repair and regeneration of the injured spinal cord: from...
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Repair and Regeneration of the Injured Spinal Cord: From Molecule to Man
Michael G. Fehlings MD PhD FRCSC FACS FRSC FCAHS
Professor of NeurosurgeryVice Chair Department of Surgery
Halbert Chair in Neural Repair and RegenerationCo-Director Spine Program
University of Toronto
www.uhn.on.ca/programs/spineNeurosurgery
Disclosures
• Chair Scientific Advisory Board Fortuna Fix• Consulting role Neuraxis• Grant support: CIHR, DOD, AOSpine, Rick
Hansen Institute, PVA, Wings for Life Foundation
• Principal Investigator: RISCIS Trial
Toronto Western Hospital
Krembil Neuroscience Center, Toronto Western Hospital, University of Toronto
AcknowledgementsSpinal Program
Krembil Neuroscience CenterUniversity Health Network, University of Toronto
• Fehlings Laboratory– James Austin – Behzad Azad – Darryl Baptiste – Josef Buttigieg – David Cadotte– Eftekhar Eftekharpour – Sarah Figley – Julio Furlan – Karina Goncharenko – Gregory Hawryluk – Spyros Karadimas– Amy Lem – Yang Liu – Dung Hoang Ngyuen – Sherri Robins – James Rowland – Desiree Schut – Lindsay Tetreault– Jian Wang – Jefferson Wilson– Wenru Yu
• SCI-NET Collaborators (CIHR-NET)C. TatorC. MorsheadM. ShoichetD. van der KooyG. Stanisz
Funding AgenciesCanadian Institutes of Health ResearchPhysician Services Incorporated FoundationOntario Neurotrauma FoundationCervical Spine Research SocietyChristopher Reeve Paralysis Foundation
Contact information
www.uhn.on.ca/programs/spine
• Collaborating Scientists SCI Program KNCA. Velumian; S. Karimi
• Collaborators STADYS fMRI ProjectP. Stroman; D. Mikulis; K. Smith; R. Pokrupa
Persian Empire 2600 BC (British Museum)
Paul Gauguin - 1897
D'où Venons Nous / Que Sommes Nous / Où Allons Nous
Paul Gauguin - 1897
D'où Venons Nous / Que Sommes Nous / Où Allons Nous
Where Do We Come From? / What are We? / Where Are We Going?
Case Vignette: The Clinical Dilemma
• 39-year-old man• Dove into shallow water• C4 level ASIA-A
complete cervical spinal cord injury
Key Concepts• Neuroprotective approaches
– Time is Spine– Re-evaluation of the role of steroids– Riluzole, minocycline, hypothermia, G-CSF ; IvIg
• Promoting plasticity of neural circuits– Activation of latent circuits to rescue breathing– Epidural stimulation for chronic SCI
• Bioengineered scapholds• Cellular therapies
– Neural stem cells– Schwann cells
Mechanisms of Acute Traumatic Spinal Cord Injury
Normal 8 hours 24 hrs
NF200 Degradation
Early Intervention for Acute Spinal Cord Injury: Time is Spine
Michael G. Fehlings MD PhD FRCSC FACS
Neurosurgery
Professor of NeurosurgeryHalbert Chair in Neural Repair and Regeneration
Vice Chair Research Department of SurgeryCo-Chair Spinal Program
University of Toronto
www.uhn.on.ca/programs/spine
Clinical Practice Guidelines for the Management of Degenerative Cervical Myelopathy and Acute Traumatic
Spinal Cord Injury
http://journals.sagepub.com/toc/gsja/7/3_suppl
• AOSpine North America• AOSpine International• Cervical Spine Research
Society• American Association/Congress
of Neurologic Surgeons
Open AccessGlobal Spine JournalVolume 7, Issue 3_suppl, September 2017
A Clinical Practice Guideline for the Management of Patients with Acute Spinal Cord Injury and Central Cord Syndrome:
Recommendations on the Timing (≤24 hours versus >24 hours) of Decompressive Surgery
On Behalf of the Guideline Development GroupSponsored by AANS/CNS, AOSpine North America and
International and Rick Hansen Institute
Final Recommendations
• We suggest that early surgery (within 24 hours) be considered as a treatment option in adult patients with traumatic central cord syndrome
• We suggest that early surgery be offered as an option for adult acute SCI patients regardless of level.
Methylprednisolone for Acute Incomplete Spinal Cord Injury: AOSpine Guidelines
Michael G. Fehlings MD PhD FRCSC FACS FRSCProfessor of Neurosurgery
Vice Chair Research Department of SurgeryHalbert Chair in Neural Repair and Regeneration
University of TorontoHead Spinal Program, Krembil Neuroscience Centre
Chairman AOSpine North AmericaChair AOSpine SCI Knowledge Forum
www.uhn.on.ca/programs/spineNeurosurgery
Updated Meta‐Analysis
• Conducted by a group of external methodologists to reduce bias
Motor score in patients treated within 8 hours at final follow‐up of 6‐12 months
Mean Weighted Difference in motor score recovery for MPSS vs. MPSS Non-treated Patients :3.21 (95%CI: 0.10, 6.33)
Risk Difference for Death24 hour MPSS vs. Control
Difference in rates of death for MPSS vs. Control Patients:-1.51% (95%CI: -4.13, 1.12)
21
In Cervical SCI Cases, Steroids have a 12.6% reduced risk of complications
Independent analysis of STASCIS data: Joseph Detorri PhD; Spectrum Research
M1
Slide 21
M1 MGF, 10/18/2013
Key Questions and Points of Consideration• What is the overall certainty of this evidence?
• Is there important uncertainty about how much people value the main outcomes?
• Are the desirable anticipated effects large?
• Are the undesirable anticipated effects small?
• Are the desirable effects large relative to undesirable effects?
• Are the resources required small?
• Is the incremental cost small relative to the net benefits?
• What would be the impact on health inequities?
• Is the option acceptable to key stakeholders?
• Is the option feasible to implement?
Our Recommendations
MPSSWhen started within 8 hours of injury, we suggest that a 24 hour infusion of high dose MPSS be offered to adult patients with acute SCI as a treatment option
We suggest not offering a 24 hour infusion of high dose MPSS to adult patients who present after 8 hours with acute SCI
For adult patients with acute SCI, we suggest not offering a 48 hour infusion of high dose MPSS
Overall Conclusion
• IV MPSS post SCI should be considered a valid option
• Importantly, there is no existing evidentiary basis to recommend against its use as a treatment option in this context
• Decisions surrounding this therapy should be left to the discretion of the physician
– -considering the characteristics of the presenting patient
• Consider the use of MPSS (24 hrs infusion; started within 8 hrs) in cervical SCI and incomplete SCI in combination with surgical decompression
Emerging Neuroprotective Strategies for Acute SCI
• Riluzole• Minocycline• G-CSF• Hypothermia
– Systemic– Local delivery
• Modulating the Immune Response to Injury – Intravenous Immunoglobulin G
Neuroprotection with Sodium Channel Blocker (Riluzole)*
Riluzole
Registry
56.6
52.5
40.2
50.9
41.9
24.5
20.420
30
40
50
60
Mea
n M
otor
Sco
re
1 42 90 180 200Days Post Injury
Riluzole: Day 1 n = 25 Day 42 n = 25 Day 90 n=24 Day 180 n = 20Registry: Day 1 n = 26 Day 90 n = 26 Day 180 n = 20
Total: AIS A + AIS B + AIS CCervical Injuries: Motor Score by Days Post InjuryPercent Conversion of AIS Grade
RISCIS
• Phase III RCT (RISCIS: Riluzole in Spinal Cord Injury Study); FDA clearance to proceed received
• Trial launched January 2014– 178 patients enrolled
• AOSpine-NACTN-DOD-Rick Hansen Institute partnership-Ontario Neurotrauma Foundation
Hypothermia in SCIProven neuroprotective properties of Therapeutic Hypothermia (TH)History:- 1960-70s: Albin, localized in primate model- 1970-80s: Wells and Hansebout, localized in canine and human models- 1990-2000s: Many efforts to use TH for SCI via CSF, systemic, crude local- 2010-Present: Miami Project, ICED (Australia) - systemic TH
Systemic hypothermia via intravascular delivery currently used:Protecting the Spinal Cord during Thoracic and Abdominal Aortic Aneurysm RepairPost Cardiac ArrestStroke treatmentOngoing clinical studies for spine trauma (Miami Project, ICED)
Systemic delivery of hypothermia presents challenges-technically demanding-potential complications (cardiovascular; coagulopathy;immunosuppression)
Not easily controlledNo spine specific solution is availableNeed for neuromonitoringTime to induce is long (many hours)Return to normothermia is long (many hours)
Obstacles for Therapeutic Hypothermia in SCI
• Effective localized hypothermia
• Quickly cool local tissue intraoperatively (~15 min to target temperature)
• Compatible with neuromonitoring
• Minimal deviation from current care
• Cooled instruments or implants already used at the injury site
• Can continue local cooling post-operatively
• Can be used in conjunction with other treatments for multifaceted approach
Specialized tools for local hypothermia during spine surgery
Cooled soft tissue retractor blades Cooled dural pad for spinal cord protection
Fenestrated pedicle screws to locally cool spinal structures using contained perfusion
Neuroinflammation if Key to the Pathophysiology of Spinal Cord Injury (SCI)
Primary Injury: contusion, compression, laceration of tissue
Secondary Injury: Vascular disruptions,
ischemia, and edemaGlutamate excitoxicityNeuroinflammationCell deathDemyelinationAxonal degeneration
Traumatic SCI triggers a robust inflammatory response
Donnelly D, Popovich P. Experimental Neurology 209: 378‐388, 2007
Inflammation: A double-edged sword in SCI
1. leukocytes secrete matrix-metalloproteinase, pro-inflammatory cytokines, and ROS exacerbate damage
2. Blockade of neutrophils, monocytes, or matrixproteinase knock-out improve function recovery
3. Anti-inflammatory treatments also improve functional recovery after SCI
GOOD1. Remove cellular debris and
secrete trophic factors
2. Immune-deficient mice have worse function recovery than wild-type mice
3. Proinflammatory therapies improve functional recovery after SCI
BAD
Methylpredisolone current anti-inflammatory treatment for SCI systemic immunosuppression can have detrimental
effects especially given that patients with SCI have a compromised immune system
A need for immuno-modulatory therapies!
Immunoglobulin G: A potential immuno-modulatory therapy for SCI
• Isolate from pooled human serum (2000-50,000 donors)
• Many reported immuno-modulatory mechanisms.
• Clinically used to treat autoimmune disorders such as: GuillainBarre-Syndrome, myasthenia gravis, and Kawasaki disease.
• Reported to enhance functional recovery in experimental models of stroke, traumatic brain injury, and multiple sclerosis.
• Based on strong prrof-of-concept, we hypothesize that IgG attenuates inflammation-mediated damage to the spinal cord by modulating the inflammatory response after SCI.
CNS
Systemic
Leukocytes
MMP, Elastase, ROS, cytokines
Leukocytes
Exacerbate Damage
Endothelial cells
TNF‐a, IL‐1B
NOs
IL-6, LIF, Chemokines
IgG
?
Proposed detrimental side of the neuroinflammation cascade
IvIg Promotes Functional Repair of the Neurovascular Unit
IvIg Reduces Neutrophil Infiltration and Activation in the Injured Spinal Cord
IvIg Promotes Neurobehavioural Recovery after Traumatic Spinal cord Injury
IvIg after Spinal Cord Injury: Next Steps
• Time window after SCI (at least 4 hours; promising data that this could be extended to 24 hours after SCI)
• Further assessment of the effects of IvIg• RNA sequencing studies of molecular effects• Examination of local and systemic immune effects• Further delineation of effects at the blood spinal cord barrier level
Promoting Plasticity of Existing Circuits as a Therapeutic Strategy for Spinal Cord Injury
• Two examples:– Promotion of plasticity of respiratory circuits to rescue breathing after spinal cord injury
– Stimulation of the central pattern generator in the lumbar cord to enhance lower limb function
MRI of the cervical spine of a patient with ntSCIdue to degenerative cervical myelopathy.
Adequate ventilation in ntSCI despite loss of PMNs
Sham and ntSCI mice had similar arterial CO2 partial pressure, oxygen saturation, and pH.
Representative plethysmographytracings from sham and ntSCI mice.
Cervical eINs are necessary for maintaining breathing after ntSCI
Cervical glutamatergic cells are crucial for sustaining breathing after traumatic cervical SCI.
Stimulation of cervical eINs restores respiratory function immediately after SCI
Promotion of Plasticity of Respiratory Circuits
• Approaches to potentially activate latent excitatory interneuron pathways– Electrical or optogenetic stimulation
– Pharmacogenetics– Use of neural stem cells as a regenerative strategy
This article was published on September 24, 2018, at NEJM.org.DOI: 10.1056/NEJMoa1803588
Training Protocols and Outcomes
A series of photographs of independent walking. Participant 3 (top) is walking with parallel poles for trunk stability. Participant 4 (bottom) is walking using a rolling walker.
The challenge of the spinal cord injury:
Lack of CNS regeneration
Bioengineered scaffolds
Bioresorbable polymer scaffold which is composed of PLGA [Poly(lactic‐co‐glycolic acid)] and Poly‐L‐Lysine [PLL]
A highly porous scaffold that is conducive to cellular attachment and neurite outgrowth
InVivo Therapeutics (http://www.invivotherapeutics.com)
Neuro‐spinal scaffolds (InVivo Therapeutics)
Neuro‐spinal scaffolds
Neuro‐spinal scaffolds + Neural stem cell treatment reduced tissue loss from secondary injury processes as well as in diminished glial scarring
Enhanced regenerative axons and motor functional recovery in a rat and a monkey SCI
Teng YD et al., PNAS 2002 and InVivo Therapeutics (http://www.invivotherapeutics.com)
Clinical trial
Phase I/IIa clinical trial (NCT02138110; United States)
Recently completed for patients with AIS A acutethoracic SCI
Multi‐center, open‐label study Clearance given to proceed with a next phase
thoracic SCI study
3
4
1
2
3
4
Cell replacement
Trophic support
Immunomodulation
Scaffold Support
1
2
Cell Transplantation for treatment of SCI
Cell-Based Therapies
• Activated macrophages (Procord )• Embryonic stem cells (ESCs) • Schwann cells• Olfactory ensheathing cells• Mesenchymal stem cells• Skin-derived precursor cells• Neural stem cells• Endogenous stem cells
Schwann cell transplantation
Autologous transplantation Neuroprotective role in reducing inflammation Enhancing axonal regeneration and forming
myelin and motor functional recovery in rat SCI
Takami T et al., J. Neurosci 2002
Clinical trials
Phase Ⅰ clinical trial (NCT01739023; United States) In progress for patients with ISNCSCI A acute thoracic SCI Single‐center, open‐label study Study start date; November 2012 Estimated completion date; August 2016 Estimated enrollment; 10 patients
Phase Ⅰ clinical trial (NCT02354625; United States) In progress for patients with AIS A,B,C chronic thoracic
and cervical SCI Single‐center, open‐label study Study start date; November 2012 Estimated completion date; August 2016 Estimated enrollment; 10 patients
Neural Stem Cells for SCI Regeneration
Narihito Nagoshi Mohamad Khazaei Jan-Eric Ahlfors Chris Ahuja Satoshi Nori Jian Wang
Shinsuke Shibata Cindi Morshead
Functional Recovery
Transplantation into SCI
oNPCs
Patients specific drNPCs
Patients bone marrow cells
neurons
astrocytes
oligodendrocytes
Generation of Oligodendrogenic Human NPCs
o-drNPCs Enhance Tissue Sparing
o-drNPCs Improve Locomotor Function inSubacute SCI
Neural Stem Cells for SCI
– Despite the cessation in the Geron trial…– The stem cell era in spinal cord injury has started—
this will likely lead to a number of stem cell trials in SCI
» A Phase I trial of adult neural stem cells has been completed in Zurich, Toronto and Calgary in patients with severe thoracic SCI
» A Phase I cervical trial has now been undertaken (Stem Cell Inc) and a another is underway (Asterias)
» Planning underway for a Phase I trial with directly reprogrammed neural stem cells for cervical SCI (Fortuna Fix)
» The Japanese authorities have given clearance for a Phase I/II trial of IPSC-derived neural stem cells in SCI
Key Concepts• Neuroprotective approaches
– Time is Spine– Re-evaluation of the role of steroids– Riluzole, minocycline, hypothermia, G-CSF ; IvIg
• Promoting plasticity of neural circuits– Activation of latent circuits to rescue breathing– Epidural stimulation for chronic SCI
• Bioengineered scapholds• Cellular therapies
– Neural stem cells– Schwann cells