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Thread: Dr. Jerry Silver: Latest chronic SCI research results featured at Cleveland

  1. #51
    Hi Dr. Silver,
    1. When it comes to chronic vs. acute SCI, I know Gordon Mitchell (and others) theorize that the response to intermittent hypoxia has to do with inflammation - he (and others I believe) have shown that IH alone produces more pronounced responses for certain behaviors in a chronic vs. acute SCI model. What is your take on that? And, does reduced inflammation in chronic SCI vs. acute play a role for the specific results you're showing, or does it have more to do with the perineuronal net?


    2. I'm sure you are aware of the work by Randy Trumbower, Zev Rymer and others examining IH in humans with incomplete SCI showing an improvement in voluntary lower body strength as well as walking function after an single bout of IH. Is there any reason to believe the respiratory results you present would NOT occur in other systems controlled by alpha moto-neurons and skeletal muscle (hands, walking, bowel & bladder, etc)?


    3. You mention that ISRT is working on a controlled AAV vector to deliver ch'ase, and that it can be "turned off" when improvements plateau - could you elaborate on that? It was my understanding that AAV's can't necessarily be turned off.


    4. You mentioned that IH + ch'ase produced tonic activity in 1/3 of the animals, though that may wane over time - concurrently, you showed earlier in the presentation how the perineuronal net comes back naturally after a period of being reduced with ch'ase. Is it possible that ch'ase let too much serotonin "get through", so to speak, after IH, causing this augmented activity in those animals? Is there perhaps an optimal combination of ch'ase and IH that we could figure out so that we can minimize the chances of that response occurring?

    5. You mention specific targets to deliver ch'ase to at different parts of the spinal cord to target specific behaviors. Does this mean that it wouldn't be enough to deliver ch'ase just to the site of an injury, but rather we'd need to inject ch'ase all along the cord to allow for a period of plasticity to occur?


    6. Lastly, is this work published yet? I'd love to read a full report.

  2. #52
    Quote Originally Posted by lunasicc42 View Post
    I don't mean this as antagonistic, although it may sound that way...Honestly, what are the differences between what you are proposing to do and what they already testing at the university of iowa state with dogs? A different compound?

    There are substantial differences in what we are attempting to do. The Iowa state strategy involves a heat stable chondroitinase whose residence time within the cord is perhaps a few weeks. Once the enzyme looses activity the scar and net proteoglycans return. Using the viral delivery strategy, the enzyme spreads over much further distances and is stable for as long as is required (a year or more if needed) and can then be turned off. In addition, the peptide overcomes proteoglycan mediated inhibition far beyond that which the enzyme eliminates. Again, the peptide can be delivered for as long as is needed. The "double whammy" maximally overcomes the inhibition brought about by proteoglycans throughout the spinal cord.

  3. #53
    Senior Member lunasicc42's Avatar
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    Quote Originally Posted by jsilver View Post
    There are substantial differences in what we are attempting to do. The Iowa state strategy involves a heat stable chondroitinase whose residence time within the cord is perhaps a few weeks. Once the enzyme looses activity the scar and net proteoglycans return. Using the viral delivery strategy, the enzyme spreads over much further distances and is stable for as long as is required (a year or more if needed) and can then be turned off. In addition, the peptide overcomes proteoglycan mediated inhibition far beyond that which the enzyme eliminates. Again, the peptide can be delivered for as long as is needed. The "double whammy" maximally overcomes the inhibition brought about by proteoglycans throughout the spinal cord.
    Thanks for the explanation
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  4. #54
    Quote Originally Posted by jsilver View Post
    Hi Lynnifer,

    No, that is not a most hated question. It is the most important question of all. If it were up to me, we would be administering enzyme to appropriately
    selected patients tomorrow. I would like to call strong attention to the outstanding work of the International Spinal Research Trust (ISRT) in England, a non-profit
    SCI focused foundation that is dedicated to bringing chondroitinase to the people. They are working very hard on new, state of the art delivery systems for the enzyme.
    With their help and perseverance we will be in clinical trials ASAP. It is my thinking that some combination of their new and improved long-active chondroitinase plus our peptide
    will be optimal.

    I believe Invivo Therapeutics made an announcement not long ago about a spinal multisegmental delivery system, I admit to not knowing the details. But some of the description of their delivery system appears to share some of your described need. Are you aware of the cell/drug delivery system I am referring to, and why can't it be used? What are the necessities that force us to design a new ketchup bottle ( one of many great delivery systems ) would there be any time saved getting to clinical trials if device is already available to deliver a chase ?
    please . . .test what you already know; and give us what you have. we may not be dying, but we certainly are not living either

  5. #55
    Quote Originally Posted by tomsonite View Post
    hi dr. Silver,
    1. When it comes to chronic vs. Acute sci, i know gordon mitchell (and others) theorize that the response to intermittent hypoxia has to do with inflammation - he (and others i believe) have shown that ih alone produces more pronounced responses for certain behaviors in a chronic vs. Acute sci model. What is your take on that? And, does reduced inflammation in chronic sci vs. Acute play a role for the specific results you're showing, or does it have more to do with the perineuronal net?

    ANSWER: IH is thought to produce improvements in behavior via a number of different mechanisms. Evidence suggests that increases in trophic factors such as bdnf
    are involved. Other evidence suggests that increases in serotonin or its receptors are involved. The role of inflammation is largely related to trophic factor plasticity and, yes, inflammatory cascades are reduced at chronic stages. It is important to reiterate from my lecture that our model involves a complete hemisection lesion that does not spontaneously recover. Ih in our model has at best relatively minor effects compared to the effect of chondroitinase which modifies the perineuronal net.


    2. I'm sure you are aware of the work by randy trumbower, zev rymer and others examining ih in humans with incomplete sci showing an improvement in voluntary lower body strength as well as walking function after an single bout of ih. Is there any reason to believe the respiratory results you present would not occur in other systems controlled by alpha moto-neurons and skeletal muscle (hands, walking, bowel & bladder, etc)?

    ANSWER: We do believe that iH is one interesting strategy that can be used in incomplete patients to improve various locomotor behaviors in addition to improving breathing. However, it is our findings that ih works best when combined with chondroitinase in our model. The effects of the enzyme are far superior to that of ih and, indeed, ih in excess in combination with ch'ase can lead to problems at chronic stages and that gets us to your final question below.


    3. You mention that isrt is working on a controlled aav vector to deliver ch'ase, and that it can be "turned off" when improvements plateau - could you elaborate on that? It was my understanding that aav's can't necessarily be turned off.

    ANSWER: There is wealth of good evidence that aav delivery systems can be turned off if the virus is engineered properly.


    4. You mentioned that ih + ch'ase produced tonic activity in 1/3 of the animals, though that may wane over time - concurrently, you showed earlier in the presentation how the perineuronal net comes back naturally after a period of being reduced with ch'ase. Is it possible that ch'ase let too much serotonin "get through", so to speak, after ih, causing this augmented activity in those animals? Is there perhaps an optimal combination of ch'ase and ih that we could figure out so that we can minimize the chances of that response occurring?

    ANSWER: Yes, that is precisely our goal for the future. However, we did not see tonic activity in any animal with ch'ase alone. Ih was the variable that pushed things over the edge. We do need to understand precisely how much ih needs to be administered. Also,we are hoping to titer the chondroitinase response by adding our peptide incrementally.

    5. You mention specific targets to deliver ch'ase to at different parts of the spinal cord to target specific behaviors. Does this mean that it wouldn't be enough to deliver ch'ase just to the site of an injury, but rather we'd need to inject ch'ase all along the cord to allow for a period of plasticity to occur?

    ANSWER: Correct, ch'ase delivery needs to be targeted to the levels of the cord that contain the lower motor neurons involved with the major behaviors that one wishes to have returned. Thus, delivery of the enzyme just to the lesion site is not adequate.

    6. Lastly, is this work published yet? I'd love to read a full report.
    ANSWER: we will be submitting to a major journal in the next few weeks.

  6. #56
    Quote Originally Posted by Nicksdad View Post
    I believe Invivo Therapeutics made an announcement not long ago about a spinal multisegmental delivery system, I admit to not knowing the details. But some of the description of their delivery system appears to share some of your described need. Are you aware of the cell/drug delivery system I am referring to, and why can't it be used? What are the necessities that force us to design a new ketchup bottle ( one of many great delivery systems ) would there be any time saved getting to clinical trials if device is already available to deliver a chase ?
    Their model involves the production of trails that might be used to guide axons over lengthy distances. Whether this strategy will work or not could be a topic for discussion elsewhere. Our model does not need such elaborate trail making machinery. We only need to inject via a micro needle into appropriate levels of the cord. No need for invasive procedures with our technique.

  7. #57
    Thank you for your answers Dr. Silver.

  8. #58
    Quote Originally Posted by jsilver View Post
    Their model involves the production of trails that might be used to guide axons over lengthy distances. Whether this strategy will work or not could be a topic for discussion elsewhere. Our model does not need such elaborate trail making machinery. We only need to inject via a micro needle into appropriate levels of the cord. No need for invasive procedures with our technique.

    Thank you for your time and willingness to talk with us.
    I am sure I am not the only reader though that while enjoying your enthusiastic tone, also noticed your statements go from administering the enzyme tomorrow and being in clinical trials asap to not being ready for prime time and large animal studies are a bit of a hurdle. Not sure if I should have a bit of Laphroaig to cheer or have three to drown the sorrow.
    I am grateful for your efforts and for the time you give us here. I always enjoyed the respectful debate you and Dr. Young engaged in, perhaps someone from Invivo can be persuaded to have similar strategy discussions with you and Dr. Young here someday.
    please . . .test what you already know; and give us what you have. we may not be dying, but we certainly are not living either

  9. #59
    Quote Originally Posted by Nicksdad View Post
    Thank you for your time and willingness to talk with us.
    I am sure I am not the only reader though that while enjoying your enthusiastic tone, also noticed your statements go from administering the enzyme tomorrow and being in clinical trials asap to not being ready for prime time and large animal studies are a bit of a hurdle. Not sure if I should have a bit of Laphroaig to cheer or have three to drown the sorrow.
    I am grateful for your efforts and for the time you give us here. I always enjoyed the respectful debate you and Dr. Young engaged in, perhaps someone from Invivo can be persuaded to have similar strategy discussions with you and Dr. Young here someday.
    Right, I understand your frustration. I am frustrated too. If it were solely up to me we would, indeed, be in the clinic tomorrow, especially with our new results in a super chronic model. We will publish and hopefully that will energize the entire field.

  10. #60
    I offer to pay and legally absolve of any responsibility. There is certainly a way around the bureaucracy. I will take the risk.

    There is so much suffering and yet so many options I believe there is a mechanism that I do not understand that prevents real progress.

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