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New Discoveries in Spinal Cord Injury Pathophysiology and Treatment
1. New Discoveries in the Pathophysiology and Treatment of Spinal Cord InjuryThe Miami Project to Cure ParalysisW. Dalton Dietrich, PhDScientific Director www.themiamiproject.org
2. Disclosure and Conflict of Interest (W. Dalton Dietrich, PhD) NIH/NINDS – Grant Funding DOD – Grant Funding Craig Neilsen Foundation – Scientific Advisory Board Zoll Medical Corp. – Speaker Stem Cell Therapeutics – Scientific Advisory Board Pfizer – Safety Monitoring Board
3. Brain and Spinal Cord Injury Research Neuroprotection/Pathophysiology Can we protect? Transplantation/Regeneration Can we repair? Rehabilitation Can we retrain? Quality of Life Can we improve life? Clinical Trials Can we improve functional outcome? Education/Training Can we train the next generation of scientists/clinicians?
6. SCI Epidemiology 12,000 new cases each year in the U.S. Approximately 1.275million Americans living with paralysis as a result of SCI Motor vehicle accidents followed by falls, acts of violence and recreational activities are the leading causes of SCI in the U.S. Since 2000, about 78% of SCIs reported to the national database have occurred in males Currently it is believed that 5.3 million people are living in the US with paralysis due to some type of CNS injury/disorder
9. “The first demonstration of cytoprotection translated from the laboratory to man”Therapeutic Hypothermia The International Liaison Committee on Resuscitation (ILCOR) recommended cooling after resuscitation post-cardiac arrest Circulation, 108:118-21,2003 American Heart Association endorses therapeutic hypothermia for cardiac arrest patients Circulation, 112(Suppl I):IV-84-88, 2005
11. Temperature Mechanisms in Ischemia and Trauma Protein kinase-C activity (1991) Leukocyte accumulation (1991) Platelet function (1987) NMDA neurotoxicity (1991) Cytoskeletal proteins (1993) Growth factors (1994) Calcium-dependent protein phosphorylation (1990) Heat shock protein (1992) Immediate early genes (1996) NOS activity (1999) MMP expression (2003) microRNAs (2011) Metabolism (1970) pH (1992) Neurotransmitter levels (1982) Free fatty acids (1989) Blood-brain barrier (1990) Edema (1987) Glucose metabolism (1987) Cerebral blood flow (1954) Free radical activation (1994) Lipid peroxidation (1994) Calcium accumulation (1992) Protein synthesis (1991)
12. Clinical Protocols for Therapeutic Hypothermia in Central Nervous System Trauma No clinical guidelines or protocols establishing efficacy for the use of therapeutic hypothermia after human spinal cord injury have been published in peer reviewed journals Modest hypothermia treatment in SCI patients is therefore an experimental procedure Unfortunately, media attention surrounding its recent use may have given the impression it should be a standard treatment.
13. Buffalo Bills Defensive End Kevin Everett-Acute SCI During NFL Game 2:30 PM 9-11-2007 Complete ASIA A with Difficulty Breathing 12-7-2007 with fiancee Wiande 3 Months
14. Research Protocol at UMMSM/JMH The Department of Neurological Surgery/Miami Project at the UMMSM/JMH is currently conducting an IRB approved SCI research protocol This protocol will evaluate the use of modest hypothermia in patients with acute SCI for risk factors and efficacy Modest hypothermia (33o C/92o F) is induced via a cooling catheter that is placed in a large blood vessel Cooling is maintained for a 48hr period followed by a slow re-warming of one degree every 8 hours.
15. Clinical Application of Modest Hypothermiaafter Spinal Cord InjuryLevi AD, Green BA, Wang MY, Dietrich WD, Brindle T, Vanni S, Casella G, Elhammaday G, Jagid, J. J Neurotrauma 26:407-415, 2009 Fourteen patients cooled 48 hrs using systemic modest hypothermia (33oC) Average time between injury and induction of hypothermia was 9.17 hrs Positive correlation between temperature and heart rate Minimum variation of body temperature during cooling phase No increase in risk factors associated with modest hypothermia Provides critical baseline data for future outcome studies including multicenter randomized trials
17. Clinical outcomes using modest intravascular hypothermia after acute cervical spinal cord injury, Levi et al., Neurosurgery, 2010 Percent of Total ASIA A conversion ratio of 43%
19. Therapeutic Hypothermia (Michael Wang, MD (PI)) – The Department of Neurological Surgery and The Miami Project to Cure Paralysis have launched a significant initiative to study hypothermia treatment for acute spinal cord injury. A multicenter randomized clinical trial application has been submitted to NIH with the neurological emergencies trials group (NETT) to evaluate the efficacy of moderate hypothermia after severe SCI. The Dream Team
20. Clinical Protocol 212 patients 18 centers 4 patients per center per year 5 year project (3.5 year enrollment, 1 year minimum f/u, 6 month start-up) $9,991,548 total project costs
21. ARCTIC: Acute Rapid Cooling Therapy for Injuries of the Spinal Cord
22. Project Timeline January 2006 – Pilot study initiated at U. Miami February 2009 – Collaboration with NETT July 2009 - Organizational meetings, finalization of key personnel, protocol vetting October 5, 2009 - Submission to NINDS April 2010 – Grant reviewed Summer-Fall 2011 – Grant re-submission (7/5/2011 or 11/5/2011)
26. FDA Approves Geron’s GRNOPC1 INDFirst and Second Patient Treated MENLO PARK, Calif., October 11, 2010 - Geron Corporation (Nasdaq: GERN) today announced the enrollment of the first patient in the company's clinical trial of human embryonic stem cell (hESC)-derived oligodendrocyte progenitor cells, GRNOPC1. The primary objective of this Phase I study is to assess the safety and tolerability of GRNOPC1 in patients with complete American Spinal Injury Association (ASIA) Impairment Scale grade A thoracic spinal cord injuries. Participants in the study must be newly injured and receive GRNOPC1 within 14 days of the injury.
27. Advantages of Schwann cells/ SCI Promote regeneration of axons in the PNS Produce growth factors, ECM components Myelinate, ensheathe axons in CNS Restore axonal conduction upon myel. Enter cord in substantial numbers/ SCI Are readily accessible/PN Can be obtained in large numbers Can be genetically engineered Can be transplanted autologously
28. Elevation of cyclic AMP in combination with Schwann cell grafts promotes functional recovery in animals after SCI Thoracic (T8) moderate contusion AT TIME OF INJURY Subcutaneous minipumps deliver daily doses of rolipram for 2 weeks to prevent decrease of cAMP levels after injury A Transplantation of Schwann cells into the injury site 1 WEEK POST-INJURY Injections of a form of cyclic AMP above and below the injury at transplantation to increase cAMP levels to above normal B Pearse et al., Nat Med, 2004
29. Elevating Cyclic AMP Promotes Growth Of Axons From The Brain Into And Beyond Schwann Cell Grafts Axons from neurons in the brain do not grow into Schwann cell only grafts (Schwann cells in red) Many axons (green) from the brain grow into grafts after treatment with rolipram and dibutyryl–cyclic AMP Some of these axons from the brain also grow from the graft into the spinal cord beyond the graft
30. Cervical enlargement Conus Cauda Equina Rat frontal lobe to cauda equina 15 cm. in length B. Dobkin, L. Havton/ UCLA Neurologic Rehabilitation Program
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33. Proposed Human Schwann Cell Clinical Trial Specific Aims Conduct a Phase I clinical trial to determine whether or not there are any toxicities or other adverse effects produced by injecting the patient’s own SCs into the spinal cord lesion. Collect Safety and Efficacy data on a sample of 10 patients with complete (ASIA-A) or incomplete (ASIA-B) SCI for submission in support of a Phase II randomized clinical trial.
39. Intrinsic and Extrinsic Mechanisms of Axonal Regeneration after SCI Partial deficiency in intrinsic growth capacity of adult neurons Lack of neurotrophic stimulation Absence of permissive substrates to support axonal attachment & extension through lesion sites Myelin-based and extracellular matrix inhibitors Extensive secondary damage resulting from inflammatory mechanisms Tuszynski et al., 2009
40. Regenerating axons have two major barriers to overcome 1) inhibitors in myelin exposed by the damage 2) the glial scar Filbin, 2003
45. Clinical Research Programs in the Bantle Rehabilitation Research Center and VA SCI Service Intraoperative monitoring for preserving spinal cord function Male fertility Neuromuscular aspects of strength and fatigue Development and evaluation of assistive devices Spinal motor conduction and reflex organization Pain, spasticity, bowel/bladder Pharmacological management of Dyslipidemia