New Discoveries in the Pathophysiology and Treatment of Spinal Cord InjuryThe Miami Project to Cure ParalysisW. Dalton Die...
Disclosure and Conflict of Interest (W. Dalton Dietrich, PhD)<br />NIH/NINDS – Grant Funding<br />DOD – Grant Funding<br /...
Brain and Spinal Cord Injury Research<br />Neuroprotection/Pathophysiology<br />Can we protect?<br />Transplantation/Regen...
Bench to Bedside/Bedside to Bench Research Program<br />(Pre-clinical)<br />
SCI Epidemiology<br />12,000 new cases each year in the U.S.<br />Approximately 1.275million Americans living with paralys...
Promising Treatments Targeting Spinal Cord Injury<br />Erythropoetin<br />Minocycline<br />Rolipram (PDE inhibitors)<br />...
Dirnagl et al., 2003<br />
“The first demonstration of cytoprotection translated from the laboratory to man”Therapeutic Hypothermia<br />The Internat...
Yu et al., J Neurosurg, 2000<br />
Temperature Mechanisms in Ischemia and Trauma<br />Protein kinase-C activity (1991)<br />Leukocyte accumulation (1991)<br ...
Clinical Protocols for Therapeutic Hypothermia in Central Nervous System Trauma<br />No clinical guidelines or protocols e...
Buffalo Bills Defensive End Kevin Everett-Acute SCI During NFL Game<br />2:30 PM  9-11-2007<br />Complete ASIA A with Diff...
Research Protocol at UMMSM/JMH<br />The Department of Neurological Surgery/Miami Project at the UMMSM/JMH is currently con...
Clinical Application of Modest Hypothermiaafter Spinal Cord InjuryLevi AD, Green BA, Wang MY, Dietrich WD, Brindle T, Vann...
Cooling Profile of SCI Patient<br />(0.2oC/hr)<br />(0.5oC/hr)<br />
Clinical outcomes using modest intravascular hypothermia<br />after acute cervical spinal cord injury, Levi et al., Neuros...
ARCTICAcute Rapid Cooling Trial for Injuries of the spinal Cord<br />
Therapeutic Hypothermia (Michael Wang, MD (PI)) – The Department of Neurological Surgery and The Miami Project to Cure Par...
Clinical Protocol<br />212 patients<br />18 centers<br />4 patients per center per year<br />5 year project (3.5 year enro...
ARCTIC:  Acute Rapid Cooling Therapy for Injuries of the Spinal Cord<br />
Project Timeline<br />January 2006 – Pilot study initiated at U. Miami<br />February 2009 – Collaboration with NETT<br />J...
Helper Cells to Promote Regeneration and Repair<br />Peripheral nerve/Schwann cells<br />Olfactory ensheathing glia<br />A...
FDA Approves Geron’s GRNOPC1 INDFirst and Second Patient Treated <br />MENLO PARK, Calif., October 11, 2010 - Geron Corpor...
Advantages of Schwann cells/ SCI<br />Promote regeneration of axons in the PNS<br />Produce growth factors, ECM components...
Elevation of cyclic AMP in combination with Schwann cell grafts <br />promotes functional recovery in animals after SCI<br...
Elevating Cyclic AMP Promotes Growth Of Axons From The Brain Into And Beyond Schwann Cell Grafts<br />Axons from neurons i...
Cervical enlargement<br />Conus<br />Cauda Equina<br />Rat frontal lobe to cauda equina 15 cm. in length<br />B. Dobkin, L...
Proposed Human Schwann Cell Clinical Trial<br />Specific Aims<br />Conduct a Phase I clinical trial to determine whether o...
Technical Milestones for Human Schwann Cell Trial<br /><ul><li>Project Initiation (2007)
 Pre Pre-IND Consultation (September 2008)
 Pre-IND process (July 2010)
 IND submission (3rd Quarter 2011)
 Phase I Clinical Trial (2012)</li></li></ul><li>STOP<br />Regeneration in the CNS is inhibited<br />Can we find chemicals...
Intrinsic and Extrinsic Mechanisms of Axonal Regeneration after SCI<br />Partial deficiency in intrinsic growth capacity o...
Regenerating axons have two major barriers to overcome<br />1) inhibitors in myelin exposed by the damage<br />2) the glia...
Promoting Axonal Regeneration in the Adult CNS by Modulating PTEN/mTOR Pathway<br /><ul><li>Test intrinsic impediments to ...
Optic nerve preparation
Virus assisted in vivo conditional PTEN KOs
Kinasesand phosphatases regulate all aspects of cell growth/differentiation</li></ul>Park et al., Science 322: 963, 2009<b...
Clinical Research Programs in the Bantle Rehabilitation Research Center and VA SCI Service<br />Intraoperative monitoring ...
Cardiovascular/Robotic Training<br />
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Dietrich, Dalton

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Dietrich, Dalton

  1. 1. New Discoveries in the Pathophysiology and Treatment of Spinal Cord InjuryThe Miami Project to Cure ParalysisW. Dalton Dietrich, PhDScientific Director<br />www.themiamiproject.org<br />
  2. 2. Disclosure and Conflict of Interest (W. Dalton Dietrich, PhD)<br />NIH/NINDS – Grant Funding<br />DOD – Grant Funding<br />Craig Neilsen Foundation – Scientific Advisory Board<br />Zoll Medical Corp. – Speaker<br />Stem Cell Therapeutics – Scientific Advisory Board<br />Pfizer – Safety Monitoring Board<br />
  3. 3. Brain and Spinal Cord Injury Research<br />Neuroprotection/Pathophysiology<br />Can we protect?<br />Transplantation/Regeneration<br />Can we repair?<br />Rehabilitation<br />Can we retrain?<br />Quality of Life<br />Can we improve life?<br />Clinical Trials<br />Can we improve functional outcome?<br />Education/Training<br />Can we train the next generation of scientists/clinicians?<br />
  4. 4. Bench to Bedside/Bedside to Bench Research Program<br />(Pre-clinical)<br />
  5. 5.
  6. 6. SCI Epidemiology<br />12,000 new cases each year in the U.S.<br />Approximately 1.275million Americans living with paralysis as a result of SCI<br />Motor vehicle accidents followed by falls, acts of violence and recreational activities are the leading causes of SCI in the U.S.<br />Since 2000, about 78% of SCIs reported to the national database have occurred in males<br />Currently it is believed that 5.3 million people are living in the US with paralysis due to some type of CNS injury/disorder<br />
  7. 7. Promising Treatments Targeting Spinal Cord Injury<br />Erythropoetin<br />Minocycline<br />Rolipram (PDE inhibitors)<br />Cethrin® (Rho antagonist)<br />Riluzole (Na+ channel blocker)<br />Therapeutic Hypothermia (Miami Project)<br />ProCord® (activated macrophages)<br />Schwann Cells (Miami Project)<br />Human Embryonic Stem Cell-Derived Oligodendrocyte (Geron)<br />Combination Therapies<br />
  8. 8. Dirnagl et al., 2003<br />
  9. 9. “The first demonstration of cytoprotection translated from the laboratory to man”Therapeutic Hypothermia<br />The International Liaison Committee on Resuscitation (ILCOR)<br />recommended cooling after resuscitation post-cardiac arrest <br />Circulation, 108:118-21,2003<br />American Heart Association endorses therapeutic <br />hypothermia for cardiac arrest patients<br />Circulation, 112(Suppl I):IV-84-88, 2005<br />
  10. 10. Yu et al., J Neurosurg, 2000<br />
  11. 11. Temperature Mechanisms in Ischemia and Trauma<br />Protein kinase-C activity (1991)<br />Leukocyte accumulation (1991)<br />Platelet function (1987)<br />NMDA neurotoxicity (1991)<br />Cytoskeletal proteins (1993)<br />Growth factors (1994)<br />Calcium-dependent protein phosphorylation (1990)<br />Heat shock protein (1992)<br />Immediate early genes (1996)<br />NOS activity (1999)<br />MMP expression (2003)<br />microRNAs (2011)<br />Metabolism (1970)<br />pH (1992)<br />Neurotransmitter levels (1982)<br />Free fatty acids (1989)<br />Blood-brain barrier (1990)<br />Edema (1987)<br />Glucose metabolism (1987)<br />Cerebral blood flow (1954)<br />Free radical activation (1994)<br />Lipid peroxidation (1994)<br />Calcium accumulation (1992)<br />Protein synthesis (1991)<br />
  12. 12. Clinical Protocols for Therapeutic Hypothermia in Central Nervous System Trauma<br />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<br />Modest hypothermia treatment in SCI patients is therefore an experimental procedure<br />Unfortunately, media attention surrounding its recent use may have given the impression it should be a standard treatment.<br />
  13. 13. Buffalo Bills Defensive End Kevin Everett-Acute SCI During NFL Game<br />2:30 PM 9-11-2007<br />Complete ASIA A with Difficulty Breathing<br />12-7-2007 with fiancee Wiande<br />3 Months<br />
  14. 14. Research Protocol at UMMSM/JMH<br />The Department of Neurological Surgery/Miami Project at the UMMSM/JMH is currently conducting an IRB approved SCI research protocol <br />This protocol will evaluate the use of modest hypothermia in patients with acute SCI for risk factors and efficacy<br /> Modest hypothermia (33o C/92o F) is induced via a cooling catheter that is placed in a large blood vessel<br />Cooling is maintained for a 48hr period followed by a slow re-warming of one degree every 8 hours.  <br />
  15. 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 <br />Fourteen patients cooled 48 hrs using systemic modest hypothermia (33oC)<br />Average time between injury and induction of hypothermia was 9.17 hrs<br />Positive correlation between temperature and heart rate<br />Minimum variation of body temperature during cooling phase<br />No increase in risk factors associated with modest hypothermia<br />Provides critical baseline data for future outcome studies including multicenter randomized trials<br />
  16. 16. Cooling Profile of SCI Patient<br />(0.2oC/hr)<br />(0.5oC/hr)<br />
  17. 17. Clinical outcomes using modest intravascular hypothermia<br />after acute cervical spinal cord injury, Levi et al., Neurosurgery, 2010<br />Percent of Total<br />ASIA A conversion ratio of 43%<br />
  18. 18. ARCTICAcute Rapid Cooling Trial for Injuries of the spinal Cord<br />
  19. 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.<br />The Dream Team<br />
  20. 20. Clinical Protocol<br />212 patients<br />18 centers<br />4 patients per center per year<br />5 year project (3.5 year enrollment, 1 year minimum f/u, 6 month start-up)<br />$9,991,548 total project costs<br />
  21. 21. ARCTIC: Acute Rapid Cooling Therapy for Injuries of the Spinal Cord<br />
  22. 22. Project Timeline<br />January 2006 – Pilot study initiated at U. Miami<br />February 2009 – Collaboration with NETT<br />July 2009 - Organizational meetings, finalization of key personnel, protocol vetting<br />October 5, 2009 - Submission to NINDS<br />April 2010 – Grant reviewed<br />Summer-Fall 2011 – Grant re-submission (7/5/2011 or 11/5/2011)<br />
  23. 23.
  24. 24. Helper Cells to Promote Regeneration and Repair<br />Peripheral nerve/Schwann cells<br />Olfactory ensheathing glia<br />Astrocytes<br />Genetically engineered cells<br /> Fibroblasts<br />Schwann cells<br />Stem Cells<br />Fetal<br />Embryonic<br />Adult<br />Induced Pluripotent SCs (iPS)<br />
  25. 25.
  26. 26. FDA Approves Geron’s GRNOPC1 INDFirst and Second Patient Treated <br />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.<br />
  27. 27. Advantages of Schwann cells/ SCI<br />Promote regeneration of axons in the PNS<br />Produce growth factors, ECM components<br />Myelinate, ensheathe axons in CNS<br />Restore axonal conduction upon myel.<br />Enter cord in substantial numbers/ SCI<br />Are readily accessible/PN<br />Can be obtained in large numbers<br />Can be genetically engineered<br />Can be transplanted autologously<br />
  28. 28. Elevation of cyclic AMP in combination with Schwann cell grafts <br />promotes functional recovery in animals after SCI<br />Thoracic (T8) moderate contusion<br />AT TIME OF INJURY<br />Subcutaneous minipumps deliver daily doses of rolipram for 2 weeks to prevent decrease of cAMP levels after injury<br />A<br />Transplantation of Schwann cells<br />into the injury site<br />1 WEEK POST-INJURY<br />Injections of a form of cyclic AMP above and below the injury at transplantation to increase cAMP levels to above normal<br />B<br />Pearse et al., Nat Med, 2004<br />
  29. 29. Elevating Cyclic AMP Promotes Growth Of Axons From The Brain Into And Beyond Schwann Cell Grafts<br />Axons from neurons in the brain do not grow into Schwann cell only grafts (Schwann cells in red)<br />Many axons (green) from the brain grow into grafts after treatment with rolipram and dibutyryl–cyclic AMP<br />Some of these axons from the brain also grow from the graft into the spinal cord beyond the graft<br />
  30. 30. Cervical enlargement<br />Conus<br />Cauda Equina<br />Rat frontal lobe to cauda equina 15 cm. in length<br />B. Dobkin, L. Havton/ UCLA Neurologic Rehabilitation Program<br />
  31. 31.
  32. 32.
  33. 33. Proposed Human Schwann Cell Clinical Trial<br />Specific Aims<br />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.<br />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.<br />
  34. 34. Technical Milestones for Human Schwann Cell Trial<br /><ul><li>Project Initiation (2007)
  35. 35. Pre Pre-IND Consultation (September 2008)
  36. 36. Pre-IND process (July 2010)
  37. 37. IND submission (3rd Quarter 2011)
  38. 38. Phase I Clinical Trial (2012)</li></li></ul><li>STOP<br />Regeneration in the CNS is inhibited<br />Can we find chemicals that overcome inhibition?<br />
  39. 39. Intrinsic and Extrinsic Mechanisms of Axonal Regeneration after SCI<br />Partial deficiency in intrinsic growth capacity of adult neurons<br />Lack of neurotrophic stimulation<br />Absence of permissive substrates to support axonal attachment & extension through lesion sites<br />Myelin-based and extracellular matrix inhibitors<br />Extensive secondary damage resulting from inflammatory mechanisms<br />Tuszynski et al., 2009<br />
  40. 40. Regenerating axons have two major barriers to overcome<br />1) inhibitors in myelin exposed by the damage<br />2) the glial scar<br />Filbin, 2003<br />
  41. 41. Promoting Axonal Regeneration in the Adult CNS by Modulating PTEN/mTOR Pathway<br /><ul><li>Test intrinsic impediments to axonal regrowth
  42. 42. Optic nerve preparation
  43. 43. Virus assisted in vivo conditional PTEN KOs
  44. 44. Kinasesand phosphatases regulate all aspects of cell growth/differentiation</li></ul>Park et al., Science 322: 963, 2009<br />
  45. 45. Clinical Research Programs in the Bantle Rehabilitation Research Center and VA SCI Service<br />Intraoperative monitoring for preserving spinal cord function<br />Male fertility<br />Neuromuscular aspects of strength and fatigue<br />Development and evaluation of assistive devices<br />Spinal motor conduction and reflex organization<br />Pain, spasticity, bowel/bladder<br />Pharmacological management of Dyslipidemia<br />
  46. 46.
  47. 47. Cardiovascular/Robotic Training<br />
  48. 48. Activating the nervous system<br />to make a difference today<br />
  49. 49. Combination Therapy <br />Neuroprotection<br />Bridging strategies<br />Cellular transplants<br />Growth/inhibitory factors<br />Improving axonal function<br />Rehabilitation—retraining the injured CNS<br />
  50. 50. Summary<br />Neuroprotection<br />New targets<br />New compounds<br />Combination approaches<br />Cellular transplantation<br />What cell type?<br />Engineering<br /><ul><li>Rehabilitation
  51. 51. Conditioning
  52. 52. Locomotor training
  53. 53. Clinical Trials
  54. 54. Neuroprotection
  55. 55. Reparative strategies</li></li></ul><li>
  56. 56. The Miami Project Faculty 2011<br />Supported by NIH, DOD, State of Florida, Miami Project to Cure Paralysis and the Buoniconti Fund<br />
  57. 57. Thank You<br />

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