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    Regeneration vs Cell Replacement Therapies

    REGENERATION VS CELL REPLACEMENT THERAPIES

    It seems to me that there is some confusion concerning spinal cord regeneration and cell replacement. Let me try to comment on these two goals and some therapies relevant to these goals of spinal cord injury research. I have written this fairly rapidly and ask forgiveness for typographical and grammatical errors.

    Regeneration

    Regeneration usually refers to regrowth of something that has been partially damaged. For example, when one talks about regenerating part of the body, the body is still assumed to be present. Likewise, when one is regenerating an organ, part of the organ is still present. In general, when scientists talk about neural regeneration, they are talking about regrowing part of a neuron that is still alive. Neurons in the brain and lower spinal cord send axons that respectively descend and ascend in the spinal cord. Injury to the spinal cord damages the axons but usually leaves the neurons of origin intact. However, the part of the axon that has been cut off from the neuronal cell body usually dies. Therefore, the process of regeneration is the regrowth of the axon across the injury site and all the way to the neurons that it originally made contact with.

    Many therapies have been reported to regenerate the spinal cord. One category of therapies include drugs or antibodies that inhibit a family of molecules called Nogo. Nogo is usually expressed in normal myelin (the membrane that surrounds axons and is made by a cell called oligodendroglia). When growing axons encounter Nogo, they stop growing. For many years, Nogo was considered to be the primary obstacle to regeneration in the central nervous system. However, much data now suggest that several other class of molecules may inhibit axonal growth. For example, a family of extracellular proteins called chondroitin-6-sulfate-proteoglycan (CSPG) will inhibit axonal growth and an enzyme called chondroitinase ABC that breaks down CSPG will stimulate regeneration in mammalian spinal cords. Growth factors also contribute to regeneration and these include neurotrophins such as glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), neutrophic factor 3 (NT-3), and nerve growth factor (NGF). Recent studies suggest that the intracellular cAMP governs the response of axons to growth inhibitors. Many other therapies have been reported to stimulate regeneration, including inosine, alternating electrical currents, cell adhesion molecules such as L1.

    Axons don't like to grow across empty spaces. The injury site may be bereft of molecules that support axonal growth. Axons grow on surfaces and they are attracted to cell adhesion molecules for which they have receptors. Growing axons express a cell adhesion molecule called L1 and this molecule has been shown to stimulate regeneration in contused spinal cords. Another approach is to transplant cells that express such cell adhesion molecules. For example, olfactory ensheathing glia (OEG) cells obtained from the nose or the olfactory bulb express a variety of cell adhesion molecules such as laminin and L1. Schwann cells likewise express laminin and L1 and therefore provide attractive substrates for axonal growth across the injury site. Finally, recent studies indicate the increasing cAMP levels in the spinal cord with a phosphodiesterase-4 inhibitor Rolipram and injecting a cAMP analog into the spinal cord will markedly stimulate regeneration in the spinal cord, when combined with Schwann cell or bone marrow stem cell transplants.

    Regenerated axons must not only cross the injury site but they must grow all the way from the injury site to neurons present in the lower spinal cord in the case of motor axons and to neruons in the brainstem or brain in the case of sensory axons. Axons grow very slowly, typically no faster than the rate of hair growth, probably less than a mm per day. Given this slow rate of growth, regeneration of axons may take many months or even years. Note that in the case of cervical spinal cord injuries, the distance of motor axonal growth from the cervical spinal cord to the lower spinal cord may exceed 500 mm while the distance of sensory axonal growth to the brainstem and brain may be 50-100 mm. The expectation is faster recovery of sensory function and slower recovery of motor function for regenerative therapies of cervical spinal cord. However, the reverse is true for injuries to the lower thoracic spinal cord where sensory axons may have to grown 500 mm or longer while motor axons only have to grow 100 mm or less.

    In summary, regeneration of axons is a major objective of spinal cord injury therapies. Many therapies have been shown to regenerate axons. If and when it occurs, regeneration should be relatively slow and may take months to years. Treatments that block growth inhibitors present in the spinal cord, cell transplants that improve the environment of the injury site for axonal growth, and growth factors and other therapies that stimulate axonal regeneration have been shown to improve locomotor recovery in animals. If the neurons that give rise to the axons are damaged or the neurons that the axons connect do are damaged, there may limited numbers of axons or limited targets to which the axons can connect to. In such cases neuronal replacement therapies are required.

    Cell Replacement

    Trauma kills cells in the spinal cord, at the injury site and often above and below the injury site. Until recently, most scientists believed that the central nervous system cannot replace neurons. If true, it means that the neurons we die with are the same cells that we were born with. As we age, the number of neurons should decline. Likewise, if we injure our central nervous system, there may be precipitous losses of neurons in the brain and spinal cord. However, much evidence in the past decade indicate that neurogenesis (the creation of new neurons) occur throughout adult life in parts of the brain. There is still some controversy whether neurogenesis occurs in the cortex and the spinal cord but there is strong evidence that neurogenesis occurs in the hippocampus and olfactory bulb.

    In spinal cord injury, three types of neuronal loss may occur. First, trauma or ischemia kills neurons in the gray matter at the injury site or where the ischemia occurs. This is particularly problematical in the cervical or lumbosacral enlargement where most of the neurons that control the arms and legs respectively are situated. Second, damage to the axons, particularly when the damage is situated close to the neurons, may kill the neurons from which the axons originate. Some neurons in the cortex and the brain and brainstem may die after spinal cord injury. For example, neurons in the red nucleus, the sources of the rubrospinal tract, undergo atrophy and sometimes death after spinal cord injury. Several studies suggest that local administration of neurotrophins can prevent death and reverse atrophy of rubrospinal neurons. Third, the target neurons that the axons connect to may die as a result of loss of denervation. This too has been claimed but evidence that target spinal neurons die is very limited. However, damage to motoneuronal axons in spinal roots or peripheral nerve will lead to atrophy of muscles to which the axons connect.

    Loss of neurons reduces the number of axons that can regenerate and the number of targets to which they will connect. The latter, in particular, is problematical for many people with cervical or lumbosacral spinal cord injuries. Please note that the spinal cord ends at vertebral level L1, even though the spinal roots continue to go down the spinal canal below L1 and exit the appropriate openings of the L1-L5 and S1-S5. The L1 spinal cord is situated about T10, L2-L5 spinal cord at T11-T12 vertebral levels, and the S1-S5 spinal cord is situated at L1 vertebral canal. So, trauma or ischemia to T10-L1 may result in loss of neurons that control the legs. Likewise, trauma or ischemia to the cervical spinal cord will kill neurons that control the arms and hands, as well as phrenic respiratory neurons at C3-4. Because the upper thoracic spinal cord contains relatively little gray matter, damage to neurons is usually minor in such cases and involve only local neurons responsible for chest and abdomenal muscles.

    Trauma or ischemia also damage cells called oligodendroglia. These cells myelinate axons in the brain and spinal cord. Most rapid-conducting axons in the spinal cord are myelinated. Myelin consists of membranes wrapped many times around axons, providing a form of "insulation" that allows myelinated axons to conduct much more rapidly than unmyelinated axons. In the central nervous system, cells called oligodendroglia myelin between 15-20 axons. Trauma to the spinal cord will damage oligodendroglia and the inflammation of the spinal cord can cause oligodendroglial apoptosis, both of which will result in demyelination. Various infectious diseases, autoimmune, and inflammatory diseases may cause demyelination as well. Although the spinal cord contains stem cells that can produce new oligodendroglia, remyelination may be incomplete. Also, regenerated axons need to be myelinated. Thus, myelination is important for functional recovery.

    Many therapies have been shown to remyelinate the spinal cord after injury. One is to transplant oligodendroglial precursors, embryonic or neural stem cells that produce oligodendroglial precursors. A second approach is to provide growth factors that stimulate oligodendroglial precursors to grow and myelinate axons. This includes factors such as neuregulin. A third approach is to transplant peripheral myelinating cells into the central nervous system. For example, both Schwann cells and olfactory ensheathing glia have been reported to myelinate axons in the spinal cord. Both of these cells have been transplanted into the spinal cord of humans. There is very strong incentive for such research because it wold be beneficial not only for people with spinal cord injury but also people with multiple sclerosis and other demyelinating diseases.

    Neuronal replacement is more difficult to do. In the spinal cord, two types of neurons are present: interneurons and lower motoneurons. Interneurons connect to other neurons while motoneurons connect to muscle. Note that there are so-called "upper motoneurons" and these are are situated in the brain and send axons to the spinal cord to connect with either interneurons or motoneurons in the spinal cord. Injury may damage both interneurons and motoneurons in the spinal cord. Many interneurons are inhibitory in function and therefore loss of these neurons may produce increased excitation. Loss of motoneurons results in denervation of muscle. The muscles that the lost motoneurons use to connect to typically will undergo atrophy. Neuronal replacement therapy must not only make new neurons but also get them to connect to the right place.

    Several therapies have may produce new neurons in the spinal cord. The first is fetal neurons. Isolated from fetal brains, fetal neurons or their precursors have been used for some time to treat Parkinson's disease and stroke. A second approach is transplantation of fetal neural stem cells that have the capability of producing a wide range of neural cells including astrocytes, oligodendroglia, and neurons. In the fetus, the stem cell that produces neurons is the radial glial cell. A third approach is transplantation of embryonic stem cells that have been predifferentiated in culture to produce neurons. A recent study from Johns Hopkins showed that such transplants can produce motoneurons that send their axons out of the ventral roots of the spinal cord. A fourth approach is to use adult neural stem cells. Several researchers have shown that adult brain contains neural stem cells that producing neurons. Some scientists have advocated taking adult neural stem cells from one part of the brain and transplant them to another part of the brain or spinal cord but this is rather invasive and begs the question why we do not simply try to stimulate the stem cells to proliferate and migrate to the appropriate sites.

    Post-natal stem cells (e.g. umbilical cord blood and bone marrow mesenchymal stem cells) are pluripotent and can replace neurons and other cells in the spinal cord. Indeed, several researchers have claimed that such cell transplants have beneficial effects on recovery of function, possibly by stimulating remyelination, regeneration, and replacement of neurons. However, although these treatments may be beneficial, evidence that bone marrow or umbilical cord blood cells can produce new and functioning neurons or myelinating cells in the brain and spinal cord is still controversial. One possibility is that these cells are neuroprotective or stimulates endogenous cells in the brain and spinal cord. These issues are likely to be resolved in the near future as many laboratories are now actively investigating these areas.

    In summary, cell replacement therapy is an integral part of the cure for spinal cord injury. Loss of neurons is common after spinal cord injury. Axonal regeneration alone may not be sufficient to restore all function when neurons providing axons and target neurons have been lost or myelin-producing cells are lost. Finally, there may also be a role of stem cells in repairing the spinal cord both in the acute and chronic stages after injury. The exciting possibility is that some cell transplant therapies may be able to stimulate regeneration and replace cells. For example, Schwann cells and olfactory ensheathing glia stimulate regeneration and myelinate spinal axons. Embryonic and fetal stem cells have been shown to produce neurons in the spinal cord. While post-natal stem cells from bone marrow or umbilical cord blood have been shown to be pluripotent, evidence that they produce new neurons in the spinal cord is still limited and controversial. I expect substantial progress in these areas of research in the coming year.

    [This message was edited by Wise Young on 07-27-04 at 11:56 PM.]

    #2
    Dr Young, thanks again for another great summary. Not sure if this is an appropriate question to ask here but how do these therapies differ in chronic vs acute SCI? I'm not even sure what the difference is between chronic and acute but I know in several posts people have mentioned that some therapies will only work in acute or chronic. Thanks again.

    T12 Incomplete - Walking with Walker, Oct 2003
    T12 Incomplete - Walking with Crutches, Injured in Oct 2003

    Comment


      #3
      MikeC, this is really only about chronic. Wise.

      Comment


        #4
        So in other words we are very close.

        And great explanation!

        [This message was edited by QuadPro on 07-27-04 at 08:08 PM.]
        A CURE NOW!

        Comment


          #5
          Originally posted by QuadPro:

          So in other words we are very close.
          those words sound familar. i wonder where i hear them before.

          Comment


            #6
            Wise,

            Excellent description of what is need to restore function after substaining a sci...
            now what?
            thanks~ [img]/forum/images/smilies/wink.gif[/img]

            Gods speed for a cure~

            Comment


              #7
              I think an example might be in order. Let's take me. I have a small lesion around C6. Complete regeneration of ascending and descending tracts in the spinal cord might not restore complete function to my triceps and wrists. But I would expect full return of my fingers, trunk, abs, hips, legs, bowel, bladder and sexual function.

              Or, for instance, someone who has a high cervical injury and gets complete regeneration could experience restoration of walking/trunk/abs/b/b/s but not breathing function if there were no undamaged neurons to innervate the phrenic nerves.

              I think thoracic injuries might be less dependent on neuron replacement.

              SCI Research has traditionally focused on neuron protection and regeneration. Within the last few years the concept of neuron replacement has become accepted. We will benefit from both.

              ~See you at the SCIWire-used-to-be-paralyzed Reunion ~
              ~See you at the CareCure-used-to-be-paralyzed Reunion ~

              Comment


                #8
                Originally posted by DA:

                Originally posted by QuadPro:
                So in other words we are very close.
                those words sound familar. i wonder where i hear them before.
                geez, I heard them words before myself, maybe it was in my dreams?

                What one man can do another can do
                A good friend is someone who will come to bail you out of jail. A TRUE friend is the guy sitting next to you behind the same set of bars saying, "boy we sure f*cked up this time huh?"

                Comment


                  #9
                  Wise,

                  It does sound like you understand how to fix the problem area as of today...

                  These things of which you speak about could make it possible for us to attain a cure, right?

                  Would you or have you done this yet on any human being or has anyone else? If not this is very sad and i would love to help you help us if you tell me what you need to make this happen.
                  ________________________________________________

                  My opinion for an effective combination for a cure:

                  1) eliminate barries- (scar tissue, NOGO,)

                  2) replace lost neurons- (stem cells)

                  3) stimultate axonal growth- (GDNF, BDNF, Inosine, NT3, NGF, CNTF,replicons-genetic therapy)

                  4) remylination (OEC, Schwan cell or Oligodendrisits)

                  5) Snapitic genisis

                  6) Intensive PT

                  7) these are what i have found to be effective in my personal research within the last year or so, but i am sure there is more that you aware of..??..

                  Some of these have been around for decades. We need an effective combonation to restore function and accomplish a cure.

                  Gods speed,
                  Susan

                  [This message was edited by Superstar on 08-05-04 at 12:57 AM.]

                  Comment


                    #10
                    Wise, thanks a lot for that *great* summary. I understand that we may still have a long way before cells replacement, but, like Susan said, you seem to know perfectly what to do to have major axons sprout and remyelination. Am I wrong?... [img]/forum/images/smilies/cool.gif[/img]
                    So what are we waiting for?... Money?... Patients?... or a neurosurgeon that understand SCI is a case of emergency and we cannot wait 20 years for phases I, II, III approval?...
                    I'm 26 years post, I remember I've been to Washington DC in 1981. There was a neurosurgeon named Carl Kao. He was performing schwann cells graft on humans. 23 years later, you write:
                    Schwann cells likewise express laminin and L1 and therefore provide attractive substrates for axonal growth across the injury site.
                    ... so what?... Where are we?... I don't know what to say, Wise. This looks like a joke. A joke that lasts 26 years. My life. [img]/forum/images/smilies/biggrin.gif[/img]
                    You want another joke?... Do you remember IN-1 and Nogo stuff?... That was *before* 1990. On July 13 2004, 15 years later, Lisa Schnell said:
                    Once the anti-Nogo system is shown to be safe in other animal models, the first human patients with spinal cord injuries will be considered for treatment.

                    "The first patients we would try this technique on would probably be recently injured young men and women with severe injuries who have no hope of spontaneous recovery," says Schnell.
                    Keep smiling, my friends... [img]/forum/images/smilies/smile.gif[/img]
                    George

                    http://www.paratetra.net

                    Comment


                      #11
                      George and Susan (Superstar),

                      I have been giving a lot of thought to the question that Susan asked me several weeks ago... concerning what therapy I think should go into clinical trial. As Susan knows, I responded by saying that this must be a consensus decision of the clinicians. Of course I have very strong opinions concerning what therapies would be best and I make that choice every day in the laboratory. But what really matters is the opinion of the community. For too long, the community has not had a voice in what therapies should be in clinical trial. For that reason, I have been reluctant to impose my views on the community except to provide new information, to correct misinformation, and, when necessary, to try to move people away from views that may be harmful to themselves or the field. Like everybody here, I am learning and do not have a monopoly on the truth or a crystal ball to see the future.

                      There are now many therapies for spinal cord injury that have been reported to be effective. Scientists are advocates for their therapies and you must always listen to their views with the knowledge that they are human and therefore biased towards the therapies they have worked on and care about. Nogo antibodies (IN-1) was the first therapy that was widely accepted as a regenerative therapy. It has been a great disappointment to me that it has not gone further than it has in the past 15 years. This was not for the lack of trying by Martin Schwab, Lisa Schnell, and others. Their particular magic potion did not attract the necessary funding and clinical support that it needed. I was very hopeful when they managed to convince Novartis to take up the cudgel on behalf of Nogo but it is still not yet in clinical trial. While they received a major boost with the identification of the Nogo gene, the nogo receptor (by Strittmatter), and demonstration that Nogo receptor blockade stimulates regeneration and improves neurological recovery in animals, the ligand and receptor technology unfortunately went to separate companies.

                      We should also be very aware that scientific theories are only good for a period of time. The theory that Nogo is the main inhibitor of axonal regeneration in spinal cord injury has been overturned by the discovery that chondroitinase will stimulate regeneratioin and improve recovery as well or better than Nogo blockers. Likewise, the recent findings that increasing cAMP levels in the spinal cord will stimulate regeneration, especially when combined with cell transplants. These are the first of a series of combination therapies that will be reported this fall.

                      The coming months are really crucial for the spinal cord injury community. Because of the current budgetary deficit of the the U.S. government, we should not really expect a major increase in clinical trial funding for the field for at least a year. This means that we do not have the luxury of many clinical trials. In fact, I expect that we might be able to raise funds for only a single multicenter trial for chronic spinal cord injury research in the U.S. during the coming year. The choice of the therapy and the clinical trial design therefore must be carefully chosen.

                      I am really sorry we are currently in this situation. I had worked for years to avoid it but did not anticipate the 9/11 attack that essentially dried up on governmental funding of spinal cord injury research. While we have been working very hard to diversify our options by lobbying for state funds and encouraging overseas clinical trials, these remain limited. So, this places a particular onus on the decisions of the coming months. If we have one chance at a clinical trial in the coming year, what should it be?

                      This is the discussion that I am hoping to stimulate in the spinal cord injury community. I believe that this is a decision that the community should have a voice in.

                      Wise.

                      Comment


                        #12
                        Wise,

                        thank you and i personally will do everything of which you ask and believe with all of my heart and soul that you can find that hidden cure for paralysis!

                        Remember that money offer, it still stands! [img]/forum/images/smilies/wink.gif[/img]

                        Just give me your number and we can work on this...

                        CCC, the ball is in our court, please play with it!

                        I have my opinions, will voice them shortly..

                        Gods speed for a cure~
                        Susan Fajt

                        Comment


                          #13
                          Dear Wise,
                          Thanks a lot for clarifying the situation. I'd like to apologize for my acid words concerning the research. I didn't mean to criticize any scientist working on SCIES...
                          George

                          Comment


                            #14
                            Susan,

                            Congress should pass a bill instructing NIH to set up a clinical trial network for spinal cord injury and allocate funding for the network. This would galvanize NIH to put out a request for proposal (RFA) for clinical trial centers to join the network, peer-review to select the best centers, and then organize the membership of the network to meeting regularly to establish the outcome measure, the treatment that would be tested, and the clinical trials that would be carried out. The network selects a data-coordinating center that will collect the data and enforce the protocol. This may take a year or so to do, if the money were allocated.

                            The path is clear but the will is simply not there in Congress.

                            Wise.

                            [This message was edited by Wise Young on 08-03-04 at 03:50 AM.]

                            Comment


                              #15
                              "The path is clear but the will is simply not there in Congress."

                              This is what is so frustrating for anyone with a sci. Curing our condition is simply not trendy - we can live good lives in our chairs so why bother trying to cure it. It is our fault for creating the happy crip culture and not being vocal about wanting our bodily functions back again.

                              Comment

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