.

      I probably have more thoughts that I will add to the Frequency Therapeutics thread.
       
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    15. AUTHOR
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      FGG
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      FGG Member Podcast Patron Benefactor Ambassador Hall of Fame Advocate

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    16. dmorg

      dmorg Member Benefactor

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      Holy Smokes! Thank you for all of this. Do you ever sleep!?
       
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    17. annV
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      annV Member

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      Attached Files:

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    18. Aaron91
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      Aaron91 Member Podcast Patron Benefactor Ambassador Advocate

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      Great question. I had the same question and the only example I was able to find was in zebrafish but there could be others as well. Here's the relevant quote from the study though:

      "We found that pharmacological inhibition of HDACs using trichostatin A (TSA) or valproic acid (VPA) increased histone acetylation in the regenerated neuromasts following neomycin-induced damage. We also showed that treatment with TSA or VPA decreased the number of supporting cells and regenerated hair cells in response to hair cell damage"​

      So to your point it would appear it promotes both neurite growth and hair cell regeneration, but also confirms my theory that VPA does deplete support cells in the process of regeneration. The question I guess now is whether this is applicable to humans. I'm going to keep looking for other papers.
       
    19. Zugzug

      Zugzug Member Podcast Patron Benefactor Ambassador Hall of Fame Advocate

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      After glancing at the paper, it seems odd they would fail to mention this fact for humans if it was proven to be the case. The introduction paints a picture of human focus, but with zebrafish as something available to show this phenomena. Unless it happened after 2014...
       
    20. AUTHOR
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      FGG
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      FGG Member Podcast Patron Benefactor Ambassador Hall of Fame Advocate

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      Interestingly, in the paper @annV just linked (you rule as always), it describes one of the functions of VPA as increasing LGR5+ expression so that more support cells can be used as progenitor cells.

      The paper also talks about the synergistic effects of notch and wnt co-activation on hair cell regeneration without depleting support cells.

      Your paper, @Aaron91 shows VPA on its own depleting support cells. I'm kind of fascinated by the idea that either notch inhibition *or* activation on its own depletes support cells (that's kind of hard for me to wrap my head around).

      But maybe you are right. Maybe Frequency Therapeutics designed the drug to "underdose" VPA relative to their proprietary compound.
       
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    21. Aaron91
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      Aaron91 Member Podcast Patron Benefactor Ambassador Advocate

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      Thank you for the kind words further above @Zugzug, you are too kind.

      I don't have any answers about the molecular weight thing, that would be a whole other rabbithole lol, but hopefully someone else can chime in.

      When you say "they", do you mean Frequency Therapeutics or the team who authored the paper I linked? I must admit it's strange if Frequency Therapeutics know that VPA alone would seem to deplete support cells and not disclose it in any of their communications. Just as an FYI, I understand that the reason zebrafish are often used is because their auditory hair cells are on their skin and so directly and immediately visible. But again, I have no idea how cross-applicable they are to humans.
      I can't get my head around it either, but I'm going to go away and do a bit more reading and see what I can find.

      Just to make it clear, I am very much speculating about all this and I know I'm out of my depth in trying to make sense of this stuff. As always I'm just trying to get a conversation going between the brighter minds here.
       
    22. Tezcatlipoca

      Tezcatlipoca Member

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      Sorry, even after reading all of this, I can't quite get it. Could you explain it to me like I was a 5-year-old? Please, I really suck with science/medicine stuff.
       
    23. Aaron91
      Jaded

      Aaron91 Member Podcast Patron Benefactor Ambassador Advocate

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      Haha! Not much these days, to be honest. Hyperacusis has turned my life upside down and I'm on a mission to hack this thing or die trying.
       
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    24. AUTHOR
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      FGG
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      FGG Member Podcast Patron Benefactor Ambassador Hall of Fame Advocate

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      This article was helpful (I think):

      Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells

      It was dealing with VPA's effects on neuroblastoma cells but I think some of the concepts are similar/the same.

      "VPA induces loss of proliferative capacity and promotes differentiation"

      I believe that CHIR stimulates proliferation (support cell division) through the wnt pathway but VPA promotes differentiation (through its effects on notch), more below.

      I liked this part, btw:

      "The mechanisms behind these effects are still not clear"

      Oh good :).

      "In light of the finding that VPA inhibits HDAC activity, we have studied the effects of the drug on the Notch signalling cascade in NB cells, since this cascade is dependent of HDAC activity and seem to play a role in NB cell differentiation. We here report that VPA induces a more mature phenotype of NB cells along with an increased activity of the Notch signalling cascade."

      It looks like VPA induces the notch pathway but inhibits part of its normal signaling cascade. I.e. it initiates notch but then stops it at a point in the cascade.

      How I'm putting this all together:

      The notch pathway is responsible for "lateral inhibition", which is basically cell to cell communication telling a neighbor cell not to divide because there is already another cell next to it. My impression (not sure how right I am on this) is that inhibiting this in some way seems vital (and VPA seems to inhibit part of the pathway) so that a support cell (an LGR5+ one) starts dividing again even though it's adjacent to other intact support cells. Without this, notch might prevent the wnt activation from producing new cells.

      I could be way off here. Other thoughts?
       
    25. just1morething
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      just1morething Member Benefactor Hall of Fame

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      I don’t think anyone will understand it.

      Maybe you should be working for Frequency Therapeutics?

      I will be happy if it works for tinnitus, not really caring how it works.

      If you are a scientist in that field I can see how you might be interested though. I would think all the average person would need to know would be on their website.
       
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