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Thread: Jerry Silver update

  1. #11
    Dr. Silver--would you please provide a simple explanation as to why ChABC, when injected below the level of injury, tends to encourage neurons and axions to penetrate the glial scar tissue and reconnect below. In the past, you have mentioned that the glial scar is quite a formidable barrier. Also, am wondering if injecting above and below the injury site would amplify the current positive results you are seeing in the lab.

  2. #12
    Quote Originally Posted by 6 Shooter View Post
    Dr. Silver--would you please provide a simple explanation as to why ChABC, when injected below the level of injury, tends to encourage neurons and axions to penetrate the glial scar tissue and reconnect below. In the past, you have mentioned that the glial scar is quite a formidable barrier. Also, am wondering if injecting above and below the injury site would amplify the current positive results you are seeing in the lab.

    Thanks for the question. We were not actually targeting the scar that surrounds the lesion, which was made at cervical level 2. We were targeting the so-called perineuronal net (PNN), a cocoon-like matrix structure made of proteoglycans that surrounds the connections that occur between neurons, called synapses. It was previously thought that one of the major functions of the perineuronal net was to stabilize synapses but, in doing so, prevents sprouting of new connections. We have discovered during our work that the net actually functions also to block the activity of newly regenerating connections that are forming very slowly below the level of the lesion in the spinal cord. In simple terms, over time, the spinal cord tries very hard to fix the paralysis that occurs after spinal cord injury by expanding (ie., sprouting) the axonal arbor of special types of interneurons that can amplify the much reduced signals coming from above (ie., those few that are spared after the injury). There is also a very slow sprouting of spared axons of the serotonergic system below the level of injury which is also a way of amplifying the signals from above. But the most bizarre thing happens --- instead of allowing this sprouting to occur readily, the spinal cord instead increases (rather than decreases) the density of the inhibitory proteoglycans in the perineuronal net which not only slows down the sprouting but, surprisingly, blocks synaptic transmission. So the new connections can't even work once they have sprouted. Indeed, the harder one works to use rehabilitative training to improve recovery the thicker the net becomes. It's formation is activity dependent. Therefore, we injected the enzyme farther down the spinal cord at the level of C4-5 to remove the net around the motor nerve cells that receive the newly sprouted amplifying connections from the local interneurons and serotonergic system. In turn, the motor neurons send their axons out to the muscles (we targeted motor neurons that go out to the diaphragm and upper forearm). The results were amazing with full and rapid recovery after a near lifetime of paralysis. We think this fast recovery is due to the enzyme unmasking the new connections that had already formed over time. Thus, the longer the time after injury the better was the recovery. One important caveat is that when we pushed respiratory rehab too hard in combination with the enzyme ( a strategy called acute intermittent hypoxia) then in some animals, instead of getting nicely patterned respiratory functional recovery, a debilitating chaotic activity developed. We learned that this unwanted activity occurred because the combo strategy caused too much serotonergic sprouting. So we now have to work out what the optimal strategy is to maximize the speed and amount of recovery.

  3. #13
    Dr. Silver, this is fascinating. I've rented equipment from hypoxico.com that let me do two 2-week sessions of acute hypoxic therapy with my home health care aides and it took me a while to realize I wasn't doing it quite right and then I burned a small hole in the hose. It did help my legs move faster for a while. I wish I had better instructions so I could get better results next time. I was using a walker and briefly walking then. Now after two falls and no 4-AP use, I'm barely standing...

  4. #14
    Dr. Silver, all the respect and appreciation for your dedication and the amazing work you’re conducting in order to hopefully help us some day, the sooner the less suffering and hardship we’ll have to endure.
    That’s why I have to raise the golden question again, as this is what it’s all about, when can we approximately see, The Human Trials?
    I’m aware that it might still be a long way until it happens, but it would still be great to know that they will happen at some point. Please give a rough estimate on plans for future trials. I do also apologise if the question was too forward.
    Thank you very much Dr. Silver.

  5. #15
    Quote Originally Posted by jsilver View Post
    Thanks for the question. We were not actually targeting the scar that surrounds the lesion, which was made at cervical level 2. We were targeting the so-called perineuronal net (PNN), a cocoon-like matrix structure made of proteoglycans that surrounds the connections that occur between neurons, called synapses. It was previously thought that one of the major functions of the perineuronal net was to stabilize synapses but, in doing so, prevents sprouting of new connections. We have discovered during our work that the net actually functions also to block the activity of newly regenerating connections that are forming very slowly below the level of the lesion in the spinal cord. In simple terms, over time, the spinal cord tries very hard to fix the paralysis that occurs after spinal cord injury by expanding (ie., sprouting) the axonal arbor of special types of interneurons that can amplify the much reduced signals coming from above (ie., those few that are spared after the injury). There is also a very slow sprouting of spared axons of the serotonergic system below the level of injury which is also a way of amplifying the signals from above. But the most bizarre thing happens --- instead of allowing this sprouting to occur readily, the spinal cord instead increases (rather than decreases) the density of the inhibitory proteoglycans in the perineuronal net which not only slows down the sprouting but, surprisingly, blocks synaptic transmission. So the new connections can't even work once they have sprouted. Indeed, the harder one works to use rehabilitative training to improve recovery the thicker the net becomes. It's formation is activity dependent. Therefore, we injected the enzyme farther down the spinal cord at the level of C4-5 to remove the net around the motor nerve cells that receive the newly sprouted amplifying connections from the local interneurons and serotonergic system. In turn, the motor neurons send their axons out to the muscles (we targeted motor neurons that go out to the diaphragm and upper forearm). The results were amazing with full and rapid recovery after a near lifetime of paralysis. We think this fast recovery is due to the enzyme unmasking the new connections that had already formed over time. Thus, the longer the time after injury the better was the recovery. One important caveat is that when we pushed respiratory rehab too hard in combination with the enzyme ( a strategy called acute intermittent hypoxia) then in some animals, instead of getting nicely patterned respiratory functional recovery, a debilitating chaotic activity developed. We learned that this unwanted activity occurred because the combo strategy caused too much serotonergic sprouting. So we now have to work out what the optimal strategy is to maximize the speed and amount of recovery.
    Dr. Silver--Thank you for that detailed and complex explanation. Think I learned two important things in your explanation. First, the injection of the enzyme was at 2-3 levels (C4-5) below the level of injury at C2, and not focused on the glial scar area. Second, too much focused rehab after the injection was a hindrance to the best possible recovery. In the long run, this may help solve and reduce the time, effort, and cost issue of extensive and expensive walking 6/6/6/ rehab thought to be completely necessary to regain function. So pleased with the testing on chronic injuries.

  6. #16
    Dr. Silver, in the paper it states that the study was not “optimised for effects upon the forelimb” in your rodents. Will your very next study be? If not, will it be a central focus in the near future? And a deep thank you for committing your life to this work.

  7. #17
    Quote Originally Posted by UpAndAdam View Post
    Dr. Silver, in the paper it states that the study was not ?optimised for effects upon the forelimb? in your rodents. Will your very next study be? If not, will it be a central focus in the near future? And a deep thank you for committing your life to this work.

    Thanks for the question. In our initial study we were attempting to target only the motor neurons that project out to the diaphragm. They are called "phrenic" motor neurons and they form a cigar shaped collection of cells that lie between cervical level 3 (C3) thru cervical level 6 (C6). So we focused our one-time, single microinjection of the enzyme only at C4. However, there are also motor neuron pools at C5 that project out to some of the muscles of the upper arm. Thus, likely because of diffusion of the enzyme a bit more "south" to levels C5-6, return of upper arm function occurred but was not targeted by design. It was just a nice and unexpected side effect. The major motor neuron pools for hand function are down a bit lower around C6-8. So, we are now repeating our experiments but focusing on levels C5-8.

  8. #18
    Dr Silver--About how long did it take from the time of the injections to when your team began to notice changes in function in the mice experiments? If possible, could you forecast a guess as to how long this change of function time would take in humans if your experiments worked as well in humans. Further, IF this treatment worked as well in chronic humans, would you expect to see one area of the body recovering or all areas below the injury site gaining some functional recovery?

  9. #19
    Quote Originally Posted by 6 Shooter View Post
    Dr Silver--About how long did it take from the time of the injections to when your team began to notice changes in function in the mice experiments? If possible, could you forecast a guess as to how long this change of function time would take in humans if your experiments worked as well in humans. Further, IF this treatment worked as well in chronic humans, would you expect to see one area of the body recovering or all areas below the injury site gaining some functional recovery?
    Just to be clear, our experiments were in adult rats, not mice. Even up to 1.5 years following the spinal cord injury, we began to see recovery in a little as 1 week following enzyme administration. By 3 weeks, recovery was maximal with full restoration of diaphragm function in all animals even though they had persistent and total diaphragm paralysis. If the biology is similar in humans ( and I have no reason to believe that such basic mechanisms would be remarkably different) then I would not be surprised to see recovery in the same rapid time frame. We will have to do further experiments to maximize recovery in other systems below the level of the phrenic motor pool. However, return of upper arm function also occurred rapidly. Importantly, there is recent evidence from the Tuszynski lab that the chondroitinase enzyme has significant therapeutic effects in a primate model of cervical hemisection induced paralysis of the hand. However, in his work, the monkeys were not allowed to recover nearly as long as did our rats, so who knows what might happen if a much longer time post injury occurs prior to treatment.

  10. #20
    Quote Originally Posted by jsilver View Post
    Importantly, there is recent evidence from the Tuszynski lab that the chondroitinase enzyme has significant therapeutic effects in a primate model of cervical hemisection induced paralysis of the hand. However, in his work, the monkeys were not allowed to recover nearly as long as did our rats, so who knows what might happen if a much longer time post injury occurs prior to treatment.
    For those that may have missed the Tuszynski lab experiment ...LINK

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