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

Michael.fehlings@uhn.on.ca

• 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