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Thread: Ga Tech Researchers Make Headway in Treating Spinal Cord Injuries

  1. #11
    Senior Member lunasicc42's Avatar
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    They were doing work in the early 2000s?... Is this a case of another potential Treatment just "put on the shelf "? or what happened? \
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  2. #12
    Senior Member KIM's Avatar
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    Quote Originally Posted by Wise Young View Post
    George78,

    Until recently, chondroitinase had to be made prepared as a fresh solution daily and injected into the spinal cord. In solution, apparently the enzyme is heat sensitive. As a freeze-dried power, it does not degrade. Elizabeth Bradley was the first to show that if the chondroitinase is injected directly into the spinal cord, it will clear most of the chondroitin-6-sulfate-proteoglycan (CSPG) out of the way. She and Fawcett led the way in this work in the early 2000's. This discovery, i.e. creating a heat-stable form of the enzyme that continues to maintain its activity for a long time, should allow delivery of the enzyme to the spinal cord through a pump.

    Wise.
    In a paper published November 2 in the early edition of the journal Proceedings of the National Academy of Sciences, researchers describe how they eliminated the thermal sensitivity of chABC and developed a delivery system that allowed the enzyme to be active for weeks without implanted catheters and pumps

  3. #13
    Quote Originally Posted by lunasicc42 View Post
    They were doing work in the early 2000s?... Is this a case of another potential Treatment just "put on the shelf "? or what happened? \
    Chondroitinase was discovered decades ago (in the 1970's). It was not until the 1990's when Jerry Silver at Case Western (I believe that he was the first) to suggest that it would be useful for breaking down CSPG. He and other tried it and it did not work. It was not until I think that it was 2003 when Liz Bradbury from the Fawcett laboratory tried injecting freshly prepared drug every day into the spinal cord of the rats that the first regeneration and functional recovery was seen with chondroitinase.

    A company by the name of Seikagaku in Japan held the patent for the process of isolating chondroitinase ABC from bacteria (proteus vulgaris). In the 1990's, they had the idea of using chondroitinase to soften up herniated discs. It actually went to clinical trial. Then in the late 1990's, the company took an interest when Jerry Silver and others suggested that the enzyme would be useful for regeneration.

    Much of the chondroitinase used in animal experiments came from Seikagaku, who provided a source of clinical grade chondroitinase for study. The company, however, has lost interest in chondroitinase after investing in the research for more than a decade. A couple of other companies apparently also developed ways of isolating the enzyme from bacteria without losing activity but Seikagaku held the patent for their procedure. In the meantime, Fawcett and Bradbury patented chondroitinase for the treatment of spinal cord injury. Acorda Therapeutics licensed the patent.

    In 2004, Wutian Wu and his colleagues at Hong Kong University reported in 2004 that chondroitinase plus lithium stimulates regeneration and functional recovery in the rat spinal cord but each treatment alone was not as effective. The lithium presumably stimulates the spinal cord to produce growth factors and the the chondroitinase breaks down CSPG to allow regeneration to go forward. Here are just some papers in my database reporting chondroitinase studies in spinal cord injury.

    There have been no dearth of studies, just a dearth of clinical trials.

    Wise.

    1. Zhang C, He X, Lan B, Li H. [Study on repair of subcute spinal cord injury by transplantation of olfactory ensheathing cells combined with chondroitinase ABC in adult rats]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2009;23(1):8-13.
    2. Yang YG, Jiang DM, Quan ZX, Ou YS. Insulin with Chondroitinase ABC Treats the Rat Model of Acute Spinal Cord Injury. J Int Med Res. 2009;37(4):1097-107.
    3. Tom VJ, Kadakia R, Santi L, Houle JD. Administration of chondroitinase ABC rostral or caudal to a spinal cord injury site promotes anatomical but not functional plasticity. J Neurotrauma. 2009.
    4. Nakamae T, Tanaka N, Nakanishi K, Kamei N, Sasaki H, Hamasaki T, et al. Chondroitinase ABC promotes corticospinal axon growth in organotypic cocultures. Spinal Cord. 2009;47(2):161-5.
    5. Garcia-Alias G, Barkhuysen S, Buckle M, Fawcett JW. Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat Neurosci. 2009;12(9):1145-51.
    6. Fouad K, Pearse DD, Tetzlaff W, Vavrek R. Transplantation and repair: Combined cell implantation and chondroitinase delivery prevents deterioration of bladder function in rats with complete spinal cord injury. Spinal Cord. 2009.
    7. Fawcett J. Molecular control of brain plasticity and repair. Prog Brain Res. 2009;175:501-9.
    8. English AW, Cucoranu D, Mulligan A, Sabatier M. Treadmill training enhances axon regeneration in injured mouse peripheral nerves without increased loss of topographic specificity. J Comp Neurol. 2009;517(2):245-55.
    9. Diaz-Martinez NE, Velasco I. [Axonal growth inhibition by chondroitin sulfate proteoglycans in the central nervous system]. Rev Invest Clin. 2009;61(2):140-9.
    10. Busch SA, Horn KP, Silver DJ, Silver J. Overcoming macrophage-mediated axonal dieback following CNS injury. J Neurosci. 2009;29(32):9967-76.
    11. Xia Y, Zhao T, Li J, Li L, Hu R, Hu S, et al. Antisense vimentin cDNA combined with chondroitinase ABC reduces glial scar and cystic cavity formation following spinal cord injury in rats. Biochem Biophys Res Commun. 2008.
    12. Vahidi B, Park JW, Kim HJ, Jeon NL. Microfluidic-based strip assay for testing the effects of various surface-bound inhibitors in spinal cord injury. J Neurosci Methods. 2008;170(2):188-96.
    13. Tom VJ, Houle JD. Intraspinal microinjection of chondroitinase ABC following injury promotes axonal regeneration out of a peripheral nerve graft bridge. Exp Neurol. 2008;211(1):315-9.
    14. Tester NJ, Howland DR. Chondroitinase ABC improves basic and skilled locomotion in spinal cord injured cats. Exp Neurol. 2008;209(2):483-96.
    15. Shields LB, Zhang YP, Burke DA, Gray R, Shields CB. Benefit of chondroitinase ABC on sensory axon regeneration in a laceration model of spinal cord injury in the rat. Surg Neurol. 2008;69(6):568-77; discussion 77.
    16. Nolin WB, Emmetsberger J, Bukhari N, Zhang Y, Levine JM, Tsirka SE. tPA-mediated generation of plasmin is catalyzed by the proteoglycan NG2. Glia. 2008;56(2):177-89.
    17. Nakamae T, Tanaka N, Nakanishi K, Kamei N, Sasaki H, Hamasaki T, et al. Chondroitinase ABC promotes corticospinal axon growth in organotypic cocultures. Spinal Cord. 2008.
    18. Massey JM, Amps J, Viapiano MS, Matthews RT, Wagoner MR, Whitaker CM, et al. Increased chondroitin sulfate proteoglycan expression in denervated brainstem targets following spinal cord injury creates a barrier to axonal regeneration overcome by chondroitinase ABC and neurotrophin-3. Exp Neurol. 2008;209(2):426-45.
    19. Iseda T, Okuda T, Kane-Goldsmith N, Mathew M, Ahmed S, Chang YW, et al. Single, high-dose intraspinal injection of chondroitinase reduces glycosaminoglycans in injured spinal cord and promotes corticospinal axonal regrowth after hemisection but not contusion. J Neurotrauma. 2008;25(4):334-49.
    20. Garcia-Alias G, Lin R, Akrimi SF, Story D, Bradbury EJ, Fawcett JW. Therapeutic time window for the application of chondroitinase ABC after spinal cord injury. Exp Neurol. 2008;210(2):331-8.
    21. Cafferty WB, Bradbury EJ, Lidierth M, Jones M, Duffy PJ, Pezet S, et al. Chondroitinase ABC-mediated plasticity of spinal sensory function. J Neurosci. 2008;28(46):11998-2009.
    22. Bunge MB. Novel combination strategies to repair the injured mammalian spinal cord. J Spinal Cord Med. 2008;31(3):262-9.
    23. Vavrek R, Pearse DD, Fouad K. Neuronal populations capable of regeneration following a combined treatment in rats with spinal cord transection. J Neurotrauma. 2007;24(10):1667-73.
    24. Iaci JF, Vecchione AM, Zimber MP, Caggiano AO. Chondroitin sulfate proteoglycans in spinal cord contusion injury and the effects of chondroitinase treatment. J Neurotrauma. 2007;24(11):1743-59.
    25. Curinga GM, Snow DM, Mashburn C, Kohler K, Thobaben R, Caggiano AO, et al. Mammalian-produced chondroitinase AC mitigates axon inhibition by chondroitin sulfate proteoglycans. J Neurochem. 2007;102(1):275-88.
    26. Cafferty WB, Yang SH, Duffy PJ, Li S, Strittmatter SM. Functional axonal regeneration through astrocytic scar genetically modified to digest chondroitin sulfate proteoglycans. J Neurosci. 2007;27(9):2176-85.
    27. Yang LJ, Lorenzini I, Vajn K, Mountney A, Schramm LP, Schnaar RL. Sialidase enhances spinal axon outgrowth in vivo. Proc Natl Acad Sci U S A. 2006;103(29):11057-62.
    28. Moreno-Flores MT, Avila J. The quest to repair the damaged spinal cord. Recent Patents CNS Drug Discov. 2006;1(1):55-63.
    29. Massey JM, Hubscher CH, Wagoner MR, Decker JA, Amps J, Silver J, et al. Chondroitinase ABC digestion of the perineuronal net promotes functional collateral sprouting in the cuneate nucleus after cervical spinal cord injury. J Neurosci. 2006;26(16):4406-14.
    30. Kim BG, Dai HN, Lynskey JV, McAtee M, Bregman BS. Degradation of chondroitin sulfate proteoglycans potentiates transplant-mediated axonal remodeling and functional recovery after spinal cord injury in adult rats. J Comp Neurol. 2006;497(2):182-98.
    31. Huang WC, Kuo WC, Cherng JH, Hsu SH, Chen PR, Huang SH, et al. Chondroitinase ABC promotes axonal re-growth and behavior recovery in spinal cord injury. Biochem Biophys Res Commun. 2006;349(3):963-8.
    32. Houle JD, Tom VJ, Mayes D, Wagoner G, Phillips N, Silver J. Combining an autologous peripheral nervous system "bridge" and matrix modification by chondroitinase allows robust, functional regeneration beyond a hemisection lesion of the adult rat spinal cord. J Neurosci. 2006;26(28):7405-15.
    33. Barritt AW, Davies M, Marchand F, Hartley R, Grist J, Yip P, et al. Chondroitinase ABC promotes sprouting of intact and injured spinal systems after spinal cord injury. J Neurosci. 2006;26(42):10856-67.
    34. Steinmetz MP, Horn KP, Tom VJ, Miller JH, Busch SA, Nair D, et al. Chronic enhancement of the intrinsic growth capacity of sensory neurons combined with the degradation of inhibitory proteoglycans allows functional regeneration of sensory axons through the dorsal root entry zone in the mammalian spinal cord. J Neurosci. 2005;25(35):8066-76.
    35. Ikegami T, Nakamura M, Yamane J, Katoh H, Okada S, Iwanami A, et al. Chondroitinase ABC combined with neural stem/progenitor cell transplantation enhances graft cell migration and outgrowth of growth-associated protein-43-positive fibers after rat spinal cord injury. Eur J Neurosci. 2005;22(12):3036-46.
    36. Fouad K, Schnell L, Bunge MB, Schwab ME, Liebscher T, Pearse DD. Combining Schwann cell bridges and olfactory-ensheathing glia grafts with chondroitinase promotes locomotor recovery after complete transection of the spinal cord. J Neurosci. 2005;25(5):1169-78.
    37. Caggiano AO, Zimber MP, Ganguly A, Blight AR, Gruskin EA. Chondroitinase ABCI improves locomotion and bladder function following contusion injury of the rat spinal cord. J Neurotrauma. 2005;22(2):226-39.
    38. Yick LW, So KF, Cheung PT, Wu WT. Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury. J Neurotrauma. 2004;21(7):932-43.
    39. Grimpe B, Silver J. A novel DNA enzyme reduces glycosaminoglycan chains in the glial scar and allows microtransplanted dorsal root ganglia axons to regenerate beyond lesions in the spinal cord. J Neurosci. 2004;24(6):1393-7.
    40. Chau CH, Shum DK, Li H, Pei J, Lui YY, Wirthlin L, et al. Chondroitinase ABC enhances axonal regrowth through Schwann cell-seeded guidance channels after spinal cord injury. Faseb J. 2004;18(1):194-6.
    41. Yick LW, Cheung PT, So KF, Wu W. Axonal regeneration of Clarke's neurons beyond the spinal cord injury scar after treatment with chondroitinase ABC. Exp Neurol. 2003;182(1):160-8.
    42. Moon LD, Asher RA, Fawcett JW. Limited growth of severed CNS axons after treatment of adult rat brain with hyaluronidase. J Neurosci Res. 2003;71(1):23-37.
    43. Morgenstern DA, Asher RA, Fawcett JW. Chondroitin sulphate proteoglycans in the CNS injury response. Prog Brain Res. 2002;137:313-32.
    44. Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature. 2002;416(6881):636-40.
    45. Yick LW, Wu W, So KF, Yip HK, Shum DK. Chondroitinase ABC promotes axonal regeneration of Clarke's neurons after spinal cord injury. Neuroreport. 2000;11(5):1063-7.
    46. Lemons ML, Howland DR, Anderson DK. Chondroitin sulfate proteoglycan immunoreactivity increases following spinal cord injury and transplantation. Exp Neurol. 1999;160(1):51-65.
    47. Zuo J, Neubauer D, Dyess K, Ferguson TA, Muir D. Degradation of chondroitin sulfate proteoglycan enhances the neurite-promoting potential of spinal cord tissue. Exp Neurol. 1998;154(2):654-62.
    48. Olmarker K, Stromberg J, Blomquist J, Zachrisson P, Nannmark U, Nordborg C, et al. Chondroitinase ABC (pharmaceutical grade) for chemonucleolysis. Functional and structural evaluation after local application on intraspinal nerve structures and blood vessels. Spine. 1996;21(17):1952-6.
    49. Morriss-Kay G, Tuckett F. Immunohistochemical localisation of chondroitin sulphate proteoglycans and the effects of chondroitinase ABC in 9- to 11-day rat embryos. Development. 1989;106(4):787-98.
    50. Seegmiller RE, Myers RA, Dorfman A, Horwitz AL. Structural and associative properties of cartilage matrix constituents in mice with hereditary chondrodysplasia. Connect Tissue Res. 1981;9(1):69-77.

  4. #14
    Senior Member Duran's Avatar
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    New improved enzyme could help facilitate spinal cord injuries

    Researchers have developed an improved version of an enzyme that degrades the dense scar tissue that forms when the central nervous system is damaged. By digesting the tissue that blocks re-growth of damaged nerves, the improved enzyme - and new system for delivering it - could facilitate recovery from serious central nervous system injuries.

    At physiological body temperature, chABC enzyme loses half of its enzymatic activity within one hour and their remaining functionality within three to five days. To thermostabilize the enzymes, Bellamkonda, Emory University cell biology associate professor Robert McKeon and Georgia Tech graduate student Hyun-Jung Lee mixed the enzyme with the sugar trehalose. The result -- the enzyme's activity was stabilized at internal body temperature for up to four weeks during in vitro tests.

    The researchers then used a lipid microtube-hydrogel scaffold system to deliver the thermostabilized enzymes into animals via a single injection. The scaffold provided sustained delivery of the enzyme for two weeks, with the microtubes enabling slow release and the hydrogel localizing the tubes to the lesion site. This delivery system also allowed the enzyme to diffuse deeper into the tissue than did catheter delivery.

    The delivery system also enabled the combination of therapies. Animals treated with thermostabilized chABC in combination with sustained delivery of neurotrophin-3 -- a protein growth factor that helps to support the survival and differentiation of neurons -- showed significant improvement in locomotor function and enhanced growth of sensory axons and sprouting of fibers for the neurotransmitter serotonin.

    http://www.news-medical.net/news/200...-injuries.aspx
    2016

  5. #15
    How would this work with someone who has a complete injury?

  6. #16
    I dont get it, this is safe in humans and it has been shown to reduce scar tissue. Why cant doctors give someone an injection, like they prescribe 4AP? Then go on lithium or growth hormone, and ride the FES bike or locomat. Its not a controlled experiment but, all of these things have shown potential to stimulate growth. If it didnt work out it would not kill us or cause cancer. We would also have the not so exciting benefits of FES or Locomat (ie blood circulation,weight on the bones, etc) and reduced scar tissue. i am sure there are plenty of people that would sign up for something like this and pay for it if they needed to just to see if it might work or help a little.

  7. #17
    Senior Member Duran's Avatar
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    I can't help but what I find strange in this study is while they are dealing with scar tissue problem (secondary damage to the spinal cord), the mentioned approach seems to be applicable to acute or subacute injuries, respectively.

    "The goal is that at the time the surgeon is removing the offending (vertebrae) bone after the injury you would inject this gel to sit on top of the injury site and prevent whatever new scar is forming," he said.
    http://www.ibtimes.com/contents/2009...ine-repair.htm
    2016

  8. #18
    Quote Originally Posted by boda View Post
    I dont get it, this is safe in humans and it has been shown to reduce scar tissue. Why cant doctors give someone an injection, like they prescribe 4AP? Then go on lithium or growth hormone, and ride the FES bike or locomat. Its not a controlled experiment but, all of these things have shown potential to stimulate growth. If it didnt work out it would not kill us or cause cancer. We would also have the not so exciting benefits of FES or Locomat (ie blood circulation,weight on the bones, etc) and reduced scar tissue. i am sure there are plenty of people that would sign up for something like this and pay for it if they needed to just to see if it might work or help a little.
    You bet ya!

  9. #19
    Yeah!
    Donnie: Dr. Xiao, What are your thoughts on a cure/combination therapy for SCI's??
    CG Xiao: Donnie, I don't want to disappoint you, but I think it is impossible to restore the continuity of the cord or "bridge the gap" in the near future, let's say: 50 years. Dr Wise Young has been my most respected scientist in SCI. He has dedicated and contributed to SCI no other can match.

  10. #20
    Yes, I totally agree with boda..
    If we can get rid of that damned scar tissue, let's do it *now* and let's go to a lot of exercises, FES, all that's available.. We don't know how far we could go with that, so let's go..
    The question is, can I go to my doctor and ask him to apply injection in the spinal cord. Does chondroitinase have to be delivered in the spinal fluid?.. Is there a protocol available?..
    Thansk
    G78

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