Dr. McDonald

[Red_1 Canada]

Are they at the point yet were they are looking for participants?

Have they drawn up a criteria yet?

I am two years post complete T-10 with all spasms and reflexes including tactile erections,
almost all freaking day.
I think I would be a good candidate for a trial, the lesser the injury the better the results, ie. no lower motor neuron damage.

[sbdspray]

things are beginning to look promising for those select few whose injuries are incomplete and white matter based at he low cervical level. Complete paralysis in and around the Lumbosacral spinal cord is untreatable in the long run. Those neurons in this area are a part of the local pattern generator, equaling the complexity of neural pathways promoting conciousness in the brain. Even partial restoration of senseation, sexuality, bowel, etc. is unlikely at the best. No one on this site or any scientist can refute these ugly facts. This is emphasized by the head neurosciencists at Yale. some things will never be solved, at least in the next 100 years.

sherman brayton

[david65]

I really don't think that low injuries will not heal themselves once the scar is inhibited. The human body is too advanced and can heal itself except for the scar. So keep looking up because you will soon be there also.


David

[Schmeky]

hope2findacure,

Do you know what levels McDonald has had experience with? Do you know if he plans to publish his results anytime soon?

Thanx

[member412678]

Red 1 Canada,
The key to getting to the human trials is money. He needs the funding. We donated because we believe in this project. The SCI community needs to pull together on this one. We asked him if he had the money that he needed, when would human trials begin...he indicated he thought he could be ready to start some time in 2004. That's this year! This is what we've all wanted. If he gets the funding then I guess he'll decide what the criteria is.

Brayton,
You have to start somewhere.

Schmeky,
I know you are up on the latest research... As I'm sure you're aware, there was a phase I clinical trial done in humans with xenotransplantation, the transplantation of stem cells from embryonic sources of pigs. This publication should be out this spring, or early summer. They are waiting for the last patient that had the procedure to reach the 2 year post surgery mark. All I know is that these were all chronic injuries...I don't know anything else about their injuries, or levels.

It should be noted that he's working on two things in this project:
1. The delivery method for the cells. The phase I clinical trial was done with a traditional invasive surgery. He is working on delivering the cells in a sort of epidural like injection into the spinal cord above and below the injury...as an outpatient, one day deal.

2. Somatic Nuclear Transfer of your own DNA into embryonic stem cells to replace the xenotransplantation. He's not going to be using pig cells. He said something about getting tissue from your nervous system and taking the nucleus out and putting it into the stem cell. Stem cell lines are available from private sources...as you know the ones approved by President Bush are contaminated by mouse feeder cells and other such problems. This procedure differs from other transplants in that the cells he will be transplanting will be cells that actually belong within the spinal cord.

Most of this we discussed with him in the first conversation, but we feel like we have alot better understanding of it after talking to him a second time.

[Sue Maus]

Thanks for your persistence, Hope. This is awesome. I've followed Dr. McDonalds work for quite some time. I believe in it and him.

Regards,
Sue

[berny]

Hope2, I live in Colombia, i´m trying to find out about Dr Mc Donalds work here, so i want to help in everything they need, but nobody says nothing clear about it, can you lead me to someone to talk about it?

Thanks.



Berny.

[vgrafen]

With all due respect, Schmecky and Brayton, I am heartened by the knowledge that the black opinions you two share are simply quite understandable reflex/coping mechanisms and in no way reflect what is actually going on in SCI research.

In other words, gentlemen, you're full of it.

vgrafen

[judykerperien]

Dr. Wise, Do you have any infomation on what is going on with this reserch and where we can find more infomation on it. Thanks

[sbdspray]

vgrafen-

I am tellin' ya that I was told that Lumbosacral sci's that cause complete paralysis may very well be immune to any upcoming therapies. I spoke to the head of neurology at Yale while he was in London last week at a neurotrauma/ rapairing CNS injuries summit of some sort. I do understand that this is only one man's opinion, but he is in the forefront of researching SCI therapies. Believe me, I felt as if I had been punchd in the stomach when he told me this.

sherman brayton

[Schmeky]

V,

Some things I have been called. . . .you're comment is a compliment!! Not trying to sow seeds of gloom, but to actually get back on my feet seems far away based on current research. It's a loooong way from the lab to the common person.

Yes, things are happening, thank God, but there ain't no trial money in the US. Most people view a cure like a light switch; it's more like a rheostat.

[Wise Young]

judy, the work that I was referring to concerning stem cell transplants in mice with ALS was done by John Gearhart at Johns Hopkins. Is that what you were asking for? Or were you asking for John McDonald's research? If you do a google search for John Gearhart and stem cells, you will see a number of press reports. wise.

[sbdspray]

let's be reasonable and realistic here. Other than incomplete quad's, most of us ARE NEVER going to walk again! There are exceptions, don't get me wrong, but realisitcally walking is just as much over as the first day in the ER. I just pray and donate $ in the hopes of restoration of bowel, bladder, and most of all sexual function. The more established, respected researchers I seem to get in direct contact with, the more skeptical they are of any type of "cure".

sherman brayton

[judykerperien]

It was John McDonalds research I was asking about Dr. Wise.

[Wise Young]

judy, here are some recent abstracts. In the late 1990's, Dr. McDonald published two seminal papers reporting beneficial effects of transplanting mouse embryonic stem cells into rats and mice with spinal cord injury. Wise.

• Becker D, Sadowsky CL and McDonald JW (2003). Restoring function after spinal cord injury. Neurologist. 9: 1-15. Department of Neurology, Spinal Cord Injury Neuro-Rehabilitation Section, Restorative Treatment and Research Program, Washington University School of Medicine, St Louis, Missouri 63108, USA. BACKGROUND: By affecting young people during the most productive period of their lives, spinal cord injury is a devastating problem for modern society. A decade ago, treating SCI seemed frustrating and hopeless because of the tremendous morbidity and mortality, life-shattering impact, and limited therapeutic options associated with the condition. Today, however, an understanding of the underlying pathophysiological mechanisms, the development of neuroprotective interventions, and progress toward regenerative interventions are increasing hope for functional restoration. REVIEW SUMMARY: This study addresses the present understanding of SCI, including the etiology, pathophysiology, treatment, and scientific advances. The discussion of treatment options includes a critical review of high-dose methylprednisolone and GM-1 ganglioside therapy. The concept that limited rebuilding can provide a disproportionate improvement in quality of life is emphasized throughout. CONCLUSIONS: New surgical procedures, pharmacologic treatments, and functional neuromuscular stimulation methods have evolved over the last decades that can improve functional outcomes after spinal cord injury, but limiting secondary injury remains the primary goal. Tissue replacement strategies, including the use of embryonic stem cells, become an important tool and can restore function in animal models. Controlled clinical trials are now required to confirm these observations. The ultimate goal is to harness the body's own potential to replace lost central nervous system cells by activation of endogenous progenitor cell repair mechanisms.
• Corbetta M, Burton H, Sinclair RJ, Conturo TE, Akbudak E and McDonald JW (2002). Functional reorganization and stability of somatosensory-motor cortical topography in a tetraplegic subject with late recovery. Proc Natl Acad Sci U S A. 99: 17066-71. Departments of Neurology, Radiology, Anatomy and Neurobiology, and Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA. mau@npg.wustl.edu. The functional organization of somatosensory and motor cortex was investigated in an individual with a high cervical spinal cord injury, a 5-year absence of nearly all sensorymotor function at and below the shoulders, and rare recovery of some function in years 6-8 after intense and sustained rehabilitation therapies. We used functional magnetic resonance imaging to study brain activity to vibratory stimulation and voluntary movements of body parts above and below the lesion. No response to vibratory stimulation of the hand was observed in the primary somatosensory cortex (SI) hand area, which was conversely recruited during tongue movements that normally evoke responses only in the more lateral face area. This result suggests SI reorganization analogous to previously reported neuroplasticity changes after peripheral lesions in animals and humans. In striking contradistinction, vibratory stimulation of the foot evoked topographically appropriate responses in SI and second somatosensory cortex (SII). Motor cortex responses, tied to a visuomotor tracking task, displayed a near-typical topography, although they were more widespread in premotor regions. These findings suggest possible preservation of motor and some somatosensory cortical representations in the absence of overt movements or conscious sensations for several years after spinal cord injury and have implications for future rehabilitation and neural-repair therapies.
• Dong H, Fazzaro A, Xiang C, Korsmeyer SJ, Jacquin MF and McDonald JW (2003). Enhanced oligodendrocyte survival after spinal cord injury in Bax-deficient mice and mice with delayed Wallerian degeneration. J Neurosci. 23: 8682-91. Department of Neurology, Spinal Cord Injury Neuro-Rehabilitation Section, Restorative Treatment and Research Program, and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63108, USA. Mechanisms of oligodendrocyte death after spinal cord injury (SCI) were evaluated by T9 cord level hemisection in wild-type mice (C57BL/6J and Bax+/+ mice), Wlds mice in which severed axons remain viable for 2 weeks, and mice deficient in the proapoptotic protein Bax (Bax-/-). In the lateral white-matter tracts, substantial oligodendrocyte death was evident in the ipsilateral white matter 3-7 mm rostral and caudal to the hemisection site 8 d after injury. Ultrastructural analysis and expression of anti-activated caspase-3 characterized the ongoing oligodendrocyte death at 8 d as primarily apoptotic. Oligodendrocytes were selectively preserved in Wlds mice compared with C57BL/6J mice at 8 d after injury, when severed axons remained viable as verified by antereograde labeling of the lateral vestibular spinal tract. However, 30 d after injury when the severed axons in Wlds animals were already degenerated, the oligodendrocytes preserved at 8 d were lost, and numbers were then equivalent to control C57BL/6J mice. In contrast, oligodendrocyte death was prevented at both time points in Bax-/- mice. When cultured oligodendrocytes were exposed to staurosporine or cyclosporin A, drugs known to stimulate apoptosis in oligodendrocytes, those from Bax-/- mice but not from Bax+/+ or Bax+/- mice were resistant to the apoptotic death. In contrast, the three groups were equally vulnerable to excitotoxic necrosis death induced by kainate. On the basis of these data, we hypothesize that the Wallerian degeneration of white matter axons that follows SCI removes axonal support and induces apoptotic death in oligodendrocytes by triggering Bax expression.
• McDonald JW and Becker D (2003). Spinal cord injury: promising interventions and realistic goals. Am J Phys Med Rehabil. 82: S38-49. Department of Neurology and Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri 63108, USA. Long regarded as impossible, spinal cord repair is approaching the realm of reality as efforts to bridge the gap between bench and bedside point to novel approaches to treatment. It is important to recognize that the research playing field is rapidly changing and that new mechanisms of resource development are required to effectively make the transition from basic science discoveries to effective clinical treatments. This article reviews recent laboratory studies and phase 1 clinical trials in neural and nonneural cell transplantation, stressing that the transition from basic science to clinical applications requires a parallel rather than serial approach, with continuous, two-way feedback to most efficiently translate basic science findings, through evaluation and optimization, to clinical treatments. An example of mobilizing endogenous stem cells for repair is reviewed, with emphasis on the rapid application of basic science to clinical therapy. Successful and efficient transition from basic science to clinical applications requires (1) a parallel rather than a serial approach; (2) development of centers that integrate three spheres of science, translational, transitional, and clinical trials; and (3) development of novel resources to fund the most critically limited step of transitional to clinical trials.
• McDonald JW, Becker D, Sadowsky CL, Conturo TE and Schultz LM (2002). Correction addendum to: Late recovery following spinal cord injury. J Neurosurg. 97: 405-6.
• McDonald JW, Becker D, Sadowsky CL, Jane JA, Sr., Conturo TE and Schultz LM (2002). Late recovery following spinal cord injury. Case report and review of the literature. J Neurosurg. 97: 252-65. Department of Neurology and Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri 63108, USA. mcdonald@neuro.wustl.edu. The authors of this prospective, single-case study evaluated the potential for functional recovery from chronic spinal cord injury (SCI). The patient was motor complete with minimal and transient sensory perception in the left hemibody. His condition was classified as C-2 American Spinal Injury Association (ASIA) Grade A and he had experienced no substantial recovery in the first 5 years after traumatic SCI. Clinical experience and evidence from the scientific literature suggest that further recovery would not take place. When the study began in 1999, the patient was tetraplegic and unable to breathe without assisted ventilation; his condition classification persisted as C-2 ASIA Grade A. Magnetic resonance imaging revealed severe injury at the C-2 level that had left a central fluid-filled cyst surrounded by a narrow donutlike rim of white matter. Five years after the injury a program known as "activity-based recovery" was instituted. The hypothesis was that patterned neural activity might stimulate the central nervous system to become more functional, as it does during development. Over a 3-year period (5-8 years after injury), the patient's condition improved from ASIA Grade A to ASIA Grade C, an improvement of two ASIA grades. Motor scores improved from 0/100 to 20/100, and sensory scores rose from 5-7/112 to 58-77/112. Using electromyography, the authors documented voluntary control over important muscle groups, including the right hemidiaphragm (C3-5), extensor carpi radialis (C-6), and vastus medialis (L2-4). Reversal of osteoporosis and an increase in muscle mass was associated with this recovery. Moreover, spasticity decreased, the incidence of medical complications fell dramatically, and the incidence of infections and use of antibiotic medications was reduced by over 90%. These improvements occurred despite the fact that less than 25 mm2 of tissue (approximately 25%) of the outer cord (presumably white matter) had survived at the injury level. The primary novelty of this report is the demonstration that substantial recovery of function (two ASIA grades) is possible in a patient with severe C-2 ASIA Grade A injury, long after the initial SCI. Less severely injured (lower injury level, clinically incomplete lesions) individuals might achieve even more meaningful recovery. The role of patterned neural activity in regeneration and recovery of function after SCI therefore appears a fruitful area for future investigation.
• McDonald JW and Howard MJ (2002). Repairing the damaged spinal cord: a summary of our early success with embryonic stem cell transplantation and remyelination. Prog Brain Res. 137: 299-309. Center for the Study of Nervous System Injury, Spinal Cord Injury Restorative Treatment and Research Program, Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. mcdonald@neuro.wustl.edu. Demyelination contributes to the loss of function consequent to central nervous system (CNS) injury. Optimizing remyelination through transplantation of myelin-producing cells may offer a pragmatic approach to restoring meaningful neurological function. An unlimited source of cell suitable for such transplantation therapy can be derived from embryonic stem (ES) cells, which are both pluripotent and genetically flexible. Here we review work from our group showing that neural precursor cells can be derived from ES cells and that transplantation of these cells into the injured spinal cord leads to some recovery of function. We have further examined and optimized methods for enriching oligodendrocyte differentiation from ES cells. ES cell-derived oligodendrocytes are capable of rapid differentiation and myelination in mixed neuron/glia cultures. When transplanted into the injured spinal cord of adult rodents, the neural-induced precursor cells are capable of differentiating into oligodendrocytes and myelinating host axons. The role of myelination and remyelination will be discussed in the context of regeneration strategies.
• McDonald JW and Sadowsky C (2002). Spinal-cord injury. Lancet. 359: 417-25. Department of Neurology, Spinal Cord Injury Neuro-Rehabilitation Section, and Restorative Treatment and Research Program, Washington University School of Medicine, St Louis, MO 63110, USA. mcdonald@neuro.wustl.edu. More than a decade ago, spinal-cord injury meant confinement to a wheelchair and a lifetime of medical comorbidity. The physician's armamentarium of treatments was very limited, and provision of care for individuals with spinal-cord injury was usually met with frustration. Advances in the neurosciences have drawn attention to research into spinal-cord injury. Nowadays, advanced interventions provide high hope for regeneration and functional restoration. As scientific advances become more frequent, scepticism is giving way to the ideas that spinal-cord injury will eventually be repairable and that strategies to restore function are within our grasp. We address the present understanding of spinal-cord injury, its cause, pathophysiology, diagnosis, and treatment, and look at promising research avenues. We also discuss new treatment options, including functional electric stimulation and part-weight-supported walking.
• McDonald JW, Stefovska VG, Liu XZ, Shin H, Liu S and Choi DW (2002). Neurotrophin potentiation of iron-induced spinal cord injury. Neuroscience. 115: 931-9. Department of Neurology, Washington University School of Medicine, PO Box 8111, 660 S Euclid Avenue, St Louis, MO 63110-1093, , USA. Previous studies have shown that pretreatment with neurotrophins can potentiate the vulnerability of cultured neurons to excitotoxic and free radical-induced necrosis, in contrast to their well known neuroprotective effects against apoptosis. Here we tested the hypothesis that this unexpected injury-potentiating effect of neurotrophins would also take place in the adult rat spinal cord. Fe(3+)-citrate was injected stereotaxically into spinal cord gray matter in adult rats in amounts sufficient to produce minimal tissue injury 24 h later. Twenty-four-hour pretreatment with brain-derived neurotrophic factor, neurotrophin-3, or neurotrophin-4/5, but not nerve growth factor, markedly enhanced tissue injury in the gray matter as evidenced by an increase in the damaged area, as well as the loss of neurons and oligodendrocytes. Consistent with maintained free radical mediation, the neurotrophin-potentiated iron-induced spinal cord damage was blocked by co-application of the antioxidant N-tert-butyl-(2-sulfophenyl)-nitrone. These data support the hypothesis that the overall neuroprotective properties of neurotrophins in models of acute injury to the spinal cord may be limited by an underlying potentiation of free radical-mediated necrosis.
• Rosenzweig ES and McDonald JW (2004). Rodent models for treatment of spinal cord injury: research trends and progress toward useful repair. Curr Opin Neurol. 17: 121-31. Departments of Neurology and Neurological Surgery and the Spinal Cord Injury Restorative Treatment and Research Program, and Anatomy and Neurobiology, Washington University School of Medicine, St Louis, Missouri, USA. PURPOSE OF REVIEW: In this review, we have documented some current research trends in rodent models of spinal cord injury. We have also catalogued the treatments used in studies published between October 2002 and November 2003, with special attention given to studies in which treatments were delayed for at least 4 days after injury. RECENT FINDINGS: Most spinal cord injury studies are performed with one of three general injury models: transection, compression, or contusion. Although most treatments are begun immediately after injury, a growing number of studies have used delayed interventions. Mice and the genetic tools they offer are gaining in popularity. Some researchers are setting their sights beyond locomotion, to issues more pressing for people with spinal cord injury (especially bladder function and pain). SUMMARY: Delayed treatment protocols may extend the window of opportunity for treatment of spinal cord injury, whereas continued progress in the prevention of secondary cell death will reduce the severity of new cases. The use of mice will hopefully accelerate progress towards useful regeneration in humans. Researchers must improve cross-study comparability to allow balanced decisions about potentially useful treatments.
• Sadowsky C, Volshteyn O, Schultz L and McDonald JW (2002). Spinal cord injury. Disabil Rehabil. 24: 680-7. Department of Neurology, Spinal Cord Injury Neuro-Rehabilitation Section, Washington University School of Medicine, St Louis, MO 63110, USA. PURPOSE: This article is an overview of the newer therapeutic interventions employed in the care of the spinal cord injured individual and the theoretical rationale supporting them. ISSUE: Spinal Cord Injury (SCI) care was, until recently, a maintenance type treatment, addressing systems mostly affected by complications of the original injury (e.g. bladder, skin, spasiticity). CONCLUSION: With the recent advances in the neuroscience field, more aggressive interventions geared at secondary injury prevention, neuronal regeneration and functional restoration are emerging.