New Approaches to Repair of Spinal Cord Injury Dr Windebank presentation.pdf38 Spinal Cord Injury (a best guess) • Proof of concept and biocompatibility studies in peripheral nerve

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New Approaches toRepair of

Spinal Cord Injury

New Approaches toNew Approaches to

Repair ofRepair of

Spinal Cord InjurySpinal Cord Injury

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WHY IS THE SPINAL CORD SO VULNERABLE?WHY IS THE SPINAL CORD SO VULNERABLE?

Peripheral Nerve Spinal Cord

DRG Neuron

Schwann Cell

Myelin

Collagen

Oligodendrocyte

Myelin

Axon

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WHY IS THE SPINAL CORD SO VULNERABLE?WHY IS THE SPINAL CORD SO VULNERABLE?

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WHAT HAPPENS IN A SPINAL CORD INJURY

Awareness

BrainHand

Sensation

Nerve cellAxon or

nerve fiber

Peripheral

Nervous

System

Central

Nervous

System

Disconnection

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Hand

WHAT HAPPENS IN A SPINAL CORD INJURY

Brain

Nerve cellAxon or

nerve fiber Degeneration

Direct injury and

Secondary tissue damage

Awareness

6

Hand

WHAT ARE THE BARRIERS TO REGENERATION

Brain

Nerve cellAxon or

nerve fiber

RegrowRegrow

ReconnectReconnect

This willThis will

occur occur successfully successfully

in the PNSin the PNS

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Hand

WHAT ARE THE BARRIERS TO REGENERATION

Brain

Nerve cellAxon or

nerve fiber

Lack ofLack of

GrowthGrowth

factorsfactors

InhibitorsInhibitors

Scar tissueScar tissue

Lack ofLack of

supportsupport

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Strategies for treatmentStrategies for treatment

• Prevent spinal cord injuries

• Stabilize the spinal cord (surgery)

• Prevent further acute damage

• Promote healing and regeneration

• Clear cell debris

• Prevent inhibitors from working

• Promote growth (cells/pharmaceuticals)

• Pain management, physical therapy and rehabilitation









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Strategies for treatmentStrategies for treatment

















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Information sourcesInformation sources

• http://www.mcpf.org/

• http://clinicaltrials.gov/

• clinical_trials_public_guide.pdf

• http://www.mcpf.org/

• http://clinicaltrials.gov/

• clinical_trials_public_guide.pdf

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Cell strategiesCell strategies

• Immune cells (clear debris)

• Schwann cells

• Olfactory ensheathing glia

• Adult stem cells (mesenchymal stem cells)

• Embryonic stem cells

• Immune cells (clear debris)

• Schwann cells

• Olfactory ensheathing glia

• Adult stem cells (mesenchymal stem cells)

• Embryonic stem cells

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Procord/Proneuron

• Patient-derived activated macrophages

• Initial studies in Israel

• Phase II trial in US 2005 - 2008

• 50 patients enrolled

• Suspended for “financial reasons”

Procord/Proneuron

• Patient-derived activated macrophages

• Initial studies in Israel

• Phase II trial in US 2005 - 2008

• 50 patients enrolled

• Suspended for “financial reasons”

Ongoing or recent trialsOngoing or recent trials

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Miami Project to Cure Paralysis

• Schwann cells

• Myelin-forming cells from peripheral nerves

• Patient derived

• “pre-IND”

Miami Project to Cure Paralysis

• Schwann cells

• Myelin-forming cells from peripheral nerves

• Patient derived

• “pre-IND”

Planned trialsPlanned trials

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Olfactory Ensheathing Glia

• Cells from patients olfactory (smell-detecting) system

• Support cell that may promote nerve growth

• Uncontrolled reports from Portugal, China, Australia

• Phase I safety trial proposed in England

Olfactory Ensheathing Glia

• Cells from patients olfactory (smell-detecting) system

• Support cell that may promote nerve growth

• Uncontrolled reports from Portugal, China, Australia

• Phase I safety trial proposed in England

Planned trialsPlanned trials

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Geron

• Oligodendrocyte progenitor cells (human embryonic)

• Safety study (phase I)

• Repair lost myelin

• Complete

• <14 days after injury

• Seven US centers

Geron

• Oligodendrocyte progenitor cells (human embryonic)

• Safety study (phase I)

• Repair lost myelin

• Complete

• <14 days after injury

• Seven US centers

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Mesnchymal (adult) Stem Cells (MSC’s

• Phase I safety studies (various levels of rigor)

• China, Korea, Czech Republic, Russia, Brazil

• Cells derived from bone marrow, adipose tissue, peripheral blood

• (Umbilical cord cells)

• Work at Mayo Clinic related to ALS (Lou Gehrig’s Disease)

Mesnchymal (adult) Stem Cells (MSC’s

• Phase I safety studies (various levels of rigor)

• China, Korea, Czech Republic, Russia, Brazil

• Cells derived from bone marrow, adipose tissue, peripheral blood

• (Umbilical cord cells)

• Work at Mayo Clinic related to ALS (Lou Gehrig’s Disease)

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Other Therapies

Systemic hypothermia

• Miami project single center trial (uncontrolled)

• Multicenter trial being planned

Rolipram (increases cAMP) in phase II trials

Rho inhibitors (Cethrin) planned phase II <72h after injury

Nogo antibody trials (ongoing) in Europe

Other Therapies

Systemic hypothermia

• Miami project single center trial (uncontrolled)

• Multicenter trial being planned

Rolipram (increases cAMP) in phase II trials

Rho inhibitors (Cethrin) planned phase II <72h after injury

Nogo antibody trials (ongoing) in Europe

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1. What are the properties of the peripheral nervous system that permit regeneration?

2. Make the spinal cord more like the peripheral nerve using tissue engineering tools

1.1. What are the properties of the peripheral What are the properties of the peripheral nervous system that permit nervous system that permit regeneration?regeneration?

2.2. Make the spinal cord more like the Make the spinal cord more like the peripheral nerve using tissue peripheral nerve using tissue engineering toolsengineering tools

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are needed to see this picture.

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Future DirectionsFuture Directions

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222.0MOSP

12.6O4

2.3GFAP

0.2ββββIII-tubulin

83.4Nestin

% positiveI J

>90MOSP positive

>90O4 positive

70GFAP positive

% Nestin positive

BB CC DD

FF GG HHEE

AA

NestinNestin ββββββββIIIIII--tubulintubulin GFAPGFAP

O4O4 MOSPMOSP NestinNestin/GFAP/GFAP NestinNestin/MOSP/MOSP

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PCLF IN SCIATIC NERVE

STUDYING DIFFERENT CELL TYPES STUDYING DIFFERENT CELL TYPES IN SPINAL CORD INJURYIN SPINAL CORD INJURY

PLACE CELLS

INTO SCAFFOLD

TRACER

INJECTION

Fast Blue

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D

*

*

A B C

F

E

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HOW ARE WE DOING? HOW ARE WE DOING?

• Normal Rat Spinal Cord ~330,000 MF/cord(at the T/L level)

• Total nerve fibers ~3,000,000/cord

• 7 channels (800/channel) ~5,600/scaffold

• 50% traverse from end to end ~2,800

• 10% travel 0.5 mm distally ~560

• 2% travel 1.0 mm distally ~1-200

• Need about 10% of normal ~300,000 nerves

• Normal Rat Spinal Cord ~330,000 MF/cord(at the T/L level)

• Total nerve fibers ~3,000,000/cord

• 7 channels (800/channel) ~5,600/scaffold

• 50% traverse from end to end ~2,800

• 10% travel 0.5 mm distally ~560

• 2% travel 1.0 mm distally ~1-200

• Need about 10% of normal ~300,000 nerves

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ConclusionsConclusions

STRATEGIES ARE MULTIPLESTRATEGIES ARE MULTIPLE

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New approach New approach -- adult stem cells as adult stem cells as ““delivery vehiclesdelivery vehicles””

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NT3

MSC

NT3MSC

NT3MSC

NT3

MSC

NT3

MSCNT3MSC

NT3-expressing

MSC’s for

ascending

proprioceptive

pathways


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NT3

MSC

NT3MSC

NT3MSC

NT3

MSC

NT3

MSCNT3MSC

NGF-expressing

MSC’s for

ascending

nociceptive

pathways

NT3-expressing

MSC’s for

ascending

proprioceptive

pathways


NGF

MSC

NGF

MSC

NGF

MSC

NGFMSC

NGF

MSC

NGF

MSC

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NT3

MSC

NT3MSC

NT3MSC

NT3

MSC

NT3

MSCNT3MSC

NGF-expressing

MSC’s for

ascending

nociceptive

pathways

NT3-expressing

MSC’s for

ascending

proprioceptive

pathways

BDNF

MSC

BDNF

MSC

BDNF

MSCBDNF

MSCBDNF

MSC

BDNF

MSC

BDNFMSC

BDNF-expressing

MSC’s for

descending

motors

pathways


NGF

MSC

NGF

MSC

NGF

MSC

NGFMSC

NGF

MSC

NGF

MSC

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HYPE VS HOPE THE SHARKS AND SHYSTERSHYPE VS HOPE THE SHARKS AND SHYSTERS

How can you tell the differenceHow can you tell the difference

Some simple “rules of thumb”

• If it is offered in a reputable institution inNorth America or Europe as part of a clinical trial it is probably safe

• If you have to pay for the treatment it is probably unproven and unreliable

• If you have to go to a third country (e.g. Mexico) it is probably a fraud

Some simple “rules of thumb”

• If it is offered in a reputable institution inNorth America or Europe as part of a clinical trial it is probably safe

• If you have to pay for the treatment it is probably unproven and unreliable

• If you have to go to a third country (e.g. Mexico) it is probably a fraud

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A Cell Center in EuropeA Cell Center in Europe

• ････ALS････Alzheimer

• ････Cardiovascular diseases

• ････Cerebral palsy

• ････Diabetes

• ････Erectile dysfunction

• ････Failed Back Surgery Syndrome

• ････ALS････Alzheimer

• ････Cardiovascular diseases

• ････Cerebral palsy

• ････Diabetes

• ････Erectile dysfunction

• ････Failed Back Surgery Syndrome

• ････ Macular degeneration

• ････Multiple sclerosis

• ････Osteoarthritis

• ････Parkinson

• ････Spinal cord injuries

• ････Stroke

• ････ Macular degeneration

• ････Multiple sclerosis

• ････Osteoarthritis

• ････Parkinson

• ････Spinal cord injuries

• ････Stroke

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Funding

NIH

Wilson Foundation

Neilsen Foundation

MCPF

Mayo

Acknowledgements

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And Questions??And Questions??

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WHEN WILL THIS BE COMING TO PATIENTSWHEN WILL THIS BE COMING TO PATIENTS

Polymer scaffolds

• Simple single channel ‘sleeves’ already in clinical use for repair of peripheral nerves in U.S. and Europe(e.g. Neurolac PCL Polyganics, Groningen; NeuraGen Collagen Integra, New Jersey)

• Plans to initiate trials of complex, biodegradable, ‘smart’scaffolds in peripheral nerve in ~2 years (U.S.)

Adult Stem Cells

• Bone marrow stem cell transplants in cancer patients in routine clinical use now

• Adult MSC trial to repair damaged heart muscle planned to begin in ~ 2years (Ireland)

• OEG/brachial plexus trial to begin this year in U.K.

Polymer scaffolds

• Simple single channel ‘sleeves’ already in clinical use for repair of peripheral nerves in U.S. and Europe(e.g. Neurolac PCL Polyganics, Groningen; NeuraGen Collagen Integra, New Jersey)

• Plans to initiate trials of complex, biodegradable, ‘smart’scaffolds in peripheral nerve in ~2 years (U.S.)

Adult Stem Cells

• Bone marrow stem cell transplants in cancer patients in routine clinical use now

• Adult MSC trial to repair damaged heart muscle planned to begin in ~ 2years (Ireland)

• OEG/brachial plexus trial to begin this year in U.K.

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Spinal Cord Injury (a best guess)

• Proof of concept and biocompatibility studies in peripheral nerve are ongoing

• Injections of stem cells (adult autologous) and matrix-bound, recombinant growth factors 2 - 4 years• proof of safety• acute “neuroprotective”

• Injections of genetically modified stem cells ~5 years• proof of safety• Neurotrophic effects

• Reconstructive approaches with embryonic or adult stem cells in organized matrices ~ 7-10 years

Spinal Cord Injury (a best guess)

• Proof of concept and biocompatibility studies in peripheral nerve are ongoing

• Injections of stem cells (adult autologous) and matrix-bound, recombinant growth factors 2 - 4 years• proof of safety• acute “neuroprotective”

• Injections of genetically modified stem cells ~5 years• proof of safety• Neurotrophic effects

• Reconstructive approaches with embryonic or adult stem cells in organized matrices ~ 7-10 years

WHEN WILL THIS BE COMING TO PATIENTSWHEN WILL THIS BE COMING TO PATIENTS

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• Acknowledgements• Many Colleagues at NUIG and Mayo

• Funding from National Institutes of Health, the Wilson, Mayo, Neilsen and Morton Foundations

• Funding from Science Foundation Ireland for the ETS Walton Fellowship




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Leave you with Dr. Peter Dockery who believes that no problems are insurmountable




Leave you with Dr. Peter Dockery who believes that no problems are insurmountable

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ThemesThemes• What are stem cells?

• Future success depends on multi-disciplinary collaboration.

• The central nervous system has the capacity to regenerate.

• Restoration of function depends on bridging or by-passing tissue damage

• What are stem cells?

• Future success depends on multi-disciplinary collaboration.

• The central nervous system has the capacity to regenerate.

• Restoration of function depends on bridging or by-passing tissue damage

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Stem CellsStem Cells

• Embryonic Stem Cells

• Neural Stem Cells

• Neural Progenitor Cells

• Adult-derived Stem cells

• Tissue derived

• Mesenchymal

• Embryonic Stem Cells

• Neural Stem Cells

• Neural Progenitor Cells

• Adult-derived Stem cells

• Tissue derived

• Mesenchymal

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THE END RESULT

WHAT HAPPENS IN A SPINAL CORD INJURY?

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What happens in a spinal cord injury?

Four Major consequences

All are separate therapeutic Targets


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1. Acute traumatic damage (immediate)

Prevention- seat belts- sports safety- ban guns (U.S.)

Rapid spine stabilisation- at the accident site

- surgical fixation


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2. Secondary haemorrhagic, inflammatory,oxidative stress (1 -96 hours)

Focus of ongoing trials- Steroids(??)- Anti-apoptotic agents (e.g. minocycline)

- Oxidative stress inhibitors


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2. Secondary haemorrhagic, inflammatory,oxidative stress (1 -96 hours)

3. Disruption of axonal connections (0-96 hours)4. Atrophy/dwindling of disconnected muscles,

neurons, supporting cells.

Major focus of our research


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Strategies to Restore FunctionStrategies to Restore Function

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Injury

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Injury

Injury

ByBy--passpass ElectronicElectronic--roboticrobotic

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Injury

ByBy--passpass ElectronicElectronic--roboticrobotic

BridgeBridge

Documents

New Approaches to Repair of Spinal Cord Injury Dr Windebank presentation.pdf38 Spinal Cord Injury (a best guess) • Proof of concept and biocompatibility studies in peripheral nerve