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Thread: Now what?

  1. #121
    Quote Originally Posted by paolocipolla View Post
    Thanks for the clarification,

    are you considering to do a trial using cethrin on patints with SCI within 2 weeks of injury or/and on chronic SCI patients?

    Do you know if Lisa McKerracher has done any animal study on any chronic SCI model?

    Paolo
    I am not aware of any published reports of Cethrin treatment of chronic contused spinal cords. The following is two abstracts of its use in acute spinal cord injury.

    Wise.

    1. Ellezam B, Dubreuil C, Winton M, Loy L, Dergham P, Selles-Navarro I and McKerracher L (2002). Inactivation of intracellular Rho to stimulate axon growth and regeneration. Prog Brain Res 137: 371-80. Departement de Pathologie et Biologie Cellulaire, Centre de Recherche en Sciences Neurologiques, Universite de Montreal, Montreal, PQ H3T 1J4 Canada. Our studies indicate that the small GTPase Rho is an important intracellular target for promoting axon regrowth after injury. In tissue culture, inactivation of the Rho signaling pathway is effective in promoting neurite growth on growth inhibitory CNS substrates by two different methods: inactivation of Rho with C3 transferase, and inactivation by dominant negative mutation of Rho. In vivo, we have documented the regeneration of transfected axons after treatment with C3 in two different animals models, microcrush lesion of the adult rat optic nerve, and over-hemisection of adult mouse spinal cord. Mice treated with C3 after SCI showed impressive functional recovery, notwithstanding the fact that mice differ from rats in their response to spinal cord injury, especially in the extent of cavitation at the lesion site (Steward et al., 1999). It remains to be determined to what extent the regeneration of specific descending and ascending spinal axons contribute to the recovery, and whether inactivation of Rho enhances the spontaneous plasticity of axonal and dendritic remodeling after SCI. Inactivation of Rho with C3 to promote regeneration and functional recovery after SCI is simple, and our studies reveal the potential for a new, straightforward technique to promote axon regeneration.

    2. Lord-Fontaine S, Yang F, Diep Q, Dergham P, Munzer S, Tremblay P and McKerracher L (2008). Local Inhibition of Rho Signaling by Cell-Permeable Recombinant Protein BA-210 Prevents Secondary Damage and Promotes Functional Recovery following Acute Spinal Cord Injury. J Neurotrauma 25: 1309-22. BioAxone Therapeutic Inc., Montreal, Quebec, Canada. Abstract Spinal cord injury (SCI) leads to robust Rho activation at the lesion site. Here, we demonstrate that BA-210, a cell-permeable fusion protein derived from C3 transferase, formulated in fibrin sealant and delivered topically onto the dura matter, diffuses into the spinal cord and inactivates Rho in a dose-dependent manner. Treatment with BA-210 in rats with thoracic spinal cord contusion increased tissue sparing around the lesion area and led to significant improvement of locomotor function. In mice, BA-210 improved functional outcome when treatment was either applied at the time of injury or delayed by 24 h. In both rats and mice, treatment with BA-210 was well tolerated. Rats gained body weight normally, and BA-210 treatment had no impact on the development of allodynia. Inactivating Rho with BA-210 holds promise for treating patients with SCI.

  2. #122
    I respect what you're saying. I simply have developed a different perspective in the past couple of years. If you wish to fund raise directly for RIRC, I suggest you contact Karen Miner and Research for Cure. She's awesome. You can find her profile here. If not, PM me and I'll put you in direct contact.

    I can tell you NowhereMan that I am part of a small local team that has committed to a 6 figure fund raising attempt. It's too early to say much more about that. Due to this effort, we have carefully reviewed all the potential targets for the funds and as a committee made some semi-final decisions. Our criteria is chronic research.

    If you Skype, PM your Skype contact ID and your time zone.

    Quote Originally Posted by NowhereMan View Post
    I respectfully disagree. If one's goal is to donate to an organization that will help go to Chronic SCI research, then they should donate it to organizations that actually do chronic SCI research. For Example, RHI, does not spend ANY money on Chronic SCI cure research, so a donation to them would be a giant waste. From what I see, CDRF spends a lot more money on Acute SCI research. That is great and necessary, but it won't help anybody already on this message board.

    Any amount of money raised by the SCI community is doomed to be small. It should at the very least be put to the most efficient use. I personally believe that Reeve Irvine is the best place to donate to. They have shown small regeneration in the spinal cord for the first time ever. I think this is the first and only real breakthrough for Chronically injured SCI that need their spinal cord regenerated. Now it is time to help fund them. It won't be a few years, it will take a long time, if ever.

    I'm not saying put all of the money on one horse, but there really only seems to be one horse entered in the race.

    One needs to be constantly assessing the current environment to decide who to support. Things are constantly changing.
    My blog: Living Life at Butt Level

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    Dawna Markova Author of Open Mind.

  3. #123
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    Quote Originally Posted by Wise Young View Post
    Being skeptical is good but be careful that you do not slip into therapeutic nihilism. A therapeutic nihilist is what I call a person who not only decides that there are no therapies that can restore function but goes out of his or her way to deny the possibility of a cure. This happens frequently amongst medical doctors who tell patients that they will never recover. People are frequently shocked to find that many people in the spinal cord injury community do not support cure research.

    Many people on CareCure have given up and some even avoid the cure forum because they don't want to get on that roller coaster ride of hope and despair that goes nowhere. This is what I want to change. We should be on a train ride to effective therapies. People need to settle down and not jump up and down saying that we have reached the cure station because we are nowhere close. There are of course critics and naysayers.

    We are trying to regenerate long tracts in the spinal cord in our current series of trials. If umbilical cord blood mononuclear cells (UCBMC) and lithium work, that is good. Whether UCBMC and lithium restore function or not, we will continue to test other promising therapies. The train keeps moving. That is the way all diseases are cured. We must keep testing the best therapies and combinations. Eventually, we will have therapies that restore function to most people with spinal cord injury. Then we can start thinking cure. I don't know how long it will take. All that I know is that if we don't start, we won't get there.

    Walking is a low-hanging fruit. We know that 90% of incomplete spinal cord injuries will recover walking within a year after injury. If UCBMC+lithium converts a person from complete to incomplete, that person should recover walking. It may take a long time and locomotor training is likely to be necessary. We chose UCBMC because they have a long and well-established safety record and are HLA-matchable for immune-compatibility. We chose lithium because several groups have shown that it stimulates regeneration and endogenous neural stem cells to produce neurons. Lithium is also safe if properly administered.

    The decision to go to phase III is based on phase II data showing that the transplants are safe and that some subjects recover sensory or motor function. Obviously, we would not go ahead to a phase III trial if the treatment is not safe and we see no evidence of improvement. We have reached the threshold for the decision but that does not mean that the subjects are not continuing to recover. I also want to remind everybody that 6 months is not a long time for recovery of function and we anticipate that recovery will contine beyond 6 months.

    Our current phase II trials are still going on. We closed patient recruitment in May and should get all the 6-month data by November. After checking all the data and finalizing the data set, we will analyze the data, write it up, and submit the study for publication. So, sometime before the end of the year, we will submit the paper. Because release of the data may jeopardize publication, we need to wait until the paper is accepted for publication before presenting the data in detail in public forums.

    Regenerating long tracts may not help everybody. For people with lumbosacral spinal cord injury, they may have lost the targets for regenerating fibers. That is why we are limiting subjects to C5 through T11. We are planning trials to treat subjects with lumbosacral injuries. We will need to replace the neurons. Therefore, we are looking for an immune-compatible source of neural stem cells. We also will want to encourage plasticity and reduce the influence of growth inhibitors such as Nogo and chondroitin sulfate proteoglycans. Therefore, we are considering using adult stem cells that can be readily differentiated to neural stem cells and Cethrin, a well known drug that has already shown promise in phase I/II trials.

    Finally, while locomotor training may restore walking to people with incomplete injuries, we don't know whether training alone will do so in most people with ASIA A injuries at C5 through T11. Training by itself may help some people and we hope that our phase 3 trials will help ascertain whether training alone is necessary or sufficient for locomotor recovery. We also don't know yet whether lithium improves recovery after UCBMC transplants. So there is much to learn and to do.

    Wise.
    Thank you so much! That clears it up a bit. Looking forward to data and phase 3. Even though some wont admit ... it means a world to all of us.

  4. #124
    Quote Originally Posted by JenJen View Post
    Again, we have to give up our love affairs with the labs/organizations that are living off our funds no matter how great they sound and move on. I'm not sure everyone is ready for that.
    I agree. I do check Charity Navigator to find how a National charity is doing that I'm interested in giving money to. http://www.charitynavigator.org/

    They work on a 4 star system to rank the charity. You simply type in the name of the national charity you are interested to retrieve the information and their ranking. The 4 star system is explained here.

  5. #125
    Quote Originally Posted by Wise Young View Post
    I am not aware of any published reports of Cethrin treatment of chronic contused spinal cords. The following is two abstracts of its use in acute spinal cord injury.

    Wise.

    1. Ellezam B, Dubreuil C, Winton M, Loy L, Dergham P, Selles-Navarro I and McKerracher L (2002). Inactivation of intracellular Rho to stimulate axon growth and regeneration. Prog Brain Res 137: 371-80. Departement de Pathologie et Biologie Cellulaire, Centre de Recherche en Sciences Neurologiques, Universite de Montreal, Montreal, PQ H3T 1J4 Canada. Our studies indicate that the small GTPase Rho is an important intracellular target for promoting axon regrowth after injury. In tissue culture, inactivation of the Rho signaling pathway is effective in promoting neurite growth on growth inhibitory CNS substrates by two different methods: inactivation of Rho with C3 transferase, and inactivation by dominant negative mutation of Rho. In vivo, we have documented the regeneration of transfected axons after treatment with C3 in two different animals models, microcrush lesion of the adult rat optic nerve, and over-hemisection of adult mouse spinal cord. Mice treated with C3 after SCI showed impressive functional recovery, notwithstanding the fact that mice differ from rats in their response to spinal cord injury, especially in the extent of cavitation at the lesion site (Steward et al., 1999). It remains to be determined to what extent the regeneration of specific descending and ascending spinal axons contribute to the recovery, and whether inactivation of Rho enhances the spontaneous plasticity of axonal and dendritic remodeling after SCI. Inactivation of Rho with C3 to promote regeneration and functional recovery after SCI is simple, and our studies reveal the potential for a new, straightforward technique to promote axon regeneration.
    2. Lord-Fontaine S, Yang F, Diep Q, Dergham P, Munzer S, Tremblay P and McKerracher L (2008). Local Inhibition of Rho Signaling by Cell-Permeable Recombinant Protein BA-210 Prevents Secondary Damage and Promotes Functional Recovery following Acute Spinal Cord Injury. J Neurotrauma 25: 1309-22. BioAxone Therapeutic Inc., Montreal, Quebec, Canada. Abstract Spinal cord injury (SCI) leads to robust Rho activation at the lesion site. Here, we demonstrate that BA-210, a cell-permeable fusion protein derived from C3 transferase, formulated in fibrin sealant and delivered topically onto the dura matter, diffuses into the spinal cord and inactivates Rho in a dose-dependent manner. Treatment with BA-210 in rats with thoracic spinal cord contusion increased tissue sparing around the lesion area and led to significant improvement of locomotor function. In mice, BA-210 improved functional outcome when treatment was either applied at the time of injury or delayed by 24 h. In both rats and mice, treatment with BA-210 was well tolerated. Rats gained body weight normally, and BA-210 treatment had no impact on the development of allodynia. Inactivating Rho with BA-210 holds promise for treating patients with SCI.
    Thank you Wise,
    so I assume you are planning to use Cethrin in an acute clinical trial since there are no studies that suggest cethrin can work on chronic SCI.

    Is that correct?

    Paolo
    In God we trust; all others bring data. - Edwards Deming

  6. #126
    Quote Originally Posted by paolocipolla View Post
    Thank you Wise,
    so I assume you are planning to use Cethrin in an acute clinical trial since there are no studies that suggest cethrin can work on chronic SCI.

    Is that correct?

    Paolo
    No, we are planning to test Cethrin in chronic spinal cord injury. We will be studying it in animals as soon as a source becomes available. Wise.

  7. #127
    Quote Originally Posted by Wise Young View Post
    No, we are planning to test Cethrin in chronic spinal cord injury. We will be studying it in animals as soon as a source becomes available. Wise.
    Thanks Wise, that is what I suspected. So first you have to do the animal studies on chronic SCI (which will take at best a year, but mybe 2 or 3), then JUST IF it works animals with chronic SCI you can start clinical trials with cethrin on people with chronic SCI.
    I think these are very relavant details you should have included in your presentation at the last open house.

    Paolo
    In God we trust; all others bring data. - Edwards Deming

  8. #128
    Quote Originally Posted by paolocipolla View Post
    Thanks Wise, that is what I suspected. So first you have to do the animal studies on chronic SCI (which will take at best a year, but mybe 2 or 3), then JUST IF it works animals with chronic SCI you can start clinical trials with cethrin on people with chronic SCI.
    I think these are very relavant details you should have included in your presentation at the last open house.

    Paolo
    Paolo,

    These are all very relevant questions you are raising. Good job! Animal experiments showing efficacy before human trials. Makes sense to me.

    jerry

  9. #129
    Senior Member
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    Hello Dr. Silver - Can you start a topic about your clinical trials? Seems things are finally picking up. Thanks, Ilya .

  10. #130
    Quote Originally Posted by jsilver View Post
    Paolo,

    These are all very relevant questions you are raising. Good job! Animal experiments showing efficacy before human trials. Makes sense to me.

    jerry
    Thanks Dr. Silver,

    actually there are many CC members smarter than me who have started quetioning what's going on in SCI research long before me, and I have learned from them in the past.
    Probably at the moment I am just one who ask questions in a more visible way than others as I feel I have nothing to loose and I am fed up with things that defy common sense.
    In any case IMO researchers and SCI orgs that are honestly dedicated to find a cure for SCI should not be afraid of any question coming from the SCI community.

    Paolo
    In God we trust; all others bring data. - Edwards Deming

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