FAQ #2: When will the Cure be Available for Spinal Cord Injury?

FAQ #2: When will the Cure be Available for Spinal Cord Injury?
Wise Young, Ph.D., M.D., Rutgers University
W. M. Keck Center for Collaborative Neuroscience
604 Allison Rd, Piscataway, NJ 08854-8082
First posted 23 December 2008, final version 3 January 2009

Introduction

When will a cure for spinal cord injury be available?  This is the second most frequently asked question, usually asked right after the first most frequently asked question, “Will there be a cure for spinal cord injury?” While I don’t have a crystal ball for the future, some therapies are already beginning to restore function in people with spinal cord injury with spinal cord injury, several regenerative therapies have begun clinical trials, and the first combination therapies will soon go into clinical trial.  If we work hard, the resources are available, and we are lucky, we should expect the first restorative therapies within 5 years and perhaps the first curative combination therapies within a decade.

First generation therapies for spinal cord injury are already restoring some function to some people with spinal cord injury.  Methylprednisolone (MP) was the first therapy to show any beneficial effects when given after spinal cord injury.  MP improves motor and sensory recovery by about 20% compared to control.  A second therapy is Fampridine (4-aminopyridine), which is restoring function to some people with demyelination. The third therapy is locomotor training for people with “incomplete” spinal cord injuries.

Second generation therapies are now or will soon be in clinical trial.  These include cell transplants (olfactory ensheathing glia, Schwann cells, bone marrow stem cells, neural stem cells, oligodendroglial progenitor cells, embryonic stem cells), nogo and nogo receptor blockers, chondroitinase, growth factors, lithium, and many others. These therapies are likely to stimulate modest regeneration in the spinal cord and restore more function to more people.

Third generation therapies will be combination therapies that will bring substantially more function to most people, fulfilling the definition of what many people may call “cures” for spinal cord injury.  The optimal combination will probably differ depending on the individual.  The combination therapies should include not only therapies that regenerate spinal axons but also remyelination and neuronal replacement, including motoneurons.

What can we learn from these experiences?  I will describe below eight examples of therapies for spinal cord injury, i.e. methyprednisolone, locomotor training, fampridine, cethrin, nogo antibody, and human embryonic stem cells, bone marrow stem cells, and combination therapy with cord blood mononuclear cells and lithium.  I chose these treatments because each have undergone or are going through clinical trial.  I will describe the development of each of the therapies to date, the lessons from this experience, and the probability of the first restorative therapies and combination therapies.

Methylprednisolone (MP)

MP was the first therapy shown to be effective for acute spinal cord injury.  In the 1970’s, neurosurgeons were using high doses of the anti-inflammatory glucocorticoid drug methylprednisolone (MP) to treat arachnoiditis [1] and head injury [2].  Some clinicians wondered if MP would be effective for acute spinal cord injury [3, 4].  In 1979, ten spinal cord injury centers joined to do the first double blind randomized clinical trial of high-dose and low-dose MP for acute spinal cord injury.

The first National Acute Spinal Cord Injury Study (NASCIS 1) randomized 300 patients to 1000 mg/day or 100 mg/day of intravenous MP for 10 days starting within 24 hours after injury. The trial found no significant difference between the two doses of MP [5].  However, in 1982, animal studies showed that much higher doses (30 mg/kg) were required to inhibit lipid peroxidation [6] and that very early treatment was necessary for to reduce extracellular calcium entry into cells and to prevent post-traumatic ischemia [7].  The opiate receptor blocker naloxone was beneficial in animal models [8, 9] and a phase 2 trial [10].

The second National Acute Spinal Cord Injury Study (NASCIS 2) therefore randomized 487 patients to placebo, high-dose MP (30 mg/kg bolus followed by 5.4 mg/kg/hour over 24 hours), and naloxone (5.4 mg/kg + 3.0 mg/kg/hour over 24 hours).  Starting in 1985, the trial proposed to segregate patients by the median treatment time, which was 8 hours, assess the effects of treatment timing.  NASCIS 2 [11] showed that high-dose MP improved motor and sensory recovery compared to placebo when treatment started within 8 hours but not when started later than 8 hours [12].  Naloxone had intermediate effects between MP and placebo.  MP was not associated with significant morbidity or mortality. From 1991-1993, <50% of people with acute spinal cord injury in Colorado received MP [13] and physicians tended to give the drug to more severely injured patients.

The third National Acute Spinal Cord Injury Study (NASCIS 3) randomized 499 patients with acute spinal cord injury and treated all within 8 hours with a 30 mg/kg MP bolus, followed by 5.4 mg/kg/hour for 24 hours (MP24), MP given for 48 hours (MP48), or tirilazad mesylate (TM) 2.5 mg bolus given every 6 hours for 48 hours (TM48).  The median treatment time was 3 hours.  All three treatment groups had similar outcomes when started within 3 hours but MP48 was better than either MP24 or TM48 when given more than 3 hours after injury [14, 15].  The treatments were not associated with significant mortality or morbidity except for an increase in severe pneumonia after MP48.

The NASCIS group recommended MP24 when it could be started within 3 hours, MP48 between 3-8 hours, and no MP if it could not be started within 8 hours after injury. Several randomized trials [16-19] have confirmed beneficial effects and safety of MP use in human acute spinal cord injury and related conditions [20, 21].  However, one small randomized trial [22] and several retrospective studies [23-27] suggested MP may be ineffective. One study suggested that MP Retrospective studies are biased because clinicians tend to give MP to more severely injured patients.  Nevertheless, criticisms of NASCIS mounted [28-36].  Today, MP is an option and not a standard treatment of acute spinal cord injury in the United States.

Locomotor Training

Most doctors believe that recovery of walking is unlikely after spinal cord injury and thus few encourage their patients to walk after injury.  In 1992, Wernig & Muller [37] reported that intensive treadmill training restored unassisted walking to 8 patients, starting at 5-20 months after spinal cord injury.  By 1995, Wernig et al. [38] had studied 89 patients (44 chronic, 45 acute) with spinal cord injury.  Of 44 chronic patients trained for 3-20 weeks, 33 were initially wheelchair-bound and could not stand or walk.  After training, 25 (76%) of the 33 wheelchair-bound patients achieved unassisted walking.  Of 11 patients who were walking before training, all had better speed and endurance.  In a 1998 followup [39], at 6-72 months after training, 31 of 35 chronic patients who recovered unassisted walking maintained, three improved, and one stopped walking.  Of 41 initially acute spinal cord injuries, 15 improved and one stopped walking.

In 1998, the National Institutes of Health (NIH) commissioned a multicenter study to compare weight-supported treadmill and overground walking training in spinal cord injury.  The Spinal Cord Injury Locomotor Trial or SCILT [40] showed that <10% of patients with ASIA B, 92% of those with ASIA C, and 100% of ASIA D recovered walking at >0.8 meter/second and over 260 meters in 6 minutes.  An ASIA (American Spinal Injury Association) B classification refers to an injury that preserves only sensation below the injury site, including anal sensation.  ASIA C indicate injuries that preserve anal sensation or sphincter function and motor function below the injury site but less than half of ten key muscles have strength grades exceeding 3 of 5 (0=paralyzed, 1=slight, 2=definite, 3=anti-gravity, 4=against resistance, 5=normal).  ASIA D indicates injuries with 5 or more key muscles with strength grades of 3 or more.  SCILT indicated no difference between training with weight-supported treadmill and overground walking.

Although intensive training can restore locomotion in animals after even severe spinal cord injuries [41-45], the finding that >90% of people with incomplete spinal cord injury can recover unassisted walking even without treadmill training nonetheless took many clinicians by surprise.  Despite initial resistance, this finding is transforming rehabilitation of spinal cord injury.  Motor incomplete patients can walk.  Many investigators are now examining the effects of treadmill training patients with ASIA A (complete) or B (sensory incomplete).  Others are assessing other training approaches, in combination with functional electrical stimulation [46], serotonin receptor agonists [47], and other methods of increasing motor control [48].

In summary, early studies in the 1990’s reported that weight-supported treadmill training could restore unassisted locomotion to people with chronic spinal cord injury.  In 1998, the NIH funded SCILT to study weight-supported treadmill training of patients with incomplete spinal cord injuries.  The study surprisingly showed that >90% of motor incomplete patients recovered unassisted locomotion, whether they were trained by treadmill or overground walking, suggesting that most people who have preserved motor function after injury can recover locomotion if they worked on it.  Many investigators are examining various adjuncts to locomotor training.

Fampridine (4-AP)

Trauma, ischemia, and inflammation demyelinate the spinal cord. 4-aminopyridine (4-AP or fampridine) blocks potassium channels on demyelinated axons, improves conduction, and increases neurotransmitter release [49].  In 1981, Bostock, et al. [50] reported that 4-AP improves conduction in demyelinated axons and Zangger, et al. [51] showed that it also facilitates L-DOPA induced spinal locomotor rhythms in spinal-injured animals.  In 1986, Eliasson, et al. [52] showed that 4-AP restores conduction in heat-injured nerve and spinal roots in animals.  In 1987, Bowe, et al. [53] confirmed that 4-AP improves conduction in demyelinated axons and Blight & Gruner [54] found that 4-AP improved vestibulospinal free fall responses in spinal-injured cats.  In 1989, Blight et al. studied the effects of 4-AP in dogs [55] and proposed clinical trials of 4-AP in spinal cord injury.

In 1993, Hansebout, et al. [56] did the a double-blind, crossover trial of 4-AP in eight patients, finding the drug improved motor and sensory function.  Hayes, et al. [57] confirmed the 4-AP effects on function [58] and motor evoked potentials [59] in patients with spinal cord injury.  In 1997, Segal & Brunnemann [60] found that 4-AP improves pulmonary function in quadriplegic humans with chronic spinal cord injury [60].  In 1997, Acorda Therapeutics licensed the use patent for 4-AP treatment of spinal cord injury. In 1998, Potter, et al. [61] did a randomized crossover trial of a sustained release 4-AP (Fampridine SR) made by Elan.  In 1999, Acorda partnered with Elan to develop Fampridine SR, including preclinical studies [62, 63], studies to assess pharmacokinetics of intravenous [64], intrathecal [65], oral [66] 4AP in humans and animals [67].

In 2001, van der Bruggen, et al. [68] found that 4-AP (0.5 mg/kg) did not improve neurological function of 20 patients with chronic incomplete spinal cord injury.  However, 4-AP improved motor evoked potentials patients with chronic spinal cord injury [69] and Grijalva, et al. [70] randomized 27 patients to 4-AP or placebo, and found that 30 mg/day 4AP for 12 weeks improved neurological function in 69% compared to 46% on placebo. In 2004, Deforge, et al. [71] found no difference between 4-AP (40 mg/day) or placebo in 15 people who were walking after spinal cord injury.

From 2005 to 2007, after a phase 2 [72], more pharmacokinetics [73, 74] and safety trials [75], Acorda did two large randomized placebo-controlled phase 3 trials involving over 800 patients with chronic spinal cord injury to assess Fampridine SR effects on spasticity.  Both trials [not yet published] showed no significant difference between Fampridine SR and placebo.  However, Acorda also did two phase 3 clinical trials that showed that Fampridine SR significantly improves walking performance in multiple sclerosis (MS).

In summary, over a decade of clinical trials yielded promising and conflicting results concerning 4-AP effects on chronic spinal cord injury.  The trials surprisingly revealed that people with spinal cord injury are susceptible to placebo.  Over 40% of patients responded to placebo and perhaps half of the patients responded to 4-AP.  Until better outcome measures can be found, it may be better to choose a condition that is more responsive to 4-AP and go back later to demonstrate efficacy for spinal cord injury.

Nogo-A Antibody

In 1990, Schwab, et al. stunned the world with his study showing that IN-1, an antibody against an as-yet-unidentified myelin component [76], stimulates regeneration of rat corticospinal tract [77].  The first demonstration of a treatment that regenerates the spinal cord, the work convinced many neuroscientists that Aguayo and David [78-80] were right in their proposal that there is something about central myelin that stops axonal growth.  Unfortunately, the IN-1 antibody was promiscuous and bound to many proteins.  It took ten years before Schwab and his colleagues were able to isolate and clone the gene for the protein, now named Nogo [81-86].  With the purified protein finally available, Novartis licensed the patent for Nogo antibody treatment of spinal cord injury and embarked on an intensive program to develop the first regenerative therapy for spinal cord injury.

Many investigators tried different approaches to using the discovery of myelin-based growth inhibitory proteins to regenerate the spinal cord injury.  For example, Huang, et al. [87] reported that vaccinating mice with spinal cord may have induced antibodies that stimulated spinal cord regeneration, an approach that was later validated when the nogo protein itself was available to determine whether the vaccination induced the antibodies against nogo [88, 89].  If vaccination will induce antibodies that can stimulate spinal cord regeneration, this would be a very powerful approach indeed.

Novartis developed specific nogo-A antibodies that improve behavioral outcome and corticospinal plasticity in rats after experimental stroke [90], stimulated corticospinal regeneration in marmosets [91], increased plasticity in many different preparations [92-94].  After demonstrating that the antibodies penetrated into the spinal cord when infused intrathecally [95] and showing that the anti-Nogo-A antibody stimulated sprouting of corticospinal axons in macaque monkeys [96] and the treatment restores serotonin projections in rats after spinal cord injury [97], the Nogo-A antibody was taken to clinical trial in patients with chronic spinal cord injury.

The Novartis phase 1 trial of Nogo-A-antibody (ATI355) was recently completed.  The phase 1 trial (ClinicalTrials.gov identifier NCT00406016) was an open-label multicenter study to assess feasibility, safety, and tolerability of continuous infusing five doses of ATI355 intrathecally into patients starting 4-14 days after injury.  Paraplegic and ASIA A tetraplegic patients were included.  Tetraplegic patients who require artificial respiration could receive treatment as late as 60 days after injury, as soon as they were weaned off the respirator.  Patient with complete anatomical transection or obstruction of the spinal canal, multiple spinal cord lesions, cauda equina injury, brachial or lumbar plexus injury, significant head injury and systemic disease were excluded.  A phase 2 trial has started, indicating that the phase 1 trial has shown safety and feasibility.

In summary, the development of the Nogo antibody has taken nearly 2 decades since the initial discovery that that something in myelin inhibits spinal axonal regeneration.  The treatment has been validated in many laboratory studies and completed phase 1, indicating feasibility and safety.  Upcoming phase 2 trials will optimize the therapy and outcome measures, to be followed by pivotal phase 3 studies to show efficacy.

Cethrin

In 2001, Strittmatter et al. [98-107] described the receptor for Nogo.  The receptor, like many others that stop axonal growth and cellular migration, inhibits axonal growth by activating the intracellular messenger rho with rho kinase [108].  The Strittmatter laboratory identified a 66-amino acid fragment of Nogo that blocks the Nogo receptor [109-112] and other Nogo receptor blockers [113-124].  They even showed that MP and Nogo-66 have a synergistic effect on regeneration [125].  Working with Biogen, they subsequently found that the soluble Nogo receptor protein itself tightly bind molecules that inhibit axonal growth [123] and improves recovery after spinal cord contusion [126].

In the meantime, after studies of rho activation patterns in the spinal cord [127], Lisa McKerracher proposed [128] a new approach to target rho to stimulate repair and regeneration after spinal cord injury.  She used the bacterial toxin C3 to inhibit rho, modifying it so that it entered cells.  She formed the company Bioaxone to develop the drug.  The resulting cell-permeable recombinant protein BA-210 prevented secondary damage and promoted function recovery in spinal cord injury [129].  BA-210 or Cethrin subsequently went to phase 1 clinical trial [130, 131].  Bioaxone was recently bought be Alseres Pharmaceuticals (formerly Boston Life Sciences).

The Cethrin trial (ClinicalTrials.gov identifier NCT00500812) was a Phase I/IIa dose-ranging study to evaluate the safety, tolerability, and pharmacokinetics of BA-210 and the neurological status of patients following administration of a single extradural application of Cethrin during surgery for acute thoracic and cervical Spinal Cord Injury.  All the patients were ASIA A (complete).  Carried out from February 2005 to October 2008, the final data collection of the trial will be in June 2009.   The trial compared 0.3, 1, 6, and 9 mg of BA-210 applied to the dura surface of the injured spinal cord, during surgery that exposed the spinal cord for decompression.

Presentations of the Cethrin phase 1 trial results suggest possible beneficial effects of Cethrin in recovery after spinal cord injury [132].  Of 37 patients entered into the trial, they found no serious adverse side effects.  All the patients were ASIA A on admission.  The six-month patient data indicated that 28% of the patients (10 of 36) improved by one or more ASIA grades as compared to reported literature results of 6.7% [133].  Five of the patients improved to ASIA C and two improved to ASIA D.  One patient died form acute respiratory distress syndrome.

A phase 2 trial will start soon to evaluate the safety and efficacy of Cethrin in adult subjects with acute cervical spinal cord injury [134].   The trial is a randomized, double blind, placebo controlled study that will use mean ASIA motor score change as the primary outcome measure.  Six experimental groups will be compared:  placebo, 1 mg, 3 mg, 6 mg, 12 mg, and 18 mg Cethrin.  All the treatments will be applied epidurally during surgery exposing the spinal cord for decompressive or other purposes during the first several weeks after spinal cord injury.

Olfactory Ensheathing Glia (OEG)

The olfactory nerve is the only part in the central nervous system that continuously regenerates in adult mammals.  Its regenerative ability has been attributed to olfactory ensheathing glial (OEG) cells that are born in the nasal mucosa and migrate to the olfactory bulb.  Doucette [135] suggested that OEG cells would facilitate regeneration in other parts of the central nervous system, including the spinal cord.  In 1996, Smale, et al. [136] used OEG cells to repair transected fornix in the rat.  In 1997, Li, et al. [137] used OEG cells to repair adult rat corticospinal tract.  In 1998, Ramon-Cueto, et al. [138] reported that OEG transplants promoted regeneration in transected rat spinal cords.

In 2000, Barnett, et al. [139, 140] reported that human OEG cells can remyelinate axons.  Imaizumi, et al. [141, 142] used pig OEG cells to promote regeneration and remyelination in the spinal cord.  Ramon-Cueto, et al. [143, 144] reported functional regeneration in rats after spinal cord transection.  Many investigators enthused about the promise of OEG cells to bridge the gap in spinal cord injury [145-151].  One company (Alexion) grew OEG from genetically modified pigs as a substitute for human cells.

In 2001, Lu, et al. [152] reported that transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats.  Shortly thereafter, in Portugal, Lima, et al. [153] began transplanting nasal mucosa into patients with chronic spinal cord injury and reported recovery of motor scores, as well as light touch and pinprick scores.  In total he transplanted nasal mucosa to over 160 patients with chronic spinal cord injury.  Several places, including Osaka University Medical School [154], want to continue the study.

In Brisbane, MacKay-Sim, et al. [155] successfully cultivated olfactory ensheathing cells from the nasal mucosa of 3 patients with chronic spinal cord injury and transplanted the cells into their spinal cords,  Compared with 3 patients matched for injury severity and other characteristics, the transplanted patients showed no adverse effects of the transplants. However, they also did not show any significant functional change or neuropathic pain at 3 years after the transplant.

In the largest published series to date, Huang, et al. [156] transplanted OEG isolated from olfactory bulbs of aborted fetuses into 171 patients with chronic spinal cord injury.  The patients showed significant increases in sensory scores but only modest improvements in motor function.  Dobkin, et al. [157] criticized the study, claiming that there were unreported complications and five patients did not show improvements.  Huang has denied these criticisms and published further studies suggesting that OEG transplants are safe and efficacious [158, 159].  He has transplanted OEG into over 1200 patients to date.

In summary, the discovery that OEG cells facilitate regeneration in animal spinal cords excited clinicians. Carlos Lima in Portugal transplanted autologous nasal mucosa into over 160 patients with chronic spinal cord injury with modest results.  McKay-Sim in Brisbane cultured nasal mucosa OEG cells and transplanted them into 3 patients who had no significant beneficial effects after 3 year.  Huang Beijing transplanted fetal OEG cells into more than 700 patients and find that they consistently restore significant sensory.

Human Embryonic Stem (HES) Cells

The 1977 disovery by Thomson, et al. [160] that pluripotent human embryonic stem (HES) cells can be isolated and cultivated indefinitely transformed stem cell research. The first study reporting efficacy of embryonic stem cells for spinal cord injury appeared in 1999 [172].  While several other cell transplants have reported to be beneficial for spinal cord injury, i.e. marrow stromal cells [162], fetal neural stem cells [163], and other cells [164-171], people thought that the only way to get cells for transplantation was to collect them from fetuses, blood, or bone marrow. HES cells can produce many cell types for transplants, including neural stem cells, which in turn can produce neurons, astrocytes, microglia, and oligodendroglia [161].

Geron helped fund the early work leading to the first successful cultivation of HES cells.  Working with Keirstead at UC Irvine [173-177], Geron has concentrated their attention on treating spinal cord injury with oligodendroglial progenitor cells derived from human embryonic stem cells [178-180].  However, after many announcements of clinical trials since 2005 [181], the first phase 1 trial of HES cells has not yet been approved by the FDA.

Many people assumed that the delays are due to opposition by the Bush Administration to clinical trials of HES cells in the United States, including a May 2008 hold by the FDA [182].  Some scientists are concerned that the first clinical trial of HES must be very carefully designed.  As Evan Snyder of the Burnham Institute pointed out, “The last thing we need is another Jesse Gelsinger, referring to the 18-year-old man who died during a gene therapy trial at the University of Pennsylvania in 1999.  After Gelsinger’s death, the FDA closed down many gene-therapy trials for several years.  Because it is the first time that human embryonic stem cells are being transplanted into human, the trial will be under a microscope and any adverse effect will be emphasized [183].

In statements to the public [184], Geron CEO Thomas Okarma has suggested that the company plans to study 40 people with acute spinal cord injury.  The trial will focus on patients who are “complete” (ASIA A) and within the first two weeks after injury.  It is not clear whether and how much immunosuppression will be used.  Geron scientists have reported that oligodendroglial cells differentiated from HES cells are not targets of innate and adaptive human effectors cells and are resistant to lysis by Neu5Gc antibodies [179]. However, Keirstead has suggeted that long-term immunosuppression may be necessary.

In summary, human embryonic stem cells have been the object of much hope and controversy.  Due to their pluripotency, many regard the cells to be a promising source of cells for transplantation.  Geron is one of the first companies to fund research leading to the first successful cultivation of human embryonic stem cells a decade ago.  The cells have not yet reached clinical trial stage. Geron chose to focus on spinal cord injury in their first clinical trials.  However, since 2005, despite repeated announcements, the first phase 1 trials have not yet been approved by the FDA.  The trial will likely study 40 patients with subacute spinal cord injury with oligodendroglial cells differentiated from a human embryonic stem cell line.  A major question is immune rejection of the cells and whether immunosuppression will be used.

Combination Therapies

Combination therapies achieve greater axonal growth than individual therapies [185].  To regenerate the spinal cord, therapies must address the following obstacles to regeneration.

  • Bridging the injury site.  The spinal cord injury site does not support regenerating axons for several reasons.  The injury site is disorganized, filled with inflammatory cells, lacks cellular adhesion molecules to guide axonal growth, and may contain factors the inhibit axonal growth.  Many laboratories are consequently transplanting cells or placing biomaterials to provide a bridge for axonal growth across the injury site.
  • Sustained source of growth factors.  Axons grow slowly, less than a mm a day.  They must grow long distances, as much as a meter, to reach their original targets.  To do so, there must be a sustained source of growth factors. Several neurotrophins, including NGF, NT-3, and GDNF are critical growth factors.  One way is to infuse the factors but a better way may be to stimulate either endogenous or transplanted cells to secrete growth factors.
  • Blocking growth inhibitors. Several factors block axonal growth in the spinal cord.  The best defined is the myelin-based factor Nogo.  Other include extracellular glycoproteins such as CSPG.  The former can be blocked by anti-Nogo-A antibodies, Nogo receptor blockers, rho inhibitors, and even soluble nogo receptor protein.  The latter can be digested by enzymes, including chondroitinase.

Individual therapies are being tested in clinical trials. To test combination therapies, we must have clinical trial networks that can test therapies rigorously and efficiently.  We have set up a clinical trial network to test spinal cord injury therapies in China.  Called the China Spinal Cord Injury Network (ChinaSCINet), this network currently has 25 centers in Mainland China, Hong Kong, and Taiwan, capable of randomizing many thousands of subjects per year.

ChinaSCINet is carrying out the first clinical trials of combination therapies of spinal cord injury, i.e. umbilical cord blood mononuclear cells (UCBMC) and lithium.  Many laboratories have reported beneficial effects of UCBMC on spinal cord injury [165-168, 170, 171, 186-188].  In 2004, Yick, et al. [189] reported that lithium stimulates regeneration in rat spinal cord. Subsequently, Su, et al. [190] found that lithium stimulates proliferation of neural stem cells in the spinal cord and Dill, et al. [191] showed that lithium promotes axon regeneration and recovery in rat spinal cord injury.

Lithium stimulates UCBMC cells to secrete NGF, NT-3, and GNDF and we therefore propose to carry out studies of lithium and UCBMC cells individually, in combination, and then with axonal growth inhibitor blockers such as anti-nogo-A antibody, nogo receptor protein, cethrin, and chondroitinase. UCBMC and lithium are attractive first therapies for clinical trial since both have been extensively used in humans for many years.  If UCBMC are effective, many cord blood banks are available to supply the cells.  Lithium is very low cost and can be taken orally.

Lessons Learned

What lessons have we learned from the above therapies for spinal cord injury?   Three lessons are clear:

  • Slow and Tortuous Process. Few therapies go through the development gauntlet without major hitches. The average time for therapy development exceeded a decade for all therapies described above. For example, development of MP required 13 years (1977 to 1990) from first preclinical discovery to NASCIS 2.  Weight-supported treadmill locomotor training required 14 years (1991-2005).  Fampridine (1987-now) and  Nogo-A antibody (1990-now) both are likely to take over 20 years to develop. The development of Cethrin began in 2003 and may complete clinical trials before 2013. OEG (1997-now) and embryonic stem cells (1997-now) both have taken over a decade already.
  • Rigorous proof-of-concept of treatment efficacy is required for companies, government, or foundations to invest millions of dollars into development of a therapy. In the case of companies, intellectual property protection is also necessary.  A large part of the development time for most of the therapies resulted from a prolonged period of research to establish proof-of-concept.  In certain cases, e.g. MP and locomotor training, the clinical trials and proof-of-concept research in animals proceeded in parallel.  However, both fampridine and nogo antibody therapies went through 10 years of extensive preclinical studies before the drugs was licensed.
  • Clinical Trials are Inherently Risky. A single mistake in clinical trial design can set a program by five or more years.  It is important to have systematic preclinical data before starting clinical trials.  For example, NASCIS 1 compared a ten-day course of 1000 mg/day and 100 mg/day without sufficient animal to indicate the optimal dose or timing of therapy, wasting over 5 years.  A wrong choice of outcome measures, such as the choice of spasticity as the primary outcome of the Fampridine trials added over five years to the development of fampridine for spinal cord injury.  Neither OEG nor HES cells have undergone any controlled clinical trials.

The development times for spinal cord injury therapies may have been particularly long because all of the therapies are the first in their class.  For example, MP was the first neuroprotective drug, weight-supported locomotor training the first major restorative rehabilitation treatment, fampridine was the first conduction enhancing drug, nogo antibody and cethrin are the first regenerative therapies, and OEG and HES transplants are both first of their class. Trailblazing is inherently time-consuming.

Clinical trial networks should reduce treatment development times because much time and expense of clinical trials must be spent on recruiting and train clinical trial centers. Having clinical trial networks that are ready and able to test therapies will not only improve the quality of clinical trials but should speed up and defray costs significantly. This will encourage companies to invest in spinal cord injury therapies.

Probability

How soon can we expect curative therapies of spinal cord injury?  To date, most spinal cord injury therapies have taken 10-20 years to complete clinical trials.  Establishment of clinical trial networks  and increased interest of pharmaceutical companies in spinal cord injury therapies may shorten the development time.  However, until significant new funding becomes available for spinal cord injury clinical trials, the rate of progress in developing therapies is unlikely to change significantly.

Fortunately, we are not starting from scratch and several promising therapies are already in the clinical trial pipeline.  Six of the 8 therapies described above are in or soon will be in clinical trials.  If each therapy has a 50% chance of success, we would have to be rather unlucky for all the trials will fail. In the case of 6 trials, the probability of all six trials failing is 1 in 64.  Clearly, it behooves us to have as many clinical trials going in parallel as possible.  The reason is that if one trial is successful, everybody wins.

The likelihood that a given clinical trial will be successful of course depends on the therapy and the amount of data supporting that particular therapy and clinical trial design.  If one rushes into a clinical trial without much preclinical data, one has a much greater risk of failure.  Since we have limited clinical trial funds and facilities, it would also increase the likelihood of successful clinical trials by focusing on those therapies that have the most supporting data.

The first successful clinical trial that restores function to people with subacute or chronic spinal cord injury will increase enthusiasm and funding for more clinical trials.  If any of the six therapies listed above, or dozens of therapies that are awaiting clinical trials, were to succeed, I believe that companies will begin investing in spinal cord injury therapies.   The first therapy is always the most difficult to get funded and moving.  Many of the therapies would also be the first of their classes, i.e. the first regenerative therapy, the first cell transplant therapy, the first remyelinative therapy.

Two types of clinical trial failures are harmful to the spinal cord injury community, the investigators, and the sponsors.  The first and worst are false negative trials, i.e. a trial that falsely indicates that treatment is ineffective, are particularly deleterious. Such trials may be underpowered, i.e. a trial that does not have enough subjects to establish significance.  It may also happen if the wrong outcome measure is chosen.  The second are inconclusive trials.  Inconclusive trials may result from poor followup and high drop out rates.

Finally, it is important to note that clinical trials that show that a treatment is ineffective are not “failures”.  Showing that a therapy does not work is just as important as showing that a therapy works.  It stops the waste of further time and resources on that particular therapy.  Thus, for example, many people believe that umbilical cord blood cells are beneficial for spinal cord injury.  In fact, several overseas clinics are offering and charging for umbilical cord blood treatment of spinal cord injury as if they have already been proven to be effective.  A rigorously conducted clinical trial that shows it is ineffective will stop wasteful practices.

Summary and Conclusions

Many people frequently ask how long it will take for a cure of spinal cord injury to be available.  In the last two decades, about a dozen therapies have gone to clinical trial.  To illustrate the course of therapy development, I described 8 therapies that have been through or are going into clinical trials for spinal cord injury.

  1. High-dose methylprednisolone (MP) is the first spinal cord injury treatment to be tested in a placebo-controlled randomized clinical trial.
  2. Weight-supported locomotor training is the first rehabilitation therapy that has been shown to restore function after spinal cord injury.
  3. Fampridine (4AP) is the first therapy that improves conduction in demyelinated axons but has not yet been shown to be effective in spinal cord injury.
  4. Nogo antibody is the first therapy shown to regenerate the spinal cord of rats and is currently in phase 2 clinical trials.
  5. Cethrin is a membrane-permeable recombinant bacterial toxin C3 that blocks rho, improves recovery in animals and humans, and is in phase 2 clinical trial.
  6. Olfactory ensheathing glia (OEG)  have been transplanted to >1200 patients with chronic spinal cord injury but has not yet been tested in a controlled trial.
  7. Human embryonic stem (HES) cells have been announced for clinical trial by Geron since 2005 and is still awaiting approval by the U.S. FDA.
  8. Combination therapies.  The China Spinal Cord Injury Network is now testing umbilical cord blood mononuclear cells and lithium alone and in combination.

The history of spinal cord injury therapy development teaches us three important lessons.  First, therapy development is slow and tortuous, with each therapy taking 10 or more years. Second, rigorous proof of concept is required before companies, government, or foundations will invest millions into developing a therapy. Finally, clinical trials are inherently risky.  A single mistake in trial design may set a program back by many years.

Development of curative therapies for spinal cord injury will require large clinical trial networks to test combination therapies systematically.  To regrow large numbers of axons across the injury site, therapies need to bridge the injury site with cells that support growing axons, provide a long-term source of growth factors, and block growth inhibitors in the spinal cord, as well as replace cells. We know that each of these is possible.

The China Spinal Cord Injury Network is beginning clinical trials of the first combination therapy: umbilical cord blood mononuclear cells and lithium.  Several groups had reported that cord blood cells are beneficial in animal models of spinal cord injury. Lithium enhances regeneration in the spinal cord, stimulates proliferation of cord blood cells and neural stem cells, and increases the production of neurotrophic factors.  If this combination is effective, we will add growth inhibitor blockers.

So, how long will it take?  Fortunately, we are not starting from scratch.  Six of the eight therapies described above are already in or will soon be in clinical trials.  Other therapies are achieving proof-of-concept and should reach clinical trial soon.  Even if each of these trials has only a 50% chance of success, the odds ratio that at least one will succeed in the next few years is high.  The time needed to develop curative combination therapies depends on funding and availability of clinical trial network.

References

  1. Savastano AA (1968).  Intrathecal steroid administration in postoperative arachnoiditis.  R I Med J 51: 337-8 passim.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=5240622
  2. Itani AL and Ducker TB (1976).  Effect of high and low doses of steroids on head injuries.  Surg Forum 27: 478-80.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=828324
  3. Ducker TB and Hamit HF (1969).  Experimental treatments of acute spinal cord injury.  J Neurosurg 30: 693-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=5819293
  4. Tator CH (1972).  Acute spinal cord injury: a review of recent studies of treatment and pathophysiology.  Can Med Assoc J 107: 143-5 passim.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=4557525
  5. Bracken MB, Collins WF, Freeman DF, Shepard MJ, Wagner FW, Silten RM, Hellenbrand KG, Ransohoff J, Hunt WE, Perot PL, Jr. and et al. (1984).  Efficacy of methylprednisolone in acute spinal cord injury.  Jama 251: 45-52.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=6361287
  6. Hall ED and Braughler JM (1982).  Effects of intravenous methylprednisolone on spinal cord lipid peroxidation and Na+ + K+)-ATPase activity. Dose-response analysis during 1st hour after contusion injury in the cat.  J Neurosurg 57: 247-53.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=6283042
  7. Young W and Flamm ES (1982).  Effect of high-dose corticosteroid therapy on blood flow, evoked potentials, and extracellular calcium in experimental spinal injury.  J Neurosurg 57: 667-73.  http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=0007131067
  8. Faden AI, Jacobs TP and Holaday JW (1981).  Opiate antagonist improves neurologic recovery after spinal injury.  Science 211: 493-4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7455690
  9. Young W, Flamm ES, Demopoulos HB, Tomasula JJ and DeCrescito V (1981).  Effect of naloxone on posttraumatic ischemia in experimental spinal contusion.  J Neurosurg 55: 209-19.  http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=0007252544
  10. Flamm ES, Young W, Demopoulos HB, DeCrescito V and Tomasula JJ (1982).  Experimental spinal cord injury: treatment with naloxone.  Neurosurgery 10: 227-31.  http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=0007070619
  11. Bracken MB, Shepard MJ, Collins WF, Holford TR, Young W, Baskin DS, Eisenberg HM, Flamm E, Leo-Summers L, Maroon J and et al. (1990).  A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study.  N Engl J Med 322: 1405-11.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2278545
  12. Bracken MB and Holford TR (1993).  Effects of timing of methylprednisolone or naloxone administration on recovery of segmental and long-tract neurological function in NASCIS 2.  J Neurosurg 79: 500-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8410217
  13. Gerhart KA, Johnson RL, Menconi J, Hoffman RE and Lammertse DP (1995).  Utilization and effectiveness of methylprednisolone in a population-based sample of spinal cord injured persons.  Paraplegia 33: 316-21.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7644256
  14. Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings M, Herr DL, Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot PL, Jr., Piepmeier J, Sonntag VK, Wagner F, Wilberger JE, Winn HR and Young W (1997).  Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study.  Jama 277: 1597-604.  http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=0009168289
  15. Bracken MB and Holford TR (2002).  Neurological and functional status 1 year after acute spinal cord injury: estimates of functional recovery in National Acute Spinal Cord Injury Study II from results modeled in National Acute Spinal Cord Injury Study III.  J Neurosurg 96: 259-66.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11990832
  16. Otani K, Abe H, Kadoya S, Nakagawa H, Ikata T and Tominaga S (1996).  Beneficial effect of methylprednisolone sodium succinate in the treatment of acute spinal cord injury.  Sekitsui Sekuzui J. 7: 633-47.
  17. Sun T, Xu S and Huang H (1997).  [High-methylprednisolone treatment in acute cervical spinal cord injury without fracture and dislocation].  Zhonghua Wai Ke Za Zhi 35: 735-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10677995
  18. Pettersson K and Toolanen G (1998).  High-dose methylprednisolone prevents extensive sick leave after whiplash injury. A prospective, randomized, double-blind study.  Spine 23: 984-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9589535
  19. Bracken MB (2001).  Methylprednisolone and acute spinal cord injury: an update of the randomized evidence.  Spine 26: S47-54.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11805609
  20. Araujo AQ, Afonso CR, Leite AC and Dultra SV (1993).  Intravenous methylprednisolone in HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP).  Arq Neuropsiquiatr 51: 325-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8297234
  21. Defresne P, Meyer L, Tardieu M, Scalais E, Nuttin C, De Bont B, Loftus G, Landrieu P, Kadhim H and Sebire G (2001).  Efficacy of high dose steroid therapy in children with severe acute transverse myelitis.  J Neurol Neurosurg Psychiatry 71: 272-4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11459911
  22. Pointillart V, Petitjean ME, Wiart L, Vital JM, Lassie P, Thicoipe M and Dabadie P (2000).  Pharmacological therapy of spinal cord injury during the acute phase.  Spinal Cord 38: 71-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10762178
  23. Galandiuk S, Raque G, Appel S and Polk HC, Jr. (1993).  The two-edged sword of large-dose steroids for spinal cord trauma.  Ann Surg 218: 419-25; discussion 425-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8215634
  24. Prendergast MR, Saxe JM, Ledgerwood AM, Lucas CE and Lucas WF (1994).  Massive steroids do not reduce the zone of injury after penetrating spinal cord injury.  J Trauma 37: 576-9; discussion 579-80.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7932887
  25. George ER, Scholten DJ, Buechler CM, Jordan-Tibbs J, Mattice C and Albrecht RM (1995).  Failure of methylprednisolone to improve the outcome of spinal cord injuries.  Am Surg 61: 659-63; discussion 663-4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7618802
  26. Levy ML, Gans W, Wijesinghe HS, SooHoo WE, Adkins RH and Stillerman CB (1996).  Use of methylprednisolone as an adjunct in the management of patients with penetrating spinal cord injury: outcome analysis.  Neurosurgery 39: 1141-8; discussion 1148-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8938768
  27. Heary RF, Vaccaro AR, Mesa JJ, Northrup BE, Albert TJ, Balderston RA and Cotler JM (1997).  Steroids and gunshot wounds to the spine.  Neurosurgery 41: 576-83; discussion 583-4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9310974
  28. Nesathurai S (1998).  Steroids and spinal cord injury: revisiting the NASCIS 2 and NASCIS 3 trials.  J Trauma 45: 1088-93.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9867054
  29. Coleman WP, Benzel D, Cahill DW, Ducker T, Geisler F, Green B, Gropper MR, Goffin J, Madsen PW, 3rd, Maiman DJ, Ondra SL, Rosner M, Sasso RC, Trost GR and Zeidman S (2000).  A critical appraisal of the reporting of the National Acute Spinal Cord Injury Studies (II and III) of methylprednisolone in acute spinal cord injury.  J Spinal Disord 13: 185-99.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10872756
  30. Hurlbert RJ (2000).  Methylprednisolone for acute spinal cord injury: an inappropriate standard of care.  J Neurosurg 93: 1-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10879751
  31. Short DJ, El Masry WS and Jones PW (2000).  High dose methylprednisolone in the management of acute spinal cord injury – a systematic review from a clinical perspective.  Spinal Cord 38: 273-86.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10822400
  32. Geisler FH, Coleman WP, Grieco G and Poonian D (2001).  Measurements and recovery patterns in a multicenter study of acute spinal cord injury.  Spine 26: S68-86.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11805613
  33. Hurlbert RJ (2001).  The role of steroids in acute spinal cord injury: an evidence-based analysis.  Spine 26: S39-46.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11805608
  34. Citerio G, Cormio M and Sganzerla EP (2002).  [Steroids in acute spinal cord injury. An unproven standard of care].  Minerva Anestesiol 68: 315-20.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12029237
  35. Hugenholtz H, Cass DE, Dvorak MF, Fewer DH, Fox RJ, Izukawa DM, Lexchin J, Tuli S, Bharatwal N and Short C (2002).  High-dose methylprednisolone for acute closed spinal cord injury–only a treatment option.  Can J Neurol Sci 29: 227-35.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12195611
  36. Hurlbert RJ and Moulton R (2002).  Why do you prescribe methylprednisolone for acute spinal cord injury? A Canadian perspective and a position statement.  Can J Neurol Sci 29: 236-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12195612
  37. Wernig A and Muller S (1992).  Laufband locomotion with body weight support improved walking in persons with severe spinal cord injuries.  Paraplegia 30: 229-38.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1625890
  38. Wernig A, Muller S, Nanassy A and Cagol E (1995).  Laufband therapy based on ‘rules of spinal locomotion’ is effective in spinal cord injured persons.  Eur J Neurosci 7: 823-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7620630
  39. Wernig A, Nanassy A and Muller S (1998).  Maintenance of locomotor abilities following Laufband (treadmill) therapy in para- and tetraplegic persons: follow-up studies.  Spinal Cord 36: 744-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9848480
  40. Dobkin B, Barbeau H, Deforge D, Ditunno J, Elashoff R, Apple D, Basso M, Behrman A, Harkema S, Saulino M and Scott M (2007).  The evolution of walking-related outcomes over the first 12 weeks of rehabilitation for incomplete traumatic spinal cord injury: the multicenter randomized Spinal Cord Injury Locomotor Trial.  Neurorehabil Neural Repair 21: 25-35.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17172551
  41. Barbeau H, McCrea DA, O’Donovan MJ, Rossignol S, Grill WM and Lemay MA (1999).  Tapping into spinal circuits to restore motor function.  Brain Res Brain Res Rev 30: 27-51.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10407124
  42. Fouad K, Metz GA, Merkler D, Dietz V and Schwab ME (2000).  Treadmill training in incomplete spinal cord injured rats.  Behav Brain Res 115: 107-13.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10996413
  43. Harkema SJ (2001).  Neural plasticity after human spinal cord injury: application of locomotor training to the rehabilitation of walking.  Neuroscientist 7: 455-68.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11597104
  44. Thota A, Carlson S and Jung R (2001).  Recovery of locomotor function after treadmill training of incomplete spinal cord injured rats.  Biomed Sci Instrum 37: 63-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11347446
  45. Kaegi S, Schwab ME, Dietz V and Fouad K (2002).  Electromyographic activity associated with spontaneous functional recovery after spinal cord injury in rats.  Eur J Neurosci 16: 249-58.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12169107
  46. Barbeau H, Ladouceur M, Mirbagheri MM and Kearney RE (2002).  The effect of locomotor training combined with functional electrical stimulation in chronic spinal cord injured subjects: walking and reflex studies.  Brain Res Brain Res Rev 40: 274-91.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12589926
  47. Hains BC, Everhart AW, Fullwood SD and Hulsebosch CE (2002).  Changes in serotonin, serotonin transporter expression and serotonin denervation supersensitivity: involvement in chronic central pain after spinal hemisection in the rat.  Exp Neurol 175: 347-62.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12061865
  48. Dimitrijevic MR, Persy I, Forstner C, Kern H and Dimitrijevic MM (2005).  Motor control in the human spinal cord.  Artif Organs 29: 216-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15725220
  49. Jankowska E, Lundberg A, Rudomin P and Sykova E (1977).  Effects of 4-aminopyridine on transmission in excitatory and inhibitory synapses in the spinal cord.  Brain Res 136: 387-92.
  50. Bostock H, Sears TA and Sherratt RM (1981).  The effects of 4-aminopyridine and tetraethylammonium ions on normal and demyelinated mammalian nerve fibres.  J Physiol 313: 301-15.
  51. Zangger P (1981).  The effect of 4-aminopyridine on the spinal locomotor rhythm induced by L-DOPA.  Brain Res 215: 211-23.
  52. Eliasson SG, Monafo WW and Meyr D (1986).  Potassium ion channel blockade restores conduction in heat-injured nerve and spinal nerve roots.  Exp Neurol 93: 128-37.
  53. Bowe CM, Kocsis JD, Targ EF and Waxman SG (1987).  Physiological effects of 4-aminopyridine on demyelinated mammalian motor and sensory fibers.  Ann Neurol 22: 264-8.
  54. Blight AR and Gruner JA (1987).  Augmentation by 4-aminopyridine of vestibulospinal free fall responses in chronic spinal-injured cats.  J Neurol Sci 82: 145-59.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2831307
  55. Blight AR, Toombs JP, Bauer MS and Widmer WR (1991).  The effects of 4-aminopyridine on neurological deficits in chronic cases of traumatic spinal cord injury in dogs: a phase I clinical trial.  J Neurotrauma 8: 103-19.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1870134
  56. Hansebout RR, Blight AR, Fawcett S and Reddy K (1993).  4-Aminopyridine in chronic spinal cord injury: a controlled, double-blind, crossover study in eight patients.  J Neurotrauma 10: 1-18.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8320728
  57. Hayes KC, Blight AR, Potter PJ, Allatt RD, Hsieh JT, Wolfe DL, Lam S and Hamilton JT (1993).  Preclinical trial of 4-aminopyridine in patients with chronic spinal cord injury.  Paraplegia 31: 216-24.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8493036
  58. Hayes KC, Potter PJ, Wolfe DL, Hsieh JT, Delaney GA and Blight AR (1994).  4-Aminopyridine-sensitive neurologic deficits in patients with spinal cord injury.  J Neurotrauma 11: 433-46.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7837283
  59. Qiao J, Hayes KC, Hsieh JT, Potter PJ and Delaney GA (1997).  Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury.  J Neurotrauma 14: 135-49.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9104931
  60. Segal JL and Brunnemann SR (1997).  4-Aminopyridine improves pulmonary function in quadriplegic humans with longstanding spinal cord injury.  Pharmacotherapy 17: 415-23.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9165545
  61. Potter PJ, Hayes KC, Hsieh JT, Delaney GA and Segal JL (1998).  Sustained improvements in neurological function in spinal cord injured patients treated with oral 4-aminopyridine: three cases.  Spinal Cord 36: 147-55.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9554012
  62. Shi R and Blight AR (1997).  Differential effects of low and high concentrations of 4-aminopyridine on axonal conduction in normal and injured spinal cord.  Neuroscience 77: 553-62.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9472411
  63. Shi R, Kelly TM and Blight AR (1997).  Conduction block in acute and chronic spinal cord injury: different dose-response characteristics for reversal by 4-aminopyridine.  Exp Neurol 148: 495-501.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9417828
  64. Donovan WH, Halter JA, Graves DE, Blight AR, Calvillo O, McCann MT, Sherwood AM, Castillo T, Parsons KC and Strayer JR (2000).  Intravenous infusion of 4-AP in chronic spinal cord injured subjects.  Spinal Cord 38: 7-15.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10762192
  65. Halter JA, Blight AR, Donovan WH and Calvillo O (2000).  Intrathecal administration of 4-aminopyridine in chronic spinal injured patients.  Spinal Cord 38: 728-32.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11175372
  66. Segal JL, Hayes KC, Brunnemann SR, Hsieh JT, Potter PJ, Pathak MS, Tierney DS and Mason D (2000).  Absorption characteristics of sustained-release 4-aminopyridine (fampridine SR) in patients with chronic spinal cord injury.  J Clin Pharmacol 40: 402-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10761168
  67. Hayes KC, Potter PJ, Hsieh JT, Katz MA, Blight AR and Cohen R (2004).  Pharmacokinetics and safety of multiple oral doses of sustained-release 4-aminopyridine (Fampridine-SR) in subjects with chronic, incomplete spinal cord injury.  Arch Phys Med Rehabil 85: 29-34.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14970964
  68. van der Bruggen MA, Huisman HB, Beckerman H, Bertelsmann FW, Polman CH and Lankhorst GJ (2001).  Randomized trial of 4-aminopyridine in patients with chronic incomplete spinal cord injury.  J Neurol 248: 665-71.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11569894
  69. Wolfe DL, Hayes KC, Hsieh JT and Potter PJ (2001).  Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury: a double-blinded, placebo-controlled crossover trial.  J Neurotrauma 18: 757-71.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11526982
  70. Grijalva I, Guizar-Sahagun G, Castaneda-Hernandez G, Mino D, Maldonado-Julian H, Vidal-Cantu G, Ibarra A, Serra O, Salgado-Ceballos H and Arenas-Hernandez R (2003).  Efficacy and safety of 4-aminopyridine in patients with long-term spinal cord injury: a randomized, double-blind, placebo-controlled trial.  Pharmacotherapy 23: 823-34.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12885095
  71. DeForge D, Nymark J, Lemaire E, Gardner S, Hunt M, Martel L, Curran D and Barbeau H (2004).  Effect of 4-aminopyridine on gait in ambulatory spinal cord injuries: a double-blind, placebo-controlled, crossover trial.  Spinal Cord 42: 674-85.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15356676
  72. Cardenas DD, Ditunno J, Graziani V, Jackson AB, Lammertse D, Potter P, Sipski M, Cohen R and Blight AR (2007).  Phase 2 trial of sustained-release fampridine in chronic spinal cord injury.  Spinal Cord 45: 158-68.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16773037
  73. Hayes KC, Katz MA, Devane JG, Hsieh JT, Wolfe DL, Potter PJ and Blight AR (2003).  Pharmacokinetics of an immediate-release oral formulation of Fampridine (4-aminopyridine) in normal subjects and patients with spinal cord injury.  J Clin Pharmacol 43: 379-85.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12723458
  74. Hayes KC, Potter PJ, Hansebout RR, Bugaresti JM, Hsieh JT, Nicosia S, Katz MA, Blight AR and Cohen R (2003).  Pharmacokinetic studies of single and multiple oral doses of fampridine-SR (sustained-release 4-aminopyridine) in patients with chronic spinal cord injury.  Clin Neuropharmacol 26: 185-92.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12897638
  75. Isoda WC and Segal JL (2003).  Effects of 4-aminopyridine on cardiac repolarization, PR interval, and heart rate in patients with spinal cord injury.  Pharmacotherapy 23: 133-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12587799
  76. Savio T and Schwab ME (1989).  Rat CNS white matter, but not gray matter, is nonpermissive for neuronal cell adhesion and fiber outgrowth.  J Neurosci 9: 1126-33.
  77. Schnell L and Schwab ME (1990).  Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors.  Nature 343: 269-72.  http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=2300171
  78. Aguayo AJ, David S and Bray GM (1981).  Influences of the glial environment on the elongation of axons after injury: transplantation studies in adult rodents.  J Exp Biol 95: 231-40.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7334319
  79. David S and Aguayo AJ (1981).  Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats.  Science 214: 931-3.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=6171034
  80. David S and Aguayo AJ (1985).  Axonal regeneration after crush injury of rat central nervous system fibres innervating peripheral nerve grafts.  J Neurocytol 14: 1-12.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=4009210
  81. Brosamle C, Huber AB, Fiedler M, Skerra A and Schwab ME (2000).  Regeneration of lesioned corticospinal tract fibers in the adult rat induced by a recombinant, humanized IN-1 antibody fragment.  J Neurosci 20: 8061-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11050127
  82. Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F and Schwab ME (2000).  Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1.  Nature 403: 434-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10667796
  83. Huber AB and Schwab ME (2000).  Nogo-A, a potent inhibitor of neurite outgrowth and regeneration.  Biol Chem 381: 407-19.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10937871
  84. Fouad K, Dietz V and Schwab ME (2001).  Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors.  Brain Res Brain Res Rev 36: 204-12.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11690617
  85. Merkler D, Metz GA, Raineteau O, Dietz V, Schwab ME and Fouad K (2001).  Locomotor recovery in spinal cord-injured rats treated with an antibody neutralizing the myelin-associated neurite growth inhibitor Nogo-A.  J Neurosci 21: 3665-73.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11331396
  86. Bareyre FM, Haudenschild B and Schwab ME (2002).  Long-lasting sprouting and gene expression changes induced by the monoclonal antibody IN-1 in the adult spinal cord.  J Neurosci 22: 7097-110.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12177206
  87. Huang DW, McKerracher L, Braun PE and David S (1999).  A therapeutic vaccine approach to stimulate axon regeneration in the adult mammalian spinal cord.  Neuron 24: 639-47.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10595515
  88. Merkler D, Oertle T, Buss A, Pinschewer DD, Schnell L, Bareyre FM, Kerschensteiner M, Buddeberg BS and Schwab ME (2003).  Rapid induction of autoantibodies against Nogo-A and MOG in the absence of an encephalitogenic T cell response: implication for immunotherapeutic approaches in neurological diseases.  Faseb J 17: 2275-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14563689
  89. Bourquin C, van der Haar ME, Anz D, Sandholzer N, Neumaier I, Endres S, Skerra A, Schwab ME and Linington C (2008).  DNA vaccination efficiently induces antibodies to Nogo-A and does not exacerbate experimental autoimmune encephalomyelitis.  Eur J Pharmacol 588: 99-105.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18495110
  90. Wiessner C, Bareyre FM, Allegrini PR, Mir AK, Frentzel S, Zurini M, Schnell L, Oertle T and Schwab ME (2003).  Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats.  J Cereb Blood Flow Metab 23: 154-65.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12571447
  91. Fouad K, Klusman I and Schwab ME (2004).  Regenerating corticospinal fibers in the Marmoset (Callitrix jacchus) after spinal cord lesion and treatment with the anti-Nogo-A antibody IN-1.  Eur J Neurosci 20: 2479-82.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15525289
  92. Schwab ME (2004).  Nogo and axon regeneration.  Curr Opin Neurobiol 14: 118-24.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15018947
  93. Buchli AD and Schwab ME (2005).  Inhibition of Nogo: a key strategy to increase regeneration, plasticity and functional recovery of the lesioned central nervous system.  Ann Med 37: 556-67.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16338758
  94. Liebscher T, Schnell L, Schnell D, Scholl J, Schneider R, Gullo M, Fouad K, Mir A, Rausch M, Kindler D, Hamers FP and Schwab ME (2005).  Nogo-A antibody improves regeneration and locomotion of spinal cord-injured rats.  Ann Neurol 58: 706-19.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16173073
  95. Weinmann O, Schnell L, Ghosh A, Montani L, Wiessner C, Wannier T, Rouiller E, Mir A and Schwab ME (2006).  Intrathecally infused antibodies against Nogo-A penetrate the CNS and downregulate the endogenous neurite growth inhibitor Nogo-A.  Mol Cell Neurosci 32: 161-73.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16697217
  96. Freund P, Wannier T, Schmidlin E, Bloch J, Mir A, Schwab ME and Rouiller EM (2007).  Anti-Nogo-A antibody treatment enhances sprouting of corticospinal axons rostral to a unilateral cervical spinal cord lesion in adult macaque monkey.  J Comp Neurol 502: 644-59.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17394135
  97. Mullner A, Gonzenbach RR, Weinmann O, Schnell L, Liebscher T and Schwab ME (2008).  Lamina-specific restoration of serotonergic projections after Nogo-A antibody treatment of spinal cord injury in rats.  Eur J Neurosci 27: 326-33.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18215231
  98. GrandPre T, Nakamura F, Vartanian T and Strittmatter SM (2000).  Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein.  Nature 403: 439-44.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10667797
  99. Fournier AE, GrandPre T and Strittmatter SM (2001).  Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration.  Nature 409: 341-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11201742
  100. Fournier AE and Strittmatter SM (2001).  Repulsive factors and axon regeneration in the CNS.  Curr Opin Neurobiol 11: 89-94.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11179877
  101. Fournier AE, Gould GC, Liu BP and Strittmatter SM (2002).  Truncated soluble Nogo receptor binds Nogo-66 and blocks inhibition of axon growth by myelin.  J Neurosci 22: 8876-83.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12388594
  102. Fournier AE, GrandPre T, Gould G, Wang X and Strittmatter SM (2002).  Nogo and the Nogo-66 receptor.  Prog Brain Res 137: 361-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12440378
  103. GrandPre T, Li S and Strittmatter SM (2002).  Nogo-66 receptor antagonist peptide promotes axonal regeneration.  Nature 417: 547-51.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12037567
  104. Liu BP, Fournier A, GrandPre T and Strittmatter SM (2002).  Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor.  Science 297: 1190-3.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12089450
  105. Strittmatter SM (2002).  Modulation of axonal regeneration in neurodegenerative disease: focus on Nogo.  J Mol Neurosci 19: 117-21.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12212768
  106. Wang X, Chun SJ, Treloar H, Vartanian T, Greer CA and Strittmatter SM (2002).  Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon-myelin and synaptic contact.  J Neurosci 22: 5505-15.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12097502
  107. Barton WA, Liu BP, Tzvetkova D, Jeffrey PD, Fournier AE, Sah D, Cate R, Strittmatter SM and Nikolov DB (2003).  Structure and axon outgrowth inhibitor binding of the Nogo-66 receptor and related proteins.  Embo J 22: 3291-302.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12839991
  108. Fournier AE, Takizawa BT and Strittmatter SM (2003).  Rho kinase inhibition enhances axonal regeneration in the injured CNS.  J Neurosci 23: 1416-23.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12598630
  109. Kim JE, Li S, GrandPre T, Qiu D and Strittmatter SM (2003).  Axon regeneration in young adult mice lacking Nogo-A/B.  Neuron 38: 187-99.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12718854
  110. Lee DH, Strittmatter SM and Sah DW (2003).  Targeting the Nogo receptor to treat central nervous system injuries.  Nat Rev Drug Discov 2: 872-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14668808
  111. Li S and Strittmatter SM (2003).  Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury.  J Neurosci 23: 4219-27.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12764110
  112. McGee AW and Strittmatter SM (2003).  The Nogo-66 receptor: focusing myelin inhibition of axon regeneration.  Trends Neurosci 26: 193-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12689770
  113. Hu F and Strittmatter SM (2004).  Regulating axon growth within the postnatal central nervous system.  Semin Perinatol 28: 371-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15693393
  114. Kim JE, Liu BP, Park JH and Strittmatter SM (2004).  Nogo-66 receptor prevents raphespinal and rubrospinal axon regeneration and limits functional recovery from spinal cord injury.  Neuron 44: 439-51.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15504325
  115. Lee JK, Kim JE, Sivula M and Strittmatter SM (2004).  Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity.  J Neurosci 24: 6209-17.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15240813
  116. Li S, Liu BP, Budel S, Li M, Ji B, Walus L, Li W, Jirik A, Rabacchi S, Choi E, Worley D, Sah DW, Pepinsky B, Lee D, Relton J and Strittmatter SM (2004).  Blockade of Nogo-66, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein by soluble Nogo-66 receptor promotes axonal sprouting and recovery after spinal injury.  J Neurosci 24: 10511-20.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15548666
  117. Li W, Walus L, Rabacchi SA, Jirik A, Chang E, Schauer J, Zheng BH, Benedetti NJ, Liu BP, Choi E, Worley D, Silvian L, Mo W, Mullen C, Yang W, Strittmatter SM, Sah DW, Pepinsky B and Lee DH (2004).  A neutralizing anti-Nogo66 receptor monoclonal antibody reverses inhibition of neurite outgrowth by central nervous system myelin.  J Biol Chem 279: 43780-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15297463
  118. Hu F, Liu BP, Budel S, Liao J, Chin J, Fournier A and Strittmatter SM (2005).  Nogo-A interacts with the Nogo-66 receptor through multiple sites to create an isoform-selective subnanomolar agonist.  J Neurosci 25: 5298-304.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15930377
  119. Li S, Kim JE, Budel S, Hampton TG and Strittmatter SM (2005).  Transgenic inhibition of Nogo-66 receptor function allows axonal sprouting and improved locomotion after spinal injury.  Mol Cell Neurosci 29: 26-39.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15866044
  120. McGee AW, Yang Y, Fischer QS, Daw NW and Strittmatter SM (2005).  Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor.  Science 309: 2222-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16195464
  121. Cafferty WB and Strittmatter SM (2006).  The Nogo-Nogo receptor pathway limits a spectrum of adult CNS axonal growth.  J Neurosci 26: 12242-50.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17122049
  122. Marklund N, Fulp CT, Shimizu S, Puri R, McMillan A, Strittmatter SM and McIntosh TK (2006).  Selective temporal and regional alterations of Nogo-A and small proline-rich repeat protein 1A (SPRR1A) but not Nogo-66 receptor (NgR) occur following traumatic brain injury in the rat.  Exp Neurol 197: 70-83.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16321384
  123. Lauren J, Hu F, Chin J, Liao J, Airaksinen MS and Strittmatter SM (2007).  Characterization of myelin ligand complexes with neuronal Nogo-66 receptor family members.  J Biol Chem 282: 5715-25.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17189258
  124. Hu F and Strittmatter SM (2008).  The N-terminal domain of Nogo-A inhibits cell adhesion and axonal outgrowth by an integrin-specific mechanism.  J Neurosci 28: 1262-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18234903
  125. Ji B, Li M, Budel S, Pepinsky RB, Walus L, Engber TM, Strittmatter SM and Relton JK (2005).  Effect of combined treatment with methylprednisolone and soluble Nogo-66 receptor after rat spinal cord injury.  Eur J Neurosci 22: 587-94.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16101740
  126. Wang X, Baughman KW, Basso DM and Strittmatter SM (2006).  Delayed Nogo receptor therapy improves recovery from spinal cord contusion.  Ann Neurol 60: 540-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16958113
  127. Dubreuil CI, Winton MJ and McKerracher L (2003).  Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system.  J Cell Biol 162: 233-43.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12860969
  128. McKerracher L and Higuchi H (2006).  Targeting Rho to stimulate repair after spinal cord injury.  J Neurotrauma 23: 309-17.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16629618
  129. 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.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19061375
  130. Pitts C (2005).  Data Safety Monitoring Board recommends continuation of BioAxone’s phase I/IIa clinical trial with its lead product Cethrin (R) (BA-210) in acute spinal cord injury.   http://www.newswire.ca/en/releases/archive/June2005/06/c8025.html
  131. Baptiste DC and Fehlings MG (2007).  Update on the treatment of spinal cord injury.  Prog Brain Res 161: 217-33.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17618980
  132. Anonymous (2007).  Boston Life Sciences, Inc. Announces Presentation of Cethrin Phase I/IIa 6-Month Results at 75th Annual Meeting of the American Association of Neurological Surgeons.   http://www.bio-medicine.org/medicine-technology/Boston-Life-Sciences–Inc–Announces-Presentation-of-Cethrin-Phase-0AI-IIa-6-Month-Results-at-75th-Annual-Meeting-of-the-American-0AAssociation-of-Neu-996-2/
  133. Burns AS, Lee BS, Ditunno JF, Jr. and Tessler A (2003).  Patient selection for clinical trials: the reliability of the early spinal cord injury examination.  J Neurotrauma 20: 477-82.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12803979
  134. Baptiste DC and Fehlings MG (2006).  Pharmacological approaches to repair the injured spinal cord.  J Neurotrauma 23: 318-34.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16629619
  135. Doucette R (1995).  Olfactory ensheathing cells: potential for glial cell transplantation into areas of CNS injury.  Histol Histopathol 10: 503-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7599444
  136. Smale KA, Doucette R and Kawaja MD (1996).  Implantation of olfactory ensheathing cells in the adult rat brain following fimbria-fornix transection.  Exp Neurol 137: 225-33.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8635537
  137. Li Y, Field PM and Raisman G (1997).  Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells.  Science 277: 2000-2.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9302296
  138. Ramon-Cueto A, Plant GW, Avila J and Bunge MB (1998).  Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants.  J Neurosci 18: 3803-15.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9570810
  139. Barnett SC, Alexander CL, Iwashita Y, Gilson JM, Crowther J, Clark L, Dunn LT, Papanastassiou V, Kennedy PG and Franklin RJ (2000).  Identification of a human olfactory ensheathing cell that can effect transplant-mediated remyelination of demyelinated CNS axons.  Brain 123 ( Pt 8): 1581-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10908188
  140. Smith PM, Sim FJ, Barnett SC and Franklin RJ (2001).  SCIP/Oct-6, Krox-20, and desert hedgehog mRNA expression during CNS remyelination by transplanted olfactory ensheathing cells.  Glia 36: 342-53.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11746771
  141. Imaizumi T, Lankford KL, Burton WV, Fodor WL and Kocsis JD (2000).  Xenotransplantation of transgenic pig olfactory ensheathing cells promotes axonal regeneration in rat spinal cord.  Nat Biotechnol 18: 949-53.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10973214
  142. Imaizumi T, Lankford KL and Kocsis JD (2000).  Transplantation of olfactory ensheathing cells or Schwann cells restores rapid and secure conduction across the transected spinal cord.  Brain Res 854: 70-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10784108
  143. Ramon-Cueto A (2000).  Olfactory ensheathing glia transplantation into the injured spinal cord.  Prog Brain Res 128: 265-72.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11105686
  144. Ramon-Cueto A, Cordero MI, Santos-Benito FF and Avila J (2000).  Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia.  Neuron 25: 425-35.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10719896
  145. Bartolomei JC and Greer CA (2000).  Olfactory ensheathing cells: bridging the gap in spinal cord injury.  Neurosurgery 47: 1057-69.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11063098
  146. Franklin RJ and Barnett SC (2000).  Olfactory ensheathing cells and CNS regeneration: the sweet smell of success?  Neuron 28: 15-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11086978
  147. Bunge MB (2001).  Bridging areas of injury in the spinal cord.  Neuroscientist 7: 325-39.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11488398
  148. Kwon BK and Tetzlaff W (2001).  Spinal cord regeneration: from gene to transplants.  Spine 26: S13-22.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11805602
  149. Raisman G (2001).  Olfactory ensheathing cells – another miracle cure for spinal cord injury?  Nat Rev Neurosci 2: 369-75.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11331921
  150. Ramon-Cueto A and Santos-Benito FF (2001).  Cell therapy to repair injured spinal cords: olfactory ensheathing glia transplantation.  Restor Neurol Neurosci 19: 149-56.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12082235
  151. Treloar HB, Bartolomei JC, Lipscomb BW and Greer CA (2001).  Mechanisms of axonal plasticity: lessons from the olfactory pathway.  Neuroscientist 7: 55-63.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11486344
  152. Lu J, Feron F, Ho SM, Mackay-Sim A and Waite PM (2001).  Transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats.  Brain Res 889: 344-57.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11166728
  153. Lima C, Pratas-Vital J, Escada P, Hasse-Ferreira A, Capucho C and Peduzzi JD (2006).  Olfactory mucosa autografts in human spinal cord injury: a pilot clinical study.  J Spinal Cord Med 29: 191-203; discussion 204-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16859223
  154. Iwatsuki K, Yoshimine T, Kishima H, Aoki M, Yoshimura K, Ishihara M, Ohnishi Y and Lima C (2008).  Transplantation of olfactory mucosa following spinal cord injury promotes recovery in rats.  Neuroreport 19: 1249-52.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18695502
  155. Mackay-Sim A, Feron F, Cochrane J, Bassingthwaighte L, Bayliss C, Davies W, Fronek P, Gray C, Kerr G, Licina P, Nowitzke A, Perry C, Silburn PA, Urquhart S and Geraghty T (2008).  Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial.  Brain 131: 2376-86.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18689435
  156. Huang H, Chen L, Wang H, Xiu B, Li B, Wang R, Zhang J, Zhang F, Gu Z, Li Y, Song Y, Hao W, Pang S and Sun J (2003).  Influence of patients’ age on functional recovery after transplantation of olfactory ensheathing cells into injured spinal cord injury.  Chin Med J (Engl) 116: 1488-91.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14570607
  157. Dobkin BH, Curt A and Guest J (2006).  Cellular transplants in China: observational study from the largest human experiment in chronic spinal cord injury.  Neurorehabil Neural Repair 20: 5-13.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16467274
  158. Huang H, Chen L, Wang H, Xi H, Gou C, Zhang J, Zhang F and Liu Y (2006).  Safety of fetal olfactory ensheathing cell transplantation in patients with chronic spinal cord injury. A 38-month follow-up with MRI.  Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 20: 439-43.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16683452
  159. Huang H, Wang H, Chen L, Gu Z, Zhang J, Zhang F, Song Y, Li Y, Tan K, Liu Y and Xi H (2006).  Influence factors for functional improvement after olfactory ensheathing cell transplantation for chronic spinal cord injury.  Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 20: 434-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16683451
  160. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS and Jones JM (1998).  Embryonic stem cell lines derived from human blastocysts.  Science 282: 1145-7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9804556
  161. McDonald JW, Liu XZ, Qu Y, Liu S, Mickey SK, Turetsky D, Gottlieb DI and Choi DW (1999).  Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord.  Nat Med 5: 1410-2.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10581084
  162. Dezawa M, Hoshino M, Nabeshima Y and Ide C (2005).  Marrow stromal cells: implications in health and disease in the nervous system.  Curr Mol Med 5: 723-32.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16305495
  163. Weible MW, 2nd and Chan-Ling T (2007).  Phenotypic characterization of neural stem cells from human fetal spinal cord: synergistic effect of LIF and BMP4 to generate astrocytes.  Glia 55: 1156-68.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17597119
  164. Saporta S, Kim JJ, Willing AE, Fu ES, Davis CD and Sanberg PR (2003).  Human umbilical cord blood stem cells infusion in spinal cord injury: engraftment and beneficial influence on behavior.  J Hematother Stem Cell Res 12: 271-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12857368
  165. Zhao ZM, Li HJ, Liu HY, Lu SH, Yang RC, Zhang QJ and Han ZC (2004).  Intraspinal transplantation of CD34+ human umbilical cord blood cells after spinal cord hemisection injury improves functional recovery in adult rats.  Cell Transplant 13: 113-22.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15129757
  166. Kuh SU, Cho YE, Yoon DH, Kim KN and Ha Y (2005).  Functional recovery after human umbilical cord blood cells transplantation with brain-derived neutrophic factor into the spinal cord injured rat.  Acta Neurochir (Wien) 147: 985-92.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16010451
  167. Nishio Y, Koda M, Kamada T, Someya Y, Yoshinaga K, Okada S, Harada H, Okawa A, Moriya H and Yamazaki M (2006).  The use of hemopoietic stem cells derived from human umbilical cord blood to promote restoration of spinal cord tissue and recovery of hindlimb function in adult rats.  J Neurosurg Spine 5: 424-33.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17120892
  168. Dasari VR, Spomar DG, Gondi CS, Sloffer CA, Saving KL, Gujrati M, Rao JS and Dinh DH (2007).  Axonal remyelination by cord blood stem cells after spinal cord injury.  J Neurotrauma 24: 391-410.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17376002
  169. Lim JH, Byeon YE, Ryu HH, Jeong YH, Lee YW, Kim WH, Kang KS and Kweon OK (2007).  Transplantation of canine umbilical cord blood-derived mesenchymal stem cells in experimentally induced spinal cord injured dogs.  J Vet Sci 8: 275-82.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17679775
  170. Chen CT, Foo NH, Liu WS and Chen SH (2008).  Infusion of human umbilical cord blood cells ameliorates hind limb dysfunction in experimental spinal cord injury through anti-inflammatory, vasculogenic and neurotrophic mechanisms.  Pediatr neonatol 49: 77-83.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18947003
  171. Cho SR, Yang MS, Yim SH, Park JH, Lee JE, Eom YW, Jang IK, Kim HE, Park JS, Kim HO, Lee BH, Park CI and Kim YJ (2008).  Neurally induced umbilical cord blood cells modestly repair injured spinal cords.  Neuroreport 19: 1259-63.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18695504
  172. Gage FH (2000).  Mammalian neural stem cells.  Science 287: 1433-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10688783
  173. Faulkner J and Keirstead HS (2005).  Human embryonic stem cell-derived oligodendrocyte progenitors for the treatment of spinal cord injury.  Transpl Immunol 15: 131-42.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16412957
  174. Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K and Steward O (2005).  Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury.  J Neurosci 25: 4694-705.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15888645
  175. Nistor GI, Totoiu MO, Haque N, Carpenter MK and Keirstead HS (2005).  Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation.  Glia 49: 385-96.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15538751
  176. Cloutier F, Siegenthaler MM, Nistor G and Keirstead HS (2006).  Transplantation of human embryonic stem cell-derived oligodendrocyte progenitors into rat spinal cord injuries does not cause harm.  Regen Med 1: 469-79.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17465839
  177. Coutts M and Keirstead HS (2008).  Stem cells for the treatment of spinal cord injury.  Exp Neurol 209: 368-77.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17950280
  178. Zhang YW, Denham J and Thies RS (2006).  Oligodendrocyte progenitor cells derived from human embryonic stem cells express neurotrophic factors.  Stem Cells Dev 15: 943-52.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17253955
  179. Okamura RM, Lebkowski J, Au M, Priest CA, Denham J and Majumdar AS (2007).  Immunological properties of human embryonic stem cell-derived oligodendrocyte progenitor cells.  J Neuroimmunol 192: 134-44.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17996308
  180. Puceat M and Ballis A (2007).  Embryonic stem cells: from bench to bedside.  Clin Pharmacol Ther 82: 337-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17637781
  181. Keim B (2007).  The Company Who Cried Clinical Trial: Geron’s Unfulfilled Stem Cell Promises.  blog.wired.com.  http://blog.wired.com/wiredscience/2007/07/the-company-who.html
  182. Anonymous (2008).  FDA’s delay of Geron ESC trial raises concerns.  {May 15, 2008.  http://www.fiercebiotech.com/story/fda-s-delay-of-geron-esc-trial-raises-concerns/2008-05-15?utm_medium=rss&utm_source=rss&cmp-id=OTC-RSS-FB0
  183. Philipkoski K (2005).  Race to Human Stem-Cell Trials.  Wired Magazine.  http://www.wired.com/medtech/health/news/2005/04/67266
  184. Smith A (2008).  Human stem cell tests could be near.  CNNMoney.com.  http://money.cnn.com/2008/02/11/news/companies/geron/index.htm?postversion=2008021212
  185. Lu P and Tuszynski MH (2008).  Growth factors and combinatorial therapies for CNS regeneration.  Exp Neurol 209: 313-20.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17927983
  186. Kao CH, Chen SH, Chio CC and Lin MT (2008).  Human umbilical cord blood-derived CD34+ cells may attenuate spinal cord injury by stimulating vascular endothelial and neurotrophic factors.  Shock 29: 49-55.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17666954
  187. Dasari VR, Spomar DG, Li L, Gujrati M, Rao JS and Dinh DH (2008).  Umbilical cord blood stem cell mediated downregulation of fas improves functional recovery of rats after spinal cord injury.  Neurochem Res 33: 134-49.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17703359
  188. Kang KS, Kim SW, Oh YH, Yu JW, Kim KY, Park HK, Song CH and Han H (2005).  A 37-year-old spinal cord-injured female patient, transplanted of multipotent stem cells from human UC blood, with improved sensory perception and mobility, both functionally and morphologically: a case study.  Cytotherapy 7: 368-73.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16162459
  189. Yick LW, So KF, Cheung PT and Wu WT (2004).  Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury.  J Neurotrauma 21: 932-43.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15307905
  190. Su H, Chu TH and Wu W (2007).  Lithium enhances proliferation and neuronal differentiation of neural progenitor cells in vitro and after transplantation into the adult rat spinal cord.  Exp Neurol 206: 296-307.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17599835
  191. Dill J, Wang H, Zhou F and Li S (2008).  Inactivation of glycogen synthase kinase 3 promotes axonal growth and recovery in the CNS.  J Neurosci 28: 8914-28.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18768685
Advertisements

11 Responses to “FAQ #2: When will the Cure be Available for Spinal Cord Injury?”

  1. Christopher Says:

    Great Work Dr. Wise

  2. Sue Says:

    Under HESC section might change 1977 to 1997. 🙂 And 14 years for bench to bedside for locomotor training? As the song goes “only in America”..

  3. John E. Smith Says:

    Dr. Young;

    My admiration for your dogged pursuit of a cure for SCI is boundless. You have empowered an entire generation of the SCI community. You give hope to those of living the life, both patients and family. It is not false hope based on empty promises. Rather, it is the hope of information gleaned from educating us about the science, the politics, and the spirit of human endeavor.

    Thank you.

    Many blessings for the New Year! 🙂

  4. Wise Young Says:

    John, thank you. Your admiration mean a great deal to me and I want to say that I reciprocate a profound sense of gratitude for your writing (http://www.theothersideofbroken.com/). In my opinion, you have found your true vocation.

    As you know, I have been wanting to update and expand the FAQ post that I made two years ago. It was also an opportunity to set a base for the new Spinal Cord Injury Wiki that we setting up in CareCure. One of my students is translating these articles into Chinese and we hope to establish the Wiki into two language.

    The past year has been an epiphany for me. Coupled with the recession, I have realized that we can’t wait for others to do it for us. We need to do it for ourselves.

    Wise.

  5. Spinal Injury Resources and help. | Spinal Cord Injuries Says:

    […] FAQ #2: When will the Cure be Available for Spinal Cord Injury … […]

  6. Kataweb.it - Blog - diariotip » Blog Archive » Wise Young. Says:

    […] Rif.: wiseyoung.wordpress […]

  7. Kataweb.it - Blog - diariotip » Blog Archive » Wise Young 2. Says:

    […] Rif.: wiseyoung.wordpress […]

  8. Kataweb.it - Blog - diariotip » Blog Archive » Wise Young 3. Says:

    […] Rif.: wiseyoung.wordpress […]

  9. 7 Diet Secrets of the Stars | Health JaneSeek Says:

    […] FAQ #2: When will the Cure be Available for Spinal Cord Injury? […]

  10. Daniel Says:

    Wise, your articles are always such a delight and such an education for me. Thank you for your commitment to the progress in the field of spinal cord injury research. Your work has propelled us.

  11. Mike Kadmiry Says:

    Mr young, would you recommend bone marrow stem cell injections in a spinal cord injury or no. If no what should i do with all honesty? What does it need to be done to gain back all muscle functions, full recovery? With all my respect, Please be very franc with me!

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s


%d bloggers like this: