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

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 Spinal Cord Schwann Cell Myelin DRG Neuron Oligodendrocyte Myelin Collagen Axon 2

WHY IS THE SPINAL CORD SO VULNERABLE? WHY IS THE SPINAL CORD SO VULNERABLE? 3

WHAT HAPPENS IN A SPINAL CORD INJURY Central Nerve cell Axon or Nervous nerve fiber System Peripheral Nervous System Disconnection Hand Brain Awareness Sensation 4

WHAT HAPPENS IN A SPINAL CORD INJURY Nerve cell Axon or Degeneration nerve fiber Direct injury and Secondary tissue damage Hand Brain Awareness 5

WHAT ARE THE BARRIERS TO REGENERATION Nerve cell Axon or nerve fiber This will This will occur successfully successfully occur Regrow Regrow in the PNS in the PNS Hand Brain Reconnect Reconnect 6

WHAT ARE THE BARRIERS TO REGENERATION Nerve cell Axon or nerve fiber Scar tissue Scar tissue Lack of Lack of support support Inhibitors Inhibitors Hand Brain Lack of Lack of Growth Growth factors factors 7

Strategies for treatment Strategies for treatment • Prevent spinal cord injuries • Prevent spinal cord injuries • Stabilize the spinal cord (surgery) • Stabilize the spinal cord (surgery) • Prevent further acute damage • Prevent further acute damage • Promote healing and regeneration • Promote healing and regeneration • Clear cell debris • Clear cell debris • Prevent inhibitors from working • Prevent inhibitors from working • Promote growth (cells/pharmaceuticals) • Promote growth (cells/pharmaceuticals) • Pain management, physical therapy and rehabilitation • Pain management, physical therapy and rehabilitation 8

Strategies for treatment Strategies for treatment • Prevent spinal cord injuries • Prevent spinal cord injuries • Stabilize the spinal cord (surgery) • Stabilize the spinal cord (surgery) • Prevent further acute damage • Prevent further acute damage • Promote healing and regeneration • Promote healing and regeneration • Clear cell debris • Clear cell debris • Prevent inhibitors from working • Prevent inhibitors from working • Promote growth (cells/pharmaceuticals) • Promote growth (cells/pharmaceuticals) • Pain management, physical therapy and rehabilitation • Pain management, physical therapy and rehabilitation 9

Information sources Information sources • http://www.mcpf.org/ • http://www.mcpf.org/ • http://clinicaltrials.gov/ • http://clinicaltrials.gov/ • clinical_trials_public_guide.pdf • clinical_trials_public_guide.pdf 10

Cell strategies Cell strategies • Immune cells (clear debris) • Immune cells (clear debris) • Schwann cells • Schwann cells • Olfactory ensheathing glia • Olfactory ensheathing glia • Adult stem cells (mesenchymal stem cells) • Adult stem cells (mesenchymal stem cells) • Embryonic stem cells • Embryonic stem cells 11

Ongoing or recent trials Ongoing or recent trials Procord/Proneuron Procord/Proneuron • Patient-derived activated macrophages • Patient-derived activated macrophages • Initial studies in Israel • Initial studies in Israel • Phase II trial in US 2005 - 2008 • Phase II trial in US 2005 - 2008 • 50 patients enrolled • 50 patients enrolled • Suspended for “financial reasons” • Suspended for “financial reasons” 12

Planned trials Planned trials Miami Project to Cure Paralysis Miami Project to Cure Paralysis • Schwann cells • Schwann cells • Myelin-forming cells from peripheral nerves • Myelin-forming cells from peripheral nerves • Patient derived • Patient derived • “pre-IND” • “pre-IND” 13

Planned trials Planned trials Olfactory Ensheathing Glia Olfactory Ensheathing Glia • Cells from patients olfactory (smell-detecting) system • Cells from patients olfactory (smell-detecting) system • Support cell that may promote nerve growth • Support cell that may promote nerve growth • Uncontrolled reports from Portugal, China, Australia • Uncontrolled reports from Portugal, China, Australia • Phase I safety trial proposed in England • Phase I safety trial proposed in England 14

Ongoing or recent trials Ongoing or recent trials Geron Geron • Oligodendrocyte progenitor cells (human embryonic) • Oligodendrocyte progenitor cells (human embryonic) • Safety study (phase I) • Safety study (phase I) • Repair lost myelin • Repair lost myelin • Complete • Complete • <14 days after injury • <14 days after injury • Seven US centers • Seven US centers 15

Ongoing or recent trials Ongoing or recent trials Mesnchymal (adult) Stem Cells (MSC’s Mesnchymal (adult) Stem Cells (MSC’s • Phase I safety studies (various levels of rigor) • Phase I safety studies (various levels of rigor) • China, Korea, Czech Republic, Russia, Brazil • China, Korea, Czech Republic, Russia, Brazil • Cells derived from bone marrow, adipose tissue, peripheral • Cells derived from bone marrow, adipose tissue, peripheral blood blood • (Umbilical cord cells) • (Umbilical cord cells) • Work at Mayo Clinic related to ALS (Lou Gehrig’s Disease) • Work at Mayo Clinic related to ALS (Lou Gehrig’s Disease) 16

Ongoing or recent trials Ongoing or recent trials Other Therapies Other Therapies Systemic hypothermia Systemic hypothermia • Miami project single center trial (uncontrolled) • Miami project single center trial (uncontrolled) • Multicenter trial being planned • Multicenter trial being planned Rolipram (increases cAMP) in phase II trials Rolipram (increases cAMP) in phase II trials Rho inhibitors (Cethrin) planned phase II <72h after injury Rho inhibitors (Cethrin) planned phase II <72h after injury Nogo antibody trials (ongoing) in Europe Nogo antibody trials (ongoing) in Europe 17

1. What are the properties of the peripheral 1. 1. What are the properties of the peripheral What are the properties of the peripheral nervous system that permit nervous system that permit nervous system that permit regeneration? regeneration? regeneration? 2. Make the spinal cord more like the 2. 2. Make the spinal cord more like the Make the spinal cord more like the peripheral nerve using tissue peripheral nerve using tissue peripheral nerve using tissue engineering tools engineering tools engineering tools 18

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Future Directions Future Directions QuickTime™ and a YUV420 codec decompressor are needed to see this picture. 20

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A A B B C C D D Nestin Nestin β III β III- -tubulin tubulin β β β β β β GFAP GFAP H H E G E F G F Nestin/MOSP /MOSP Nestin Nestin/GFAP /GFAP Nestin O4 O4 MOSP MOSP I % positive J % Nestin positive Nestin 83.4 GFAP positive 70 β III-tubulin β 0.2 β β GFAP 2.3 O4 positive >90 O4 12.6 MOSP positive >90 MOSP 2.0 22

PCLF IN SCIATIC NERVE 23

STUDYING DIFFERENT CELL TYPES STUDYING DIFFERENT CELL TYPES IN SPINAL CORD INJURY IN SPINAL CORD INJURY PLACE CELLS INTO SCAFFOLD Fast Blue TRACER INJECTION

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HOW ARE WE DOING? HOW ARE WE DOING? • Normal Rat Spinal Cord • Normal Rat Spinal Cord ~330,000 MF/cord ~330,000 MF/cord (at the T/L level) (at the T/L level) • Total nerve fibers • Total nerve fibers ~3,000,000/cord ~3,000,000/cord • 7 channels (800/channel) • 7 channels (800/channel) ~5,600/scaffold ~5,600/scaffold • 50% traverse from end to end • 50% traverse from end to end ~2,800 ~2,800 • 10% travel 0.5 mm distally • 10% travel 0.5 mm distally ~560 ~560 • • 2% travel 1.0 mm distally ~1-200 2% travel 1.0 mm distally ~1-200 • Need about 10% of normal • Need about 10% of normal ~300,000 nerves ~300,000 nerves 26

STRATEGIES ARE MULTIPLE STRATEGIES ARE MULTIPLE Conclusions Conclusions 27

New approach - - adult stem cells as adult stem cells as “ “delivery vehicles delivery vehicles” ” New approach 28

NT3 NT3-expressing NT3 NT3 MSC MSC MSC’s for MSC ascending NT3 NT3 proprioceptive MSC MSC pathways NT3 MSC New approach - - adult stem cells as adult stem cells as “ “delivery vehicles delivery vehicles” ” New approach 29

NT3 NT3-expressing NT3 NT3 NGF-expressing MSC MSC MSC’s for MSC MSC’s for ascending ascending NGF NT3 NT3 proprioceptive NGF nociceptive MSC MSC MSC MSC pathways pathways NGF NT3 NGF MSC MSC MSC NGF NGF MSC MSC New approach - - adult stem cells as adult stem cells as “ “delivery vehicles delivery vehicles” ” New approach 30