Announcement

Collapse
No announcement yet.

First Oral Drug for Spinal Cord Injury Improves Movement in Mice

Collapse
X
 
  • Filter
  • Time
  • Show
Clear All
new posts

    First Oral Drug for Spinal Cord Injury Improves Movement in Mice

    http://www.sciencedaily.com/releases/2013/01/

    First Oral Drug for Spinal Cord Injury Improves Movement in Mice

    Jan. 8, 2013 — An experimental oral drug given to mice after a spinal cord injury was effective at improving limb movement after the injury, a new study shows.

    The compound efficiently crossed the blood-brain barrier, did not increase pain and showed no toxic effects to the animals.
    "This is a first to have a drug that can be taken orally to produce functional improvement with no toxicity in a rodent model," said Sung Ok Yoon, associate professor of molecular & cellular biochemistry at Ohio State University and lead author of the study. "So far, in the spinal cord injury field with rodent models, effective treatments have included more than one therapy, often involving invasive means. Here, with a single agent, we were able to obtain functional improvement."
    The small molecule in this study was tested for its ability to prevent the death of cells called oligodendrocytes. These cells surround and protect axons, long projections of a nerve cell, by wrapping them in myelin. In addition to functioning as axon insulation, myelin allows for the rapid transmission of signals between nerve cells.
    The drug preserved oligodendrocytes by inhibiting the activation of a protein called p75. Yoon's lab previously discovered that p75 is linked to the death of these specialized cells after a spinal cord injury. When they die, axons that are supported by them degenerate.
    "Because we know that oligodendrocytes continue to die for a long period of time after an injury, we took the approach that if we could put a brake on that cell death, we could prevent continued degeneration of axons," she said. "Many researchers in the field are focusing on regeneration of neurons, but we specifically targeted a different type of cells because it allows a relatively long therapeutic window."
    An additional benefit of targeting oligodendrocytes is that it can amplify the therapeutic effect because a single oligodendrocyte myelinates multiple axons.
    A current acute treatment for humans, methylprednisolone, must be administered within eight but not more than 24 hours after the injury to be effective at all. An estimated 1.3 million people in the United States are living with spinal cord injuries, experiencing paralysis and complications that include bladder, bowel and sexual dysfunction and chronic pain.
    The experimental drug, called LM11A-31, was developed by study co-author Frank Longo, professor of neurology and neurological sciences at Stanford University. The drug is the first to be developed with a specific target, p75, as a potential therapy for spinal cord injury.
    The research is published in the Jan. 9, 2013, issue of The Journal of Neuroscience.
    Researchers gave three different oral doses of LM11A-31, as well as a placebo, to different groups of mice beginning four hours after injury and then twice daily for a 42-day experimental period. The scientists analyzed the compound's effectiveness at improving limb movement and preventing myelin loss.
    The spinal cord injuries in mice mimicked those caused in humans by the application of extensive force and pressure, resulting in loss of hind-limb and bladder function and experimentally calibrated baseline difficulty in walking and swimming.
    The researchers determined that the mice did not experience more pain than the placebo group at all the doses tested, suggesting that LM11A-31 does not worsen nerve pain after spinal cord injury.
    Analysis showed that the extent of myelin sparing was dependent on the dose of the drug. Each dose -- 10, 25 or 100 milligrams per kilogram of body weight -- led to increasing myelin sparing, with the highest dose demonstrating the greatest effect.
    The injury in the animals caused a loss of about 75 percent of myelinated axons in the lesion area in the placebo group. This loss was reduced so that myelinated axons reached more than half of the normal levels with LM11A-31 at 100 mg/kg. That was correlated with about a 50 percent increase in surviving oligodendrotcytes compared to those in the placebo group, Yoon said.
    In behavior tests, only the highest dose of the compound led to improvements in motor function. Mice were tested in both weight-bearing and non-weight-bearing activities over the 42 days to evaluate their functional recovery.
    Mice receiving the highest dose could walk with well-coordinated steps. In swimming tests, scientists saw similar improvements, with mice receiving the highest dose most able to coordinate hind-limb crisscross movement. The other treatment groups exhibited difficulty in walking and swimming.
    Yoon said the findings may suggest that myelin sparing needs to reach a threshold of roughly 50 percent of normal levels before motor function improvements become measurable.
    "The cellular analysis of the myelin profile detects small changes. Behavior is more complex, and we don't think functional behavior necessarily improves in a linear fashion," she said. "Still, these results clearly show that this is the first oral drug in spinal cord injury that works alone to improve function."
    This work was supported by the grants from the National Institute of Neurological Disorders and Stroke (NINDS) and the Christopher and Dana Reeve Foundation, and Ohio State Neuroscience Center Core support from NINDS.
    Additional co-authors include Chhavy Tep, Tae Hee Lim, Pyung On Ko, Sami Getahun, Jae Cheon Ryu and Virginia Goettl of the Department of Molecular & Cellular Biochemistry; and Michele Basso of the Department of Physical Therapy, all at Ohio State; and Stephen Massa of the University of California, San Francisco.
    C-5, 6 SCI. Took about 6 months to walk. Walking full time. Without any assistance since Nov. 2003 and will make a full recovery

    #2
    Acutes only? or?
    "It's not the despair, I can handle the despair! It's the hope!" - John Cleese

    Don't ask what clinical trials can do for you, ask what you can do for clinical trials. (Ox)
    Please join me and donate a dollar a day at http://justadollarplease.org and copy and paste this message to the bottom of your signature.

    Comment


      #3
      And thanks for posting it.
      "It's not the despair, I can handle the despair! It's the hope!" - John Cleese

      Don't ask what clinical trials can do for you, ask what you can do for clinical trials. (Ox)
      Please join me and donate a dollar a day at http://justadollarplease.org and copy and paste this message to the bottom of your signature.

      Comment


        #4
        man this sounds good
        http://justadollarplease.org/

        2010 SCINet Clinical Trial Support Squad Member

        "You kids and your cures, why back when I was injured they gave us a wheelchair and that's the way it was and we liked it!" Grumpy Old Man

        .."i used to be able to goof around so much because i knew Superman had my back. now all i've got is his example -- and that's gonna have to be enough."

        Comment


          #5
          heres another link

          http://www.news-medical.net/news/201...y-in-mice.aspx
          C-5, 6 SCI. Took about 6 months to walk. Walking full time. Without any assistance since Nov. 2003 and will make a full recovery

          Comment


            #6
            this reads like it's going to be tested in ALS humans

            http://www.alz.org/research/alzheime...nts=2013flongo
            http://justadollarplease.org/

            2010 SCINet Clinical Trial Support Squad Member

            "You kids and your cures, why back when I was injured they gave us a wheelchair and that's the way it was and we liked it!" Grumpy Old Man

            .."i used to be able to goof around so much because i knew Superman had my back. now all i've got is his example -- and that's gonna have to be enough."

            Comment


              #7
              First Oral Drug for Spinal Cord Injury Improves Movement in Mice

              Jan. 8, 2013 — An experimental oral drug given to mice after a spinal cord injury was effective at improving limb movement after the injury, a new study shows.

              The compound efficiently crossed the blood-brain barrier, did not increase pain and showed no toxic effects to the animals.
              "This is a first to have a drug that can be taken orally to produce functional improvement with no toxicity in a rodent model," said Sung Ok Yoon, associate professor of molecular & cellular biochemistry at Ohio State University and lead author of the study. "So far, in the spinal cord injury field with rodent models, effective treatments have included more than one therapy, often involving invasive means. Here, with a single agent, we were able to obtain functional improvement."

              The small molecule in this study was tested for its ability to prevent the death of cells called oligodendrocytes. These cells surround and protect axons, long projections of a nerve cell, by wrapping them in myelin. In addition to functioning as axon insulation, myelin allows for the rapid transmission of signals between nerve cells.

              The drug preserved oligodendrocytes by inhibiting the activation of a protein called p75. Yoon's lab previously discovered that p75 is linked to the death of these specialized cells after a spinal cord injury. When they die, axons that are supported by them degenerate.

              "Because we know that oligodendrocytes continue to die for a long period of time after an injury, we took the approach that if we could put a brake on that cell death, we could prevent continued degeneration of axons," she said. "Many researchers in the field are focusing on regeneration of neurons, but we specifically targeted a different type of cells because it allows a relatively long therapeutic window."

              An additional benefit of targeting oligodendrocytes is that it can amplify the therapeutic effect because a single oligodendrocyte myelinates multiple axons.

              A current acute treatment for humans, methylprednisolone, must be administered within eight but not more than 24 hours after the injury to be effective at all. An estimated 1.3 million people in the United States are living with spinal cord injuries, experiencing paralysis and complications that include bladder, bowel and sexual dysfunction and chronic pain.

              The experimental drug, called LM11A-31, was developed by study co-author Frank Longo, professor of neurology and neurological sciences at Stanford University. The drug is the first to be developed with a specific target, p75, as a potential therapy for spinal cord injury.

              The research is published in the Jan. 9, 2013, issue of The Journal of Neuroscience.

              Researchers gave three different oral doses of LM11A-31, as well as a placebo, to different groups of mice beginning four hours after injury and then twice daily for a 42-day experimental period. The scientists analyzed the compound's effectiveness at improving limb movement and preventing myelin loss.

              The spinal cord injuries in mice mimicked those caused in humans by the application of extensive force and pressure, resulting in loss of hind-limb and bladder function and experimentally calibrated baseline difficulty in walking and swimming.

              The researchers determined that the mice did not experience more pain than the placebo group at all the doses tested, suggesting that LM11A-31 does not worsen nerve pain after spinal cord injury.

              Analysis showed that the extent of myelin sparing was dependent on the dose of the drug. Each dose -- 10, 25 or 100 milligrams per kilogram of body weight -- led to increasing myelin sparing, with the highest dose demonstrating the greatest effect.

              The injury in the animals caused a loss of about 75 percent of myelinated axons in the lesion area in the placebo group. This loss was reduced so that myelinated axons reached more than half of the normal levels with LM11A-31 at 100 mg/kg. That was correlated with about a 50 percent increase in surviving oligodendrotcytes compared to those in the placebo group, Yoon said.

              In behavior tests, only the highest dose of the compound led to improvements in motor function. Mice were tested in both weight-bearing and non-weight-bearing activities over the 42 days to evaluate their functional recovery.

              Mice receiving the highest dose could walk with well-coordinated steps. In swimming tests, scientists saw similar improvements, with mice receiving the highest dose most able to coordinate hind-limb crisscross movement. The other treatment groups exhibited difficulty in walking and swimming.
              Yoon said the findings may suggest that myelin sparing needs to reach a threshold of roughly 50 percent of normal levels before motor function improvements become measurable.

              "The cellular analysis of the myelin profile detects small changes. Behavior is more complex, and we don't think functional behavior necessarily improves in a linear fashion," she said. "Still, these results clearly show that this is the first oral drug in spinal cord injury that works alone to improve function."

              Comment


                #8
                Originally posted by topperf View Post
                Acutes only? or?
                The article did not mention chronic injuries at all
                "I'm manic as hell-
                But I'm goin' strong-
                Left my meds on the sink again-
                My head will be racing by lunchtime"

                <----Scott Weiland---->

                Comment


                  #9
                  in case the link doesn't work for anyone else

                  http://www.sciencedaily.com/releases...0108201445.htm

                  Comment


                    #10
                    obviously acutes only... the fear is if acute sci is cured chronics will just disappear. which is good for the world but the death of chronic research. its like those afflicted with polio before the vaccine was found..

                    Comment


                      #11
                      Originally posted by Eric.S View Post
                      obviously acutes only... the fear is if acute sci is cured chronics will just disappear. which is good for the world but the death of chronic research. its like those afflicted with polio before the vaccine was found..
                      As for polio there is still research being done on post polio syndrome and there is still wild polio in central Asia.

                      But we do need to support the science that leads to a real cure. There isn't enough funding for a bit here and a little more there. It isn't just that if we fix acutes there will soon be no chronics. As long as there are people paralyzed by tumors or other surgery, spinal strokes and TM we will need chronic cures.
                      Courage doesn't always roar. Sometimes courage is the quiet voice at the end of the day saying, "I will try again tomorrow."

                      Disclaimer: Answers, suggestions, and/or comments do not constitute medical advice expressed or implied and are based solely on my experiences as a SCI patient. Please consult your attending physician for medical advise and treatment. In the event of a medical emergency please call 911.

                      Comment


                        #12
                        Originally posted by Sue Pendleton View Post
                        As for polio there is still research being done on post polio syndrome and there is still wild polio in central Asia.

                        But we do need to support the science that leads to a real cure. There isn't enough funding for a bit here and a little more there. It isn't just that if we fix acutes there will soon be no chronics. As long as there are people paralyzed by tumors or other surgery, spinal strokes and TM we will need chronic cures.
                        Sue, if you like I would be interested in your opinions on the folowing things...

                        I just had a look to a list of SCI research projects (not official yet) that will be funded soon by an important SCI org..

                        They received about 140 grant aplications, after a strict peer review process, 18 projects were selected....
                        Guess what?
                        Just two out of 18 are about chronic SCI and just one of the two is about regeneration in chronic SCI.

                        I would like to hear your opinion on how is it possible that most of SCI research still focus on acute when all the SCI advocates have chronic SCI?

                        I see a big failure of SCI advocacy efforts here. SCI advocates have been focusing mainly on getting more founding and didn't bother much about looking at how money are spent because they have had blind faith in scientists.

                        Then I believe you understand how easier it is to do clinical trials on chronic rather then on acute. That is why there are many potential acute therapies that havn't been tested yet and the few that have been tested failed, so we still have only methilprednisolone. BTW if you had to do the trial for MP today it would be unlikely to get the money to do it, assuming the preclinical work was good enough to suggest bringing it to clinical trials.
                        In my opinion SCI advocacy has failed to understand this reality and then to correct it.
                        We have to think strategically.
                        For long time (still today) the leading idea has been to fist find a cure for acute and then move it to chronic.
                        IMO that is totally wrong, the opposite is much more conveninet. Strategically thinking to focus on chronic it's the more realistic and the fastest way forward to cure all SCI.

                        Would you agree?

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

                        Comment


                          #13
                          http://www.youtube.com/watch?v=-XbmjAA0XUg
                          Last edited by Leif; 29 Mar 2013, 10:42 PM.

                          Comment


                            #14
                            I totally agree, Paolo. When we worked out the rules our SCI Research Board in Maryland would work by we had two reviews. The first review was by out of state peer reviewers in the SCI field. But when it came to how the board members voted we specifically inserted the ability to vote for proposals way down on the peer list because they were very different than the normal way of approaching SCI, due to wanting to support a non-established primary investigator or other reasons like a possible stem cell proposal not eligable for federal grants.

                            We still received a lot of RFPs returned that included pain mitigation, a better way of doing rehab, funding a census of actual injuries per year (not needed as I was able to find the stats for a year 3 years previous that had a total of SCI traumatic injuries in the state including those who were DOA) and even recreation as a mood elavator. Considering the RFPs included a copy of the very simple law's scope--regeneration or neuroprotection--we sent a lot to the reject pile on our votes. Peer reviewers did rate these but added they did not meet the stated requirement as far as end point.

                            As far as I know the Board of Public Works is still appropriating the Board's funds to other areas of the budget. Were the Board to recover its funding they could, the way the law is written, give more money to chronic proposals and just award fewer grants. After a few years I think the message would be passed that, in the case you state, only chronic proposals would be considered or mainly chronic and only highly likely to make it to trials acute treatments.

                            I would not totally write off acute proposals if they were highly likely to, say, lower the injury by 3 spinal nerve levels. IOWs, an acute treatment that would turn a C2 level to a C5 or a T10 to a L1. But any treatment that could do that would most likely be well on its way to regenerating more distant cells.
                            Courage doesn't always roar. Sometimes courage is the quiet voice at the end of the day saying, "I will try again tomorrow."

                            Disclaimer: Answers, suggestions, and/or comments do not constitute medical advice expressed or implied and are based solely on my experiences as a SCI patient. Please consult your attending physician for medical advise and treatment. In the event of a medical emergency please call 911.

                            Comment


                              #15
                              In a few threads before I also said that when we have a solution for chronic sci we have automaticly a solution for acute. Im no Phd or scientist at all but I guess the costs for chronic animal models are huge (I think Hans Keistead said that in an interview someday) and of course companys which support those studys or trials wanna get data as soon as possible and you wont get that in chronics. I think thats the big problem here

                              Comment

                              Working...
                              X