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Thread: researchblog

  1. #221
    Quote Originally Posted by jsilver View Post
    No sorry. This is going to be moving at a pace over which I have little control but we do have a meeting scheduled next week to go over new data. If anything happens that I am permitted to divulge to the public then I will.
    Would it be possible, though, to structure an agreement to license the technology so it doesn't get stuck in purgatory with respect to SCI clinical trials, like chondroitinase? What would keep the new peptide from falling into a similar fate once big pharma gets involved?

  2. #222
    "Whatever the underlying mechanisms might be it is likely that the descending axons that regenerate in our model are not myelinated. However, we still have to examine the regenerating fibers in our model to see if they are or they are not re-myleinated. The sensory fibers that regenerate in the Tuszynski paper were not myelinated and i have a suspicion because of the Tuszynski observations that ours are not myelinated either......" J.Silver
    Quote Originally Posted by jsilver View Post
    The nerve bridge contains Schwann cells which can re-myelinate spontaneously, although this undoubtedly takes some time. Re-myelination is critical to proper function of regenerated axons and this property of Schwann cells is one of the major reasons (among others) we chose the peripheral nerve autograft strategy. Np additional tricks are needed.
    Dr.Silver, make things clear, please.

  3. #223
    Quote Originally Posted by kivi66
    Dr.Silver, make things clear, please.
    OK let me expand a bit.
    There are ascending as well as descending axon systems that are fast conducting to mediate their proper function and require myelin. There are other systems of axons that are more slowly conducting and are lightly myelinated or unmyelinated. The optic nerve and tract. the dorsal column sensory system and cortico-spinal system are examples of heavily myelinated, fast conducting axon tracts. Certain pain carrying sensory fibers (c fibers) and certain centers in the brainstem such as the raphe (serotonergic system) among others and nuclei in the reticular formation that regulate bladder function project many (but not all) unmyelinated axons into the cord. The urinary system is relatively slow functioning compared to the optic or cortico-spinal systems or dorsal column system. With our bridging model to bring about recovery of forepaw (Houle et al 2006) or diaphragm (Alilain et al, 2011) function after cervical hemisection injuries, we need myelin around the regenerating axons for best function. So in this model we directed axons from above the lesion to bypass the lesion entirely with the use of our peripheral nerve grafts that contain Schwann cells that can guide and remyelinate the axons. The distal end of the graft was positioned just above the target neurons in the ventral horn further down the cord. So once the axons leave the distal graft doorway they have only a very short distance to grow until they reach the dendrites of the interneurons and motor neurons that control the limb or diaphragm. So in this model the regenerating axons get re-myelinated along most of their trajectory. In our bladder model the lesion is a full transection made at a thoracic level. The CPG centers for walking or urinary control in the cord are in the lumbar or sacral levels. We tried at first to use a very long bridge from the thoracic cord all the way down to the lumbar cord but this failed because the cord gets quite narrow farther down and the bridge insertion was causing way too much damage. So we changed our strategy and we now bridge this lesion right across its territory with multiple short pieces of peripheral nerve segments. Now when the axons regenerate, they are surrounded by Schwann cells over a relatively short distance. However, and we think quite remarkably, some types of brainstem neurons that are involved with micturition control can exit the distal graft and continue regenerating down the cord for multiple centimeters all the way to the lumbo-sacral level. While this journey takes 6 months, the axons keep going and they restore a very nice amount of urinary function. We see very minimal improvements in locomotion from a BBB score of 2 to 7. So, in summary, axons that control the urinary system are often unmyelinated normally and those that might need myelin don’t spend much time among Schwann cells in the graft. Exactly where the critical synapses need to form past the graft in order to bring about functional recovery of urination is unknown and we don’t know yet if some of the segments of regenerated axons beyond the graft do or do not get myelinated. I’m assuming they don’t, from the Tuszynski paper but we have to look. This is a description of the work done in an acute model (the results are published in an SFN abstract and are under review at the J Neuroscience) and the results of our more chronic model are now in the works (and were presented at W2W).
    Last edited by Wise Young; 01-31-2013 at 09:16 AM.

  4. #224
    Thanks, Jerry, expand, please, a little bit to the oligodendrocyte part of the story. You don't mention them at all, that disturbs.
    Schwann cells do not settle the issue.

  5. #225
    Quote Originally Posted by jsilver View Post
    Dr.Silver, make things clear, please.

    OK let me expand a bit.
    There are ascending as well as descending axon systems that are fast conducting to mediate their proper function and require myelin. There are other systems of axons that are more slowly conducting and are lightly myelinated or unmyelinated. The optic nerve and tract. the dorsal column sensory system and cortico-spinal system are examples of heavily myelinated, fast conducting axon tracts. Certain pain carrying sensory fibers (c fibers) and certain centers in the brainstem such as the raphe (serotonergic system) among others and nuclei in the reticular formation that regulate bladder function project many (but not all) unmyelinated axons into the cord. The urinary system is relatively slow functioning compared to the optic or cortico-spinal systems or dorsal column system. With our bridging model to bring about recovery of forepaw (Houle et al 2006) or diaphragm (Alilain et al, 2011) function after cervical hemisection injuries, we need myelin around the regenerating axons for best function. So in this model we directed axons from above the lesion to bypass the lesion entirely with the use of our peripheral nerve grafts that contain Schwann cells that can guide and remyelinate the axons. The distal end of the graft was positioned just above the target neurons in the ventral horn further down the cord. So once the axons leave the distal graft doorway they have only a very short distance to grow until they reach the dendrites of the interneurons and motor neurons that control the limb or diaphragm. So in this model the regenerating axons get re-myelinated along most of their trajectory. In our bladder model the lesion is a full transection made at a thoracic level. The CPG centers for walking or urinary control in the cord are in the lumbar or sacral levels. We tried at first to use a very long bridge from the thoracic cord all the way down to the lumbar cord but this failed because the cord gets quite narrow farther down and the bridge insertion was causing way too much damage. So we changed our strategy and we now bridge this lesion right across its territory with multiple short pieces of peripheral nerve segments. Now when the axons regenerate, they are surrounded by Schwann cells over a relatively short distance. However, and we think quite remarkably, some types of brainstem neurons that are involved with micturition control can exit the distal graft and continue regenerating down the cord for multiple centimeters all the way to the lumbo-sacral level. While this journey takes 6 months, the axons keep going and they restore a very nice amount of urinary function. We see very minimal improvements in locomotion from a BBB score of 2 to 7. So, in summary, axons that control the urinary system are often unmyelinated normally and those that might need myelin don’t spend much time among Schwann cells in the graft. Exactly where the critical synapses need to form past the graft in order to bring about functional recovery of urination is unknown and we don’t know yet if some of the segments of regenerated axons beyond the graft do or do not get myelinated. I’m assuming they don’t, from the Tuszynski paper but we have to look. This is a description of the work done in an acute model (the results are published in an SFN abstract and are under review at the J Neuroscience) and the results of our more chronic model are now in the works (and were presented at W2W).
    What do you think can be done, if anything, to get good BBB score improvements ie regeneration of the CST?

    Thanks

  6. #226
    Jerry, what, have absolutely nothing to share with us? Or still not allowed to divulge?
    Which assumption is more close to the real state of affairs?

  7. #227
    So far the CST remains the toughest of all. pTEN/SOCS3 deletion remains the best strategy. The ability to regulate gene knockdown of these oncogenes after injury rather than more permanent knockdown is now being developed. Also, Murray Blackmore has a new strategy to KO KLF factors in cortical neurons that looks very promising. See the U2FP website for his presentation at W2W. He was just funded by the ISRT to pursue this. Congrats to Murray.
    Last edited by jsilver; 01-31-2013 at 07:05 PM.

  8. #228
    Thanks Jerry.

  9. #229
    Quote Originally Posted by jsilver View Post
    So far the CST remains the toughest of all. pTEN/SOCS3 deletion remains the best strategy. The ability to regulate gene knockdown of these oncogenes after injury rather than more permanent knockdown is now being developed. Also, Murray Blackmore has a new strategy to KO KLF factors in cortical neurons that looks very promising. See the U2FP website for his presentation at W2W. He was just funded by the ISRT to pursue this. Congrats to Murray.
    U2FP will be doing a lab visit with Murray Blackmore in February. The report from that lab visit will be posted at the U2FP website as soon as it's available. Wishing the best of luck to Murray and his students on their aggressive projects to help with SCI.

    http://spinalcordresearchandadvocacy...012-symposium/
    Last edited by GRAMMY; 01-31-2013 at 08:21 PM.

  10. #230
    Quote Originally Posted by jsilver View Post
    We are now entering a new phase of experiments in my lab in collaboration with Dr. Yu-Shang Lee of the Cleveland Clinic. Dr. Lee was trained by Henrich Cheng where he learned the delicate surgery and spine stabilization techniques necessary to bridge a cord lesion but also fix the spinal column so as to avoid further stretching of the injury site. Even the best grafting is ruined without stabilization. Yu-Shang stresses the need for proper spinal stabilization even more than the nerve grafting in order to make this technique work. In the past those who have failed to reproduce the original Cheng/Olsen results (and have been quite verbal about their failure to replicate without publishing) likely did not master the proper surgical skills that are absolutely crucial to the success of this strategy. Our experiments moving forward in animal models will be to severely contuse the thoracic spinal cord and then at chronic stages (4-6 weeks or longer) re-enter the cord, clean out the wound and perhaps remove the scar followed by our usual repair strategy. We have a few new tricks up our sleeves as well. We will focus on the return of bladder function but also examine locomotor behavior. If the animal experiments are successful (and we already have preliminary evidence that they can be!) we will publish and push even harder for clinical trials but it is impossible to predict when that might be. Whatever we do is being communicated to Dr. Cheng who is keenly aware of our progress. Hopefully, we should be rolling along during the next year.
    Dr.Silver, "next year" is already past year. Any news?
    And, please, do me a favor, say this sweet word "oligodendrocyte", from your lips it's like soothing balm for me.

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