New Approaches to New Approaches to New Approaches to Repair of - - PowerPoint PPT Presentation

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New Approaches to New Approaches to New Approaches to Repair of Repair of Repair of Spinal Cord Injury Spinal Cord Injury Spinal Cord Injury 1 WHY IS THE SPINAL CORD SO VULNERABLE? WHY IS THE SPINAL CORD SO VULNERABLE? Peripheral Nerve

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New Approaches to Repair of Spinal Cord Injury New Approaches to New Approaches to Repair of Repair of Spinal Cord Injury Spinal 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 Brain Hand Sensation Nerve cell Axon or nerve fiber Peripheral Nervous System Central Nervous System

Disconnection

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Hand

WHAT HAPPENS IN A SPINAL CORD INJURY

Brain Nerve cell Axon or nerve fiber Degeneration

Direct injury and Secondary tissue damage

Awareness

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Hand

WHAT ARE THE BARRIERS TO REGENERATION

Brain Nerve cell Axon or nerve fiber

Regrow Regrow Reconnect Reconnect This will This will

  • ccur
  • ccur successfully

successfully in the PNS in the PNS

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Hand

WHAT ARE THE BARRIERS TO REGENERATION

Brain Nerve cell Axon or nerve fiber

Lack of Lack of Growth Growth factors factors

Inhibitors Inhibitors Scar tissue Scar tissue

Lack of Lack of support support

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Strategies for treatment Strategies 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
  • 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 treatment Strategies 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
  • 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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Information sources Information 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 strategies Cell 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 trials Ongoing 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 trials Planned 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 trials Planned trials

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Ongoing or recent trials Ongoing or recent trials

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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Ongoing or recent trials Ongoing or recent trials

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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Ongoing or recent trials Ongoing or recent trials

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 tools engineering tools

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Future Directions Future Directions

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2.0 MOSP 12.6 O4 2.3 GFAP 0.2 β β β βIII-tubulin 83.4 Nestin % positive

I J

>90 MOSP positive >90 O4 positive 70 GFAP positive % Nestin positive

B B C C D D F F G G H H E E A A

Nestin Nestin β β β β β β β βIII III-

  • tubulin

tubulin GFAP GFAP O4 O4 MOSP MOSP Nestin Nestin/GFAP /GFAP Nestin Nestin/MOSP /MOSP

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PCLF IN SCIATIC NERVE

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

STRATEGIES ARE MULTIPLE STRATEGIES ARE MULTIPLE

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New approach New approach -

  • adult stem cells as

adult stem cells as “ “delivery vehicles delivery vehicles” ”

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NT3 MSC NT3 MSC NT3 MSC NT3 MSC NT3 MSC NT3 MSC

NT3-expressing MSC’s for ascending proprioceptive pathways

New approach New approach -

  • adult stem cells as

adult stem cells as “ “delivery vehicles delivery vehicles” ”

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NT3 MSC NT3 MSC NT3 MSC NT3 MSC NT3 MSC NT3 MSC

NGF-expressing MSC’s for ascending nociceptive pathways NT3-expressing MSC’s for ascending proprioceptive pathways

New approach New approach -

  • adult stem cells as

adult stem cells as “ “delivery vehicles delivery vehicles” ”

NGF MSC NGF MSC NGF MSC NGF MSC NGF MSC NGF MSC

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NT3 MSC NT3 MSC NT3 MSC NT3 MSC NT3 MSC NT3 MSC

NGF-expressing MSC’s for ascending nociceptive pathways NT3-expressing MSC’s for ascending proprioceptive pathways

BDNF MSC BDNF MSC BDNF MSC BDNF MSC BDNF MSC BDNF MSC BDNF MSC

BDNF-expressing MSC’s for descending motors pathways

New approach New approach -

  • adult stem cells as

adult stem cells as “ “delivery vehicles delivery vehicles” ”

NGF MSC NGF MSC NGF MSC NGF MSC NGF MSC NGF MSC

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

How can you tell the difference How can you tell the difference

Some simple “rules of thumb”

  • If it is offered in a reputable institution in

North 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 in

North 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 Europe A Cell Center in Europe

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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 PATIENTS WHEN 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 PATIENTS WHEN 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

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

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

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Themes Themes

  • What are stem cells?
  • Future success depends on multi-

disciplinary collaboration.

  • The central nervous system has

the capacity to regenerate.

  • Restoration of function depends
  • n 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
  • n bridging or by-passing tissue

damage

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Stem Cells Stem 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 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

  • 1. Acute traumatic damage (immediate)

Prevention- seat belts

  • sports safety
  • ban guns (U.S.)

Rapid spine stabilisation

  • at the accident site
  • surgical fixation

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

  • 1. Acute traumatic damage (immediate)
  • 2. Secondary haemorrhagic, inflammatory,
  • xidative stress (1 -96 hours)

Focus of ongoing trials

  • Steroids(??)
  • Anti-apoptotic agents (e.g. minocycline)
  • Oxidative stress inhibitors

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

  • 1. Acute traumatic damage (immediate)
  • 2. Secondary haemorrhagic, inflammatory,
  • xidative 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

WHAT HAPPENS IN A SPINAL CORD INJURY?

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Strategies to Restore Function Strategies to Restore Function

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Strategies to Restore Function Strategies to Restore Function

Injury

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Strategies to Restore Function Strategies to Restore Function

Injury Injury By By-

  • pass

pass Electronic Electronic-

  • robotic

robotic

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Strategies to Restore Function Strategies to Restore Function

Injury By By-

  • pass

pass Electronic Electronic-

  • robotic

robotic Bridge Bridge