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  1. #1
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    Great summary of SCI research to date.

    Miracles and molecules-progress in spinal cord repair

    Andrew R. Blight

    Acorda Therapeutics, 15 Skyline Drive, Hawthorne, New York 10532, USA Correspondence should be addressed to A.R.B. (ablight@acorda.com)

    Published online 28 October 2002; doi:10.1038/nn939
    nature neuroscience supplement • volume 5 • november 2002

    ABSTRACT
    Severe spinal cord injury (SCI) leads to devastating loss of neurological function below the level of injury and adversely affects multiple body systems. Most basic research on SCI is designed to find ways to improve the unsatisfactory cellular and molecular responses of spinal cord to injury, which include an array of early processes of autodestruction and a subsequent lack of functional tissue repair. This research has brought us to the threshold of practical application along three lines of approach, derived from animal model studies: acute neuroprotection, enhanced axonal regenera-tion or plasticity, and treatment of demyelination. There is a growing commercial interest in this previously neglected therapeutic area.

    Making the paralyzed walk and the blind see have been standards of medical miracle and magic for much of recorded history, and it is not surprising that they remain with us as potent cultural images. Modern knowledge about the scientific and technologi-cal puzzles embroiled in these tasks has not blunted the impres-sion they present to public consciousness. This may help to explain the popularity of reports of even obscure scientific progress in spinal cord injury (SCI) research, many of which find their way into the daily news before they can be examined in the medical library. This cultural heritage also tends to absolve those involved in basic SCI research of a need to consider or explain too deeply the practical applications of their work. However, before examining the progress that has been achieved in this field, it is worth noting that there is much to be done aside from restor-ing locomotion.

    The effects of SCI vary with the site of damage, because of the way spinal nerves are distributed in an orderly arrangement down its length. Neural systems that can be permanently disrupted below the level of the injury involve not only the obvious con-trol of limb muscles and the sensation of touch. Functional deficits can include the cardiovascular system, breathing, sweat-ing, bowel control, bladder control, sexual function, and the pro-tective roles of temperature and pain sensation. These losses lead to a succession of secondary problems, such as pressure sores and urinary tract infections that, in earlier times, were rapidly fatal. SCI also frequently removes those unconscious control mecha-nisms that maintain the appropriate level of excitability in cir-cuitry of the spinal cord. As a result, spinal motoneurons can become spontaneously hyperactive, producing the debilitating stiffness and uncontrolled muscle spasms of spasticity, or spon-taneously active sensory systems can produce chronic neurogenic pain and paresthesias-all sorts of unpleasant sensations from numbness and tingling to aching and burning. Faced with this array of problems, it is not surprising that, for many SCI patients, restoration of walking does not top the list of desires for thera-peutic progress.

    Most basic scientific research on SCI that makes its way to public recognition and the pages of general scientific journals is directed not to any of these particular issues of the condition itself but rather to trying to improve the unsatisfactory cellu-lar and molecular responses of spinal cord to injury, which include an array of early processes of autodestruction and the subsequent lack of functional repair. Meanwhile, practitioners in the field, together with clinical and pharmaceutical researchers, have addressed individual components of the con-dition. With little fanfare, they have developed drugs and devices for control or management of urinary and cutaneous infections, pain, spasticity, bladder and bowel management, sexual and reproductive function, providing a basis for remark-able advances in rehabilitation and in societal attitudes and facilities. This rate of practical advance should he humbling for those of us engaged in the fascinating business of working upward from the molecular level.

    Neurotrauma research has emerged as a distinct field and advanced substantially in recent years. In SCI, we appear to be on the threshold of practical applications mostly along three lines of approach. All three are founded on concepts derived from ani-mal model studies-acute neuroprotection, enhanced regener-ation, and treatment of demyelination. Although the underlying concepts are not entirely independent, they provide a useful framework for evaluating progress.

    Acute neuroprotection

    The concept of a treatable secondary injury arose from histopathological evidence suggesting that not all the damage is produced at the time of a crushing impact to the spinal cord, but that additional damage accumulates over time by a variety of reactive processes. At the gross level, the spinal cord can appear initially to be remarkably little affected by a crush that leads even-tually to a major destruction of tissue and permanent function-al loss. Within hours, the central part of the cord undergoes 'hemorrhagic necrosis,' in which the cellular contents of the tis-sue appear to fall apart, starting at the center of injury, The chief architect of this concept of treatable secondary damage was A.R. Allen, with his innovative studies of spinal injury in dogs1. Over the intervening ninety years, speculation and experiment on the nature of secondary pathology have been dominated by a suc-cession of fashionable preoccupations: compromised blood flow, edema, catacholamines, oxidative damage, excitotoxicity, inflam-mation, nitric oxide and apoptosis. All these ideas have led to proposed methods of intervention for which at least some sci-entific evidence has been generated in support; the most advanced are discussed below. However, this extensive research has not been able to define just how much of the final consequences of a spinal cord injury is due to immediate mechanical damage ver-sus secondary mechanisms.

    Following many years of animal research and clinical practice in which it was assumed that corticosteroids might be useful for spinal cord injury, perhaps by reducing swelling and inflamma-tion, a series of controlled clinical trials was begun in the 1980s. These NASCIS (National Acute Spinal Cord Injury Study) trials, sponsored by NIH, examined treatments with methylprednisolone, naloxone, 'megadose' methylprednisolone, and tiri-lazad mesylate2. The effort was guided by the identification of an antioxidant mechanism of action for methylprednisolone by Hall and Braughler, then at Upjohn3. In sum, these trials provided support for the use of high-dose methylprednisolone in the first 8 hours after injury, but, since methylprednisolone was already on the market and already in use in SCI, there was limited impe-tus for further development. It was also not possible to perform additional placebo-controlled trials to satisfy regulatory require-ments and the expectations of skeptical peers because of a per-ceived ethical imperative to treat. Despite subsequent debate about trial design and data analysis, the results provided by the NASCIS trials seem to validate the concept of a treatable sec-ondary component to acute SCI.

    More recently, a large Phase 3 trial ofGM-1 ganglioside (Sygen®), sponsored by Fidia, failed to demonstrate long-term benefit in SCI4. Neither the mechanism of action nor the effi-cacy of this compound was clear from laboratory studies, but an earlier, small clinical study had indicated substantial bene-fit5. A Phase 2 trial of the NMDA antagonist gacyclidine, spon-sored by Beaufour-Ipsen/Forenap-Pharma, was performed in Europe, based on the concept that excitotoxicity is involved in secondary pathology, and on positive animal studies. The results, reported at the Society for Neuroscience meeting in 1999, showed no long-term benefit on neurological scores, and devel-opment for SCI was halted. A smaller multi-center trial of Neotrofin (AIT-082), a synthetic purine, was sponsored recent-ly by NeoTherapeutics in the US, with the proposal that this molecule may both be neuroprotective and stimulate regener-ation, though there is insufficient published data on animal studies to judge the likelihood of benefit. Proneuron has begun Phase 1 studies of injecting autologous, activated macrophages into the injured cord, based on the concept that these cells release neuroprotective molecules and may also stimulate regen-eration. There is some evidence in a rat model to support this proposal6, though the underlying biological processes are too complex for clear interpretation.

    Many other neuroprotective interventions have been tested successfully in animal models, though most are unlikely to see clinical development because of a lack of commercial opportu-nity or difficulties of practical application.

    Regeneration and transplantation

    The second dominant concept has been to stimulate otherwise abortive regeneration, based on the observation that the adult mammalian central nervous system (CNS) shows extremely limited ability to repair itself by regrowth of cut axons. This idea is usually attributed to Cajal, based on his lucid synthesis of observation and experiment, initially written before the First World War7. The reluctance of CNS nerve fibers to repair seems to result from a number of mechanisms that limit the overall plasticity of the mature CNS, perhaps for good reason. These mechanisms include membrane and extracellular matrix pro-teins that are powerful inhibitors of axonal extension, and the dependence of neurons on neurotrophic factors to support growth and survival. Many of the more newsworthy efforts in the field come from the attempt to produce in mammalian CNS the kind of spontaneous regeneration that is seen in the periph-eral nervous system, which occurs to some extent even in the CNS of lower vertebrates.

    Approaches to regeneration have seen compelling advances in scientific understanding over the past few years. In particular, the biology of the Nogo-A myelin inhibitory factor has emerged from more than 15 years of research, initially by Martin Schwab in Zurich8 and more recently by an expanding group of investi-gators, including Stephen Strittmatter ofYale, as a significant inhibitor of growth and plasticity in the adult mammalian CNS. Nogo was first seen as a therapeutic target for enhancing regen-eration of axons in the injured spinal cord9, but the morpholog-ical and functional changes produced by blocking antibodies (IN-1) to Nogo10 or blocking peptides against the Nogo recep-tor (Ng-R))' may be related to sprouting and plasticity, as much as to regeneration of severed axons. The extent to which this will translate into clinical efficacy in different neurological conditions remains to be determined. However, with the involvement of at least two large biotechnology companies, Novartis, working with IN-1, and Biogen, working with Ng-R, clinical trials of some kind are likely to begin within the next few years. The recent discovery that Ng-R is also the receptor for other known myelin inhibitory proteins12'13, and the presence of Aventis and GlaxoSmithKline in this area of research, suggest that there will be increased activ-ity around this therapeutic target.

    While inhibitory molecules in the myelin sheath have been in the spotlight, there has also been extensive research on other inhibitory components of the glial scar that forms after a CNS injury. Chondroitin sulphate proteoglycans represent a barrier to growth of axons as a component of the extracellular matrix14. Application of bacterial chondroitinase to the site of injury breaks down this barrier to axon growth and promotes substantial axon-al growth and functional recovery in a rat model of cord injury15. There maybe a number of practical hurdles to clinical develop-ment of this molecule, but the proof of concept is likely to drive commercial interest.

    A number of other methods of enhancing regeneration are entering clinical development, including conventional pharmaceuticals, biotechnological approaches and other technolo-gy, including applied electrical fields16. Boston Life Sciences is developing inosine, based on evidence of enhanced growth of corticospinal tract in animal models that appears similar to some of the effects of Nogo inhibition17. There is also com-mercial interest in the concept of targeting common intracellular signaling molecules for growth inhibition, including cyclic nucleotides18'19 and the rho pathway20. A variety of animal stud-ies support the ability of neurotrophins to stimulate regenera-tion in the spinal cord21, though none is currently in clinical development for regeneration. The wide distribution of neurotrophin receptors and the multiplicity of molecules and effects make this approach challenging, though the commercial poten-tial and the biological potency of these molecules are likely to lead to future applications.

    Studies of cellular transplantation to the injured cord have been performed for more than twenty years, initially with the concept that embryonic cells might provide a useful 'bridge' of growth-supportive substrate across the site of injury, or even act as a neural relay station, receiving synaptic input from and extending nerve fibers into the host. Initial work involving trans-plantation of embryonic nervous system components showed some degree of functional benefit and a remarkable morpholog-ical integration of graft and host. This line of research has cul-minated in exploratory clinical trials in the academic setting, which have succeeded in demonstrating the feasibility of the approach22, although there would be significant difficulties con-verting this to a widely applicable therapy. Addressing one of those problems-source of material-a clinical trial, sponsored by Diacrin, has begun to explore the safety of porcine fetal spinal cord cell xenografts in SCI.

    Over the last few years, the explosion of interest in 'stem cells' as therapeutic agents has included the field of SCI research, and many animal studies are proceeding with a variety of stem and precursor cells, mostly in the spirit of "seeing what happens" rather than a clear concept of need and mechanism, given that a shortage of cells does not seem to be the main problem in SCI (perhaps with the exception of myelinating cells; see below). However, as in the case of embryonic transplants, the replace-ment of scar tissue with a more attractive cellular substrate might lead to more functional repair.

    Treating demyelination

    The third concept, of treating demyelination, arose from detailed evaluation of the histopathology23 and pathophysiology24 of spinal cord injuries, which showed that poor myelination of sur-viving nerve fibers may be involved in permanent functional deficits. Myelin damage appears to result from inflammatory processes in the injured tissue and may involve delayed apoptotic death of oligodendrocytes25. The presence of conduction deficits in myelinated axons raised the possibility that chronic SCI might be treated by improving the function of surviving nerve fibers, even in the absence of regeneration.

    Two approaches are in clinical development. The first is pharmacological treatment with 4-aminopyridine, or fampridine, a potassium channel blocker that can restore action potential con-duction in demyelinated or partially myelinated axons in injured spinal cord26. Published clinical studies have reported beneficial effects on motor and sensory function, reduction in spasticity, and evoked potential evidence of enhanced conduction in spinal cord pathways27. The extent of benefit to an individ-ual will be expected to depend on the particular surviving pathways in the spinal cord, as well as their state of myelination. Acorda Therapeutics initiated two large, multicenter, Phase 3 trials of a sustained-release formulation of fampridine in SCI in June,2002.

    A more difficult, but possibly permanent method of treating demyelination may be offered by cellular transplantation of either Schwann cells or oligodendrocytes. There is animal data to sup-port the ability of transplanted cells to myelinate axons in ani-mal models of demyelination and to restore or enhance conduction of action potentials28. The major issues, as with most cellular therapeutic approaches, revolve around source, delivery, control and immunogenicity. Alexion has a program of clinical development for xenotransplantation of myelinating cells, includ-ing porcine Schwann cells and olfactory ensheathing glia (OEG), with potential applications in SCI. There are also data to indi-cate that OEG enhance limited functional axonal regeneration.

    Future expectations

    The benefits to be expected from partial success with any of these approaches are not yet defined. Animal models of SCI seem to rep-resent very well the pathological processes involved30, but the mea-surement of functional outcome has been dominated by evaluation of locomotor function, which is not directly comparable between quadrupeds and human beings. Hind limb function in animals is more dependent on spinal central pattern generators and more independent of descending controls than it is in humans. This makes it possible for large improvements in function to be pro-duced by setting the appropriate level of excitability in those spinal circuits, which may not require survival or regeneration of specific neural connectivity. Very little is known from animal studies about the potential for effects of small amounts of therapeutic benefit on aspects of spinal cord injury other than walking. There is current-ly much interest in the value of stimulating activity in human spinal cord locomotor centers by physical manipulation, using treadmills or direct electrical stimulation of muscles. These approaches seem to improve limb function in incomplete SCI31 and may have men-tal and physical health benefits beyond any effects they produce on improving the activity of pattern generators or reflex pathways in the spinal cord. They are likely to be useful adjuncts to any treat-ments derived from the three approaches considered above.

    This short overview of the developing commercial landscape should be remarkable to anyone who has been engaged in the field of SCI research for more than a few years. In 1992, there was almost no detectable commercial interest in SCI as a target for therapeutic development. Several small companies now include SCI as part of their central focus, and a growing number of large companies have invested in adventurous projects related to regen-eration research. There is much to learn about how practical ther-apeutics will be achieved, because there is little precedent regarding clinical trial design and interpretation, or regulatory requirements. Until there is success in taking a neuroprotective, regenerative or conduction-enhancing product from concept to approval for SCI, we will not be sure what to expect along the way. One of the important lessons we are likely to learn again over the next decade is that the development of therapeutics, unlike miracle and magic, requires a great deal of work, misstep and correction, in addition to commitment and belief.

    RECEIVED 10 JUNE; ACCEPTED 19 JULY 2002

    1. Alien, A. R. Surgery of experimental lesion of spinal cord equivalent to crush injury of fracture dislocation of spinal column: a preliminary report. JAMA
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    2. Bracken, M. B. el al. Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow up. Results of the third National Acute Spinal Cord Injury randomized controlled trial. /. Neurosurg. 89, 699-706(1998).
    3. Hall, E. D. The neuroprotective pharmacology of methylprednisolone. /. Neurosnrg. 76, 13-22 (1992).
    4. Geisler, R, Coleman, W., Grieco, G., Poonian, D. & Group, S. S. The Sygen multicenter acute spinal cord injury study. Spine 15, S87-S98 (2001).
    5. Geisler, F. H., Dorsey, F. C. & Coleman, W. P. Recovery of motor function after spinal cord injury-a randomized, placebo-controlled trial with GM-1 ganglioside.New. Eng. J. of Med./.Afed. 324, 1829-1838 (1991).
    6. Rapalino, 0. et al. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat. Med. 4, 814-821 (1998).
    7. Ramon y Cajal, S. Degeneration and Regeneration of the Nervous System (Oxford Univ. Press, London, 1928).
    8. Caroni, P. & Schwab, M. E. Two membrane protein fractions from rat central myelin with inhibitory properties for neurite growth and fibroblast spreading./. Cell Biol. 106, 1281-1288 (1988).
    9. Schnell, L. & Schwab, M. E. Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 343, 269-272 (1990).
    10. Thallmair, M. et al. Neurite growth inhibitors restrict plasticity and functional recovery following corticospinai tract lesions. Nat. Neurosci. 1, 124-131 (1998).
    11. GrandPre, T., Li, S. & Strittmatter, S. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 417, 547-551 (2002).
    12. Wang, K. et at. Oligodendrocyte-myelin giycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941-944 (2002).
    13. Uu, B., Fournier, A., GrandpPre, T. & Strittmatter, S. Myelin-associated giycoprotein as a functional ligand for the Nogo-66 receptor. Science 297, 1190-1193(2002).
    14. Snow, D. M., Lemmon, V., Carrino, D. A., Capian, A. I. & Silver, J. Sulfated proteoglycans in astroglial barriers inhibit neurite outgrowth in vitro. Exp. Neural. 109, 111-130(1990).
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    16. Borgens, R. et al. An imposed oscillating electrical field improves the recovery of function in neurologically complete paraplegic dogs. /. Neurotrauma 16, 639-657(1999).
    17. Benowitz, L. 1., Goldberg, D, E., Madsen, J. R., Soni, D. & Irwin, N. Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury. Proc. Nat], Acad. Sd. USA 96, 13486-13490 (1999).
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    26. Shi, R. & Blight, A. R. Differential effects of low and high concentrations of 4-aminopyridinc on axonal conduction in normal and injured spinal cord. Neuroscience 77, 553-562 (1997).
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  2. #2
    Excellent article but "over the next decade" sounds horribly familiar and depressing

  3. #3
    Great article ip, thanks for posting it.

  4. #4
    Senior Member Schmeky's Avatar
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    Chris2

    I agree with you 100%, and unfortunately this how I interprete the timetable on SCI research overall. We would be lucky if something became commercially available in ten years.

  5. #5
    Commercial viability of a cure application comes in many forms. It could be pharmaceutical - drugs like 4AP,inosine. It could be surgical - like macrophage, OEG, Cheng, Kao or it could be physiological like Project Walk, IMT or your own variation of the same concept.

    My point is that commercial availability is here. It may not be consistent, widespread or proven in its effectiveness but make no mistake - its here. What has to happen however is the frequency of clinical trials and the urgency in which they arrive.

    Two years ago when I was injured stem cells, OEG, macrophage didn't exist. Today they're becoming everyday vernacular for the sci community. And progress in these fields is moving rapidly.

    Ten years may prove to be the summation of the results of what ultimately works the best for curing us but until then many of us will recover through methods that are now in their infancy and currently unproven.

    Either way its all good and moving in the right direction faster than many could have predicted just 5yrs ago.

    Fortitudine Vincimus
    (Through endurance we conquer)

    [This message was edited by Chris on Dec 16, 2002 at 05:26 PM.]

  6. #6
    Senior Member Jeff's Avatar
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    I agree, Chris

    I just wish early adopters could participate in clinical trials here in the US sooner rather than later. I think, however, the earliest adopters will find their first opportunity abroad....at considerable financial expense. But hey, either way, I'm glad it's happenning.

    Just wait until future OEG patients get a cABC therapy before and extensive high-tech rehab after. I think we're looking at substantial return of function. I just want it to happen sooner than I think it will. OTOH, it's not a question of "in my lifetime, anymore." Not by any stretch of my most pessimistic imagination.

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

  7. #7
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    The main reason this article struck me was the information about the big pharmaceutical companies' involvement. I knew about Novartis and Biogen, but not about Aventis and GlaxoSmithKline. I'm a complete amateur when it comes to anylizing the potential of a therapy. Howeverm, when I see the pros get involved with a certain therapy (nogo inhibitors, and nogo receptor blockers), that tells me a lot. There seems to be something there, and I predict the best therapies will come from where the big companies are (not oeg, alt current, inosine, stem cells, m-1, etc., etc.)

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