Spinal Cord Injury Spinal Cord Injury TherapiesTherapies

Wise Young, PhD MDWise Young, PhD MDW. M. Keck Center for Collaborative NeuroscienceW. M. Keck Center for Collaborative Neuroscience

Rutgers University, Piscataway, New JerseyRutgers University, Piscataway, New Jersey

http://carecure.rutgers.eduhttp://carecure.rutgers.edu

State-of-the-Art 1995State-of-the-Art 1995 Acute and Subacute TherapiesAcute and Subacute Therapies

Methylprednisolone is neuroprotective (NASCIS, 1990)Methylprednisolone is neuroprotective (NASCIS, 1990) GM1 improves locomotor recovery in humans (Geisler, 1991)GM1 improves locomotor recovery in humans (Geisler, 1991)

Spasticity and Pain TherapiesSpasticity and Pain Therapies Intrathecal baclofen pump (Medtronics)Intrathecal baclofen pump (Medtronics) Tricyclic antidepressant amitriptyline (Elavil)Tricyclic antidepressant amitriptyline (Elavil)

Promising TherapiesPromising Therapies IN-1 antibody stimulates regeneration in rats (Schwab, 1991-)IN-1 antibody stimulates regeneration in rats (Schwab, 1991-) Intravenous 4-aminopyridine improves function in people with chronic Intravenous 4-aminopyridine improves function in people with chronic

spinal cord injury (Hansebout, 1992-)spinal cord injury (Hansebout, 1992-) Fetal tissue transplants survive in animals (Reier, 1992-)Fetal tissue transplants survive in animals (Reier, 1992-) Functional regeneration of neonatal spinal cords (Kawaguchi, 1994-)Functional regeneration of neonatal spinal cords (Kawaguchi, 1994-) Neurotrophin-secreting fibroblast transplants (Tuszynski, 1994-)Neurotrophin-secreting fibroblast transplants (Tuszynski, 1994-)

MethylprednisoloneMethylprednisolone NASCIS 3NASCIS 3

High dose (30 mg/kg bolus followed by 5.4 mg/kg/hr • 23h iv)High dose (30 mg/kg bolus followed by 5.4 mg/kg/hr • 23h iv) MP vs. Placebo: 75% vs. 59% (incomplete), 21% vs. 8% (complete)MP vs. Placebo: 75% vs. 59% (incomplete), 21% vs. 8% (complete)

More effective when started within 3 hours after injuryMore effective when started within 3 hours after injury 48h MP more effective than 24h MP when started >3h after injury48h MP more effective than 24h MP when started >3h after injury

>24h therapy may be associated with more severe pneumonia>24h therapy may be associated with more severe pneumonia Mechanisms of actionMechanisms of action

Anti-inflammatory (glucocorticoid receptor mediated mechanisms)Anti-inflammatory (glucocorticoid receptor mediated mechanisms) Immunosuppression (suppresses cytokine & antibody production)Immunosuppression (suppresses cytokine & antibody production) Anti-oxidant & lipid peroxidation inhibitor (high dose only)Anti-oxidant & lipid peroxidation inhibitor (high dose only)

Cellular effectsCellular effects Reduces necrosis and edemaReduces necrosis and edema Suppresses pro-inflammatory gene expressionSuppresses pro-inflammatory gene expression Prevents apoptosis in white matterPrevents apoptosis in white matter

Surgical Therapies (1995>)Surgical Therapies (1995>) Stabilization & decompressionStabilization & decompression

StabilizationStabilization Anterior and posterior platesAnterior and posterior plates Titanium cage & other Titanium cage & other

vertebral fusion methodsvertebral fusion methods Delayed decompression Delayed decompression

restore function (Bohlman)restore function (Bohlman) Untethering spinal cord Untethering spinal cord

improves functionimproves function Adcon gel and other methods Adcon gel and other methods

to prevent epidural scarring to prevent epidural scarring Urological proceduresUrological procedures

Suprapubic catheterization & Suprapubic catheterization & Ileal conduits (Mitrafanoff)Ileal conduits (Mitrafanoff)

Stents and artificial sphincters Stents and artificial sphincters for bladder and bowelfor bladder and bowel

Syringomyelic cystsSyringomyelic cysts Remove subdural adhesionsRemove subdural adhesions Restoring CSF flowRestoring CSF flow Dural grafts Dural grafts

Peripheral nerve bridgingPeripheral nerve bridging Implanting avulsed roots or Implanting avulsed roots or

nerves into cord fornerves into cord for Muscle reinnervationMuscle reinnervation Reduce neuropathic painReduce neuropathic pain Bladder reinnervationBladder reinnervation

Peripheral nerve bridgingPeripheral nerve bridging Bridging spinal accessory, Bridging spinal accessory,

intercostal, and ulnar nerves intercostal, and ulnar nerves to phrenic, sciatic, pudendal, to phrenic, sciatic, pudendal, and other peripheral nervesand other peripheral nerves

End-to-side anastomosesEnd-to-side anastomoses

Drug Therapies (1995>)Drug Therapies (1995>) Acute & subacute therapies Acute & subacute therapies

NASCIS 2:NASCIS 2: 24-hour methylprednisolone 24-hour methylprednisolone

<8h better than placebo<8h better than placebo NASCIS 3: NASCIS 3:

48-hour methylprednisolone 48-hour methylprednisolone (MP) is better than a 24-hour (MP) is better than a 24-hour course of MP when started >3 course of MP when started >3 hours after injury (1998).hours after injury (1998).

48-hour course of Tirilazad 48-hour course of Tirilazad mesylate after an initial bolus mesylate after an initial bolus of MP is similar to 24-hour of MP is similar to 24-hour course of MP course of MP

MP+GM1 MP+GM1 accelerates 6-week recovery accelerates 6-week recovery

compared to MP alone but compared to MP alone but not one year (Geisler, 1999)not one year (Geisler, 1999)

Chronic therapiesChronic therapies TizanidineTizanidine

Reduces spasticity with less Reduces spasticity with less side-effectsside-effects

Intrathecal baclofenIntrathecal baclofen Effectively reduces even Effectively reduces even

severe spasticity with minimal severe spasticity with minimal side-effectsside-effects

Oral 4-aminopyridineOral 4-aminopyridine May reduce pain and May reduce pain and

spasticity (Hayes, et al. 1998)spasticity (Hayes, et al. 1998) May improve bladder, bowel, May improve bladder, bowel,

and sexual functionand sexual function A third of patients may get A third of patients may get

improvement of motor and improvement of motor and sensory function on 4-APsensory function on 4-AP

Rehabilitative Therapies Rehabilitative Therapies (1995>)(1995>)

Bladder FunctionBladder Function Urodynamic studiesUrodynamic studies Intravesicular instillationIntravesicular instillation

DitropanDitropan CapsaicinCapsaicin

Neuropathic Pain TherapiesNeuropathic Pain Therapies AntidepressantsAntidepressants

Amitryptiline (Elavil)Amitryptiline (Elavil) Anti-epileptic analgesicsAnti-epileptic analgesics

High dose Neurontin High dose Neurontin (Gabapentin)(Gabapentin)

Glutamate receptor blockersGlutamate receptor blockers KetamineKetamine DextromethorphanDextromethorphan

CannabinoidsCannabinoids

Functional electrical Functional electrical stimulationstimulation Implanted hand muscle Implanted hand muscle

stimulation (Freehand)stimulation (Freehand) FES stimulatorsFES stimulators Leg/walking stimulators Leg/walking stimulators

(Parastep)(Parastep) FES exercise devicesFES exercise devices

Reversing learned non-useReversing learned non-use Forced-use trainingForced-use training Biofeedback therapy Biofeedback therapy Supported treadmill Supported treadmill

ambulation trainingambulation training Robotic exercisersRobotic exercisers

Regenerative Therapies Regenerative Therapies (1995>)(1995>)

Axonal growth inhibitor blockadeAxonal growth inhibitor blockade Anti-Nogo antibody IN-1 (Schwab, Anti-Nogo antibody IN-1 (Schwab,

et al. 1990-2001).et al. 1990-2001). Nogo receptor blockers Nogo receptor blockers

(Strittmatter, 2001-)(Strittmatter, 2001-) Chondroitinase (Bradbury, 2002)Chondroitinase (Bradbury, 2002) C3 rho inhibitor (McKerracher, C3 rho inhibitor (McKerracher,

2001)2001) Purine nucleotides Purine nucleotides

Inosine (Benowitz, et al. 1999)Inosine (Benowitz, et al. 1999) AIT-082 (Neotherapeutics)AIT-082 (Neotherapeutics) Adenosine (Chao,et al, 2000)Adenosine (Chao,et al, 2000)

Therapeutic vaccines Therapeutic vaccines Spinal cord homogenate vaccine Spinal cord homogenate vaccine

(David, et al., 1999)(David, et al., 1999) Myelin-basic protein & copaxone Myelin-basic protein & copaxone

(Schwartz, 2001)(Schwartz, 2001)

Cell TransplantsCell Transplants Activated macrophages Activated macrophages

(Schwartz, et al. 1998)(Schwartz, et al. 1998) Olfactory ensheathing glia Olfactory ensheathing glia

(Ramos-Cuetos, 2000)(Ramos-Cuetos, 2000) Nasal mucosa (Lu, et al. 2002)Nasal mucosa (Lu, et al. 2002)

Electrical stimulation Electrical stimulation AC electrical currents stimulates AC electrical currents stimulates

axonal growth and orients glia axonal growth and orients glia (Borgens, et al. 1997)(Borgens, et al. 1997)

Growth stimulatorsGrowth stimulators Nerve bridge & growth factor Nerve bridge & growth factor

cocktail (Cheng & Olson, 2996)cocktail (Cheng & Olson, 2996) cAMP & Rollipram (Filbin, 2001)cAMP & Rollipram (Filbin, 2001) L1 (Roonprapunt, et al., 2002)L1 (Roonprapunt, et al., 2002) Combination neurotrophins Combination neurotrophins

NGF+BDNF+NT3 (Xu, 2001)NGF+BDNF+NT3 (Xu, 2001)

Remyelinative Therapies Remyelinative Therapies (1995>)(1995>)

Schwann cellsSchwann cells Schwann cell invasion into the Schwann cell invasion into the

injury site (Blakemore, 1990)injury site (Blakemore, 1990) Schwann cell transplants Schwann cell transplants

(Vollmer, 1997)(Vollmer, 1997) Peripheral nerve transplants (Kao)Peripheral nerve transplants (Kao)

Oligodendroglial cellsOligodendroglial cells Endogenous stem cells produce Endogenous stem cells produce

oligodendroglial precursor cells oligodendroglial precursor cells (Gage, 1999) (Gage, 1999)

O2A cells remyelinate spinal O2A cells remyelinate spinal axons (Blakemore, et al. 1996-)axons (Blakemore, et al. 1996-)

Transplanted embryonic stem Transplanted embryonic stem cells produce oligodendroglia that cells produce oligodendroglia that remyelinate the spinal cord remyelinate the spinal cord (McDonald, 1999).(McDonald, 1999).

Stem cellsStem cells Mouse embryonic stem cell to rats Mouse embryonic stem cell to rats

(McDonald,et al 2000)(McDonald,et al 2000) Porcine fetal stem cells (Diacrin)Porcine fetal stem cells (Diacrin) Human fetal stem cells (Moscow Human fetal stem cells (Moscow

& Novosibirsk)& Novosibirsk) Olfactory ensheathing glia (OEG)Olfactory ensheathing glia (OEG)

Transplanted OEG cells Transplanted OEG cells remyelinate axons in the spinal remyelinate axons in the spinal cord (Kocsis, et al. 1999)cord (Kocsis, et al. 1999)

Antibody remyelination therapiesAntibody remyelination therapies M1 antibody stimulates M1 antibody stimulates

remyelination (Rodriguez, 1996-)remyelination (Rodriguez, 1996-) Copaxone (copolymer 2) improved Copaxone (copolymer 2) improved

recovery in rats (Schwartz, et al. recovery in rats (Schwartz, et al. 2001)2001)

Current Clinical TrialsCurrent Clinical Trials Fetal spinal cord transplants to treat progressive syringomyelia Fetal spinal cord transplants to treat progressive syringomyelia

Gainesville Florida, Rush Presbyterian Chicago, Karolinska in Sweden, Moscow, Gainesville Florida, Rush Presbyterian Chicago, Karolinska in Sweden, Moscow, Novosibirsk, and ChinaNovosibirsk, and China

4-aminopyridine for chronic SCI 4-aminopyridine for chronic SCI Acorda: Phase 3 trial in 82 U.S. & Canadian SCI CentersAcorda: Phase 3 trial in 82 U.S. & Canadian SCI Centers

Activated macrophage transplants for subacute SCI Activated macrophage transplants for subacute SCI Proneuron: Tel Aviv, Erasmus Hospital (Brussels), Craig Hospital (Denver)Proneuron: Tel Aviv, Erasmus Hospital (Brussels), Craig Hospital (Denver)

Porcine neural stem cell transplants for chronic SCI Porcine neural stem cell transplants for chronic SCI Diacrin: Albany Med. Center and Washington University in St. LouisDiacrin: Albany Med. Center and Washington University in St. Louis

Alternating current electrical stimulation for subacute SCI Alternating current electrical stimulation for subacute SCI Purdue University in IndianaPurdue University in Indiana

AIT-082 (Neotrofin) therapy of subacute spinal cord injury AIT-082 (Neotrofin) therapy of subacute spinal cord injury Neotherapeutics: Ranchos Los Amigos, Gaylord, Craig,Thomas JeffersonNeotherapeutics: Ranchos Los Amigos, Gaylord, Craig,Thomas Jefferson

Olfactory ensheathing glial (OEG) transplantsOlfactory ensheathing glial (OEG) transplants Brisbane & Lisbon (nasal mucosa), Beijing (fetal OEG)Brisbane & Lisbon (nasal mucosa), Beijing (fetal OEG)

Olfactory ensheathing glia Olfactory ensheathing glia

Fetal OEG cellsFetal OEG cells Bipolar (migrating)Bipolar (migrating) Multipolar (directing)Multipolar (directing) ““Fried egg” (ensheathing)Fried egg” (ensheathing)

MarkersMarkers Laminin Laminin L1 CAML1 CAM NestinNestin GFAPGFAP P75 (NGF receptor)P75 (NGF receptor)

Other Clinical StudiesOther Clinical Studies Supported treadmill ambulation training to reverse learned non-useSupported treadmill ambulation training to reverse learned non-use Spinal cord L2 stimulation to activate locomotor generatorSpinal cord L2 stimulation to activate locomotor generator

Hermann in Tucson and Dimitrijevic in ViennaHermann in Tucson and Dimitrijevic in Vienna Experimental surgical approachesExperimental surgical approaches

Omentum transplants (U.S., Cuba, China, and Italy)Omentum transplants (U.S., Cuba, China, and Italy) Nerve bridging of spinal cord (University of Sao Paulo)Nerve bridging of spinal cord (University of Sao Paulo) Fetal stem cell transplants (Moscow, Novosibirsk, Beijing)Fetal stem cell transplants (Moscow, Novosibirsk, Beijing) Peripheral nerve bridging to spinal cord (Brunelli in Brescia)Peripheral nerve bridging to spinal cord (Brunelli in Brescia) Peripheral nerve bridging to bladder and muscle (Zhang in Shanghai)Peripheral nerve bridging to bladder and muscle (Zhang in Shanghai) Bridging spinal cord injury site with peripheral nerves & growth factor Bridging spinal cord injury site with peripheral nerves & growth factor

cocktail (Cheng in Taiwan)cocktail (Cheng in Taiwan) Untethering, peripheral nerve transplants, omentum transplant, Untethering, peripheral nerve transplants, omentum transplant,

hyperbaric oxygen, and 4-aminopyridine (Carl Kao in Ecuador)hyperbaric oxygen, and 4-aminopyridine (Carl Kao in Ecuador) Shark embryonic transplants (Tijuana)Shark embryonic transplants (Tijuana)

Upcoming Clinical TrialsUpcoming Clinical Trials IN-1 antibody to regenerate axons in chronic SCI IN-1 antibody to regenerate axons in chronic SCI

Novartis (Schwab at University of Zurich)Novartis (Schwab at University of Zurich) M1 antibody to remyelinate spinal cordM1 antibody to remyelinate spinal cord

Acorda (Mayo Clinic)Acorda (Mayo Clinic) Inosine to stimulating sprouting in chronic spinal cord injury Inosine to stimulating sprouting in chronic spinal cord injury

BLSI (Massachusetts General Hospital)BLSI (Massachusetts General Hospital) Olfactory ensheathing glia (OEG) transplants Olfactory ensheathing glia (OEG) transplants

Porcine OEG (Alexion, Yale University)Porcine OEG (Alexion, Yale University) OEG autograft (Madrid, Miami Project)OEG autograft (Madrid, Miami Project)

Schwann cell transplants Schwann cell transplants Schwann cell autograft for MS (Yale University) & SCI (Miami Project)Schwann cell autograft for MS (Yale University) & SCI (Miami Project)

Adult stem cell transplantsAdult stem cell transplants Autografts (adult stem cells from bone marrow, fat cells)Autografts (adult stem cells from bone marrow, fat cells)

Chondrotinase ABCChondrotinase ABC Enzyme to break down chondroitin 6-sulfate proteoglycans (Seikagaku, Japan)Enzyme to break down chondroitin 6-sulfate proteoglycans (Seikagaku, Japan)

Generations of SCI TherapiesGenerations of SCI Therapies First Generation TherapiesFirst Generation Therapies

4-Aminopyridine (Acorda)4-Aminopyridine (Acorda) Growth stimulatorsGrowth stimulators

GM1 (Fidia)GM1 (Fidia) AIT-082 (Neotherapeutics)AIT-082 (Neotherapeutics) AC electrical currents (Purdue)AC electrical currents (Purdue)

Cell transplantsCell transplants Fetal spinal cord transplants (UFG)Fetal spinal cord transplants (UFG) Macrophages (Proneuron)Macrophages (Proneuron) Porcine fetal stem cells (Diacrin)Porcine fetal stem cells (Diacrin) Human fetal stem cells (Russia, China)Human fetal stem cells (Russia, China) Peripheral nerve grafts (Taiwan)Peripheral nerve grafts (Taiwan) Olfactory ensheathing glia (Beijing)Olfactory ensheathing glia (Beijing) Nasal mucosa autografts (Lisbon, Nasal mucosa autografts (Lisbon,

Brisbane)Brisbane) Neurotrophin-secreting fibroblasts Neurotrophin-secreting fibroblasts

(UCSD)(UCSD) Locomotor trainingLocomotor training

Supported ambulation treadmill training Supported ambulation treadmill training (Bonn, Zurich, UCLA, etc) (Bonn, Zurich, UCLA, etc)

Locomotor FES (Arizona, Vienna)Locomotor FES (Arizona, Vienna)

Second Generation TherapiesSecond Generation Therapies Immune therapiesImmune therapies

M1 antibody (Acorda)M1 antibody (Acorda) Copolymer Copaxone (Teva)Copolymer Copaxone (Teva)

Anti-growth inhibition therapiesAnti-growth inhibition therapies Humanized IN-1 (Novartis)Humanized IN-1 (Novartis) Rollipram (PDE-4 inhibitor)Rollipram (PDE-4 inhibitor) C3 Rho Kinase inhibitor (BioAxone)C3 Rho Kinase inhibitor (BioAxone) Chondroitinase ABC (Seigaku)Chondroitinase ABC (Seigaku) Nogo receptor blocker (Biogen)Nogo receptor blocker (Biogen)

Growth factorsGrowth factors Neurotrophins (Regeneron)Neurotrophins (Regeneron) Inosine (BLSI)Inosine (BLSI) Neuregulins (CENES)Neuregulins (CENES)

Cell TransplantsCell Transplants Adult olfactory ensheathing gliaAdult olfactory ensheathing glia Bone marrow stem cellsBone marrow stem cells Human neural stem cellsHuman neural stem cells Genetically modified stem cellsGenetically modified stem cells Enteric glial stem cellsEnteric glial stem cells

Third Generation TreatmentsThird Generation Treatments Combination therapiesCombination therapies

RegenerationRegeneration Bridging the injury siteBridging the injury site Growth factorsGrowth factors Overcoming inhibitionOvercoming inhibition Guiding axons to targetGuiding axons to target

RemyelinationRemyelination Stimulating remyelinationStimulating remyelination Remyelinating with Schwann, Remyelinating with Schwann,

OEG, O2A, stem cellsOEG, O2A, stem cells RestorationRestoration

4-aminopyridine4-aminopyridine Biofeedback therapy Biofeedback therapy Forced use therapyForced use therapy Activity induced plasticityActivity induced plasticity

Almost beyond imaginationAlmost beyond imagination Vaccine Vaccine

Regenerative vaccinesRegenerative vaccines Neuroprotective vaccines Neuroprotective vaccines Remyelinative vaccinesRemyelinative vaccines

Stem cellsStem cells Neuronal replacementNeuronal replacement Reversing atrophyReversing atrophy Replacing motoneuronsReplacing motoneurons

Guiding axonsGuiding axons Gene therapy to express Gene therapy to express

guidance moleculesguidance molecules Cell adhesion molecules Cell adhesion molecules

direct axonal growthdirect axonal growth Use of ephrins to control Use of ephrins to control

axonal pruningaxonal pruning

Preparing for RecoveryPreparing for Recovery Avoid irreversible surgical Avoid irreversible surgical

proceduresprocedures Dorsal root rhizotomiesDorsal root rhizotomies Peripheral nerve bridgesPeripheral nerve bridges Tendon transfersTendon transfers Omentum transfersOmentum transfers

Prevent muscle, bone, and Prevent muscle, bone, and neuronal atrophyneuronal atrophy

Don’t eliminate spasticityDon’t eliminate spasticity Standing exercises to put stress Standing exercises to put stress

on boneson bones Functional electrical stimulation Functional electrical stimulation

(FES) to build muscle(FES) to build muscle Stem cell implants to muscle and Stem cell implants to muscle and

spinal cordspinal cord

Relieve causes of continuing Relieve causes of continuing spinal cord damagespinal cord damage

DecompressionDecompression Reduce syringomyeliaReduce syringomyelia Untethering of cordUntethering of cord

Reverse learned non-useReverse learned non-use Physical therapyPhysical therapy Activity-induced activityActivity-induced activity

Overground ambulationOverground ambulation Weight supported treadmill Weight supported treadmill

ambulation trainingambulation training Biofeedback therapyBiofeedback therapy L2 locomotor generator L2 locomotor generator

stimulationstimulation

Restorative PrinciplesRestorative Principles ““Complete” is not completeComplete” is not complete

Severance or transections of the cord are very rareSeverance or transections of the cord are very rare <10% of axons can support substantial function, adding 5-10% sufficient<10% of axons can support substantial function, adding 5-10% sufficient

Accelerating and extending recovery processesAccelerating and extending recovery processes Continued recovery in chronic SCI over many yearsContinued recovery in chronic SCI over many years Spontaneous regeneration may occur in some peopleSpontaneous regeneration may occur in some people

Surviving axons need to be myelinatedSurviving axons need to be myelinated 4-aminopyridine improves conduction4-aminopyridine improves conduction Cell transplantation to remyelinate spinal axonsCell transplantation to remyelinate spinal axons

Spinal cord capable of remarkable “plasticity”Spinal cord capable of remarkable “plasticity” Detailed specificity of reconnection is not necessaryDetailed specificity of reconnection is not necessary Local sprouting can restore functions across the midlineLocal sprouting can restore functions across the midline

Reversing learned “non-use”Reversing learned “non-use” Even a short period of non-use can turn off circuitsEven a short period of non-use can turn off circuits Intensive “forced-use” exercise can restore functionIntensive “forced-use” exercise can restore function

Emerging TrendsEmerging Trends High-volume drug screeningHigh-volume drug screening

Systematic drug designSystematic drug design Better tissue culture modelsBetter tissue culture models More efficient animal modelsMore efficient animal models

Gene expression studiesGene expression studies Identification of endogenous Identification of endogenous

repair & regenerative factorsrepair & regenerative factors Use of gene expression as an Use of gene expression as an

outcome measure for assess outcome measure for assess therapeutic effectstherapeutic effects

Endogenous stem cellsEndogenous stem cells The genes responsible for The genes responsible for

converting any cell into stem cellsconverting any cell into stem cells Drugs to stimulate endogenous Drugs to stimulate endogenous

stem cells to proliferate and to go stem cells to proliferate and to go into reparative modeinto reparative mode

ImmunotherapiesImmunotherapies Some evidence indicates that Some evidence indicates that

immune cells (macrophages and immune cells (macrophages and lymphocytes) are reparativelymphocytes) are reparative

Therapeutic vaccines to stimulate Therapeutic vaccines to stimulate antibody productionantibody production

Use of cytokines (i.e. IL-6) to Use of cytokines (i.e. IL-6) to stimulate repair and regenerationstimulate repair and regeneration

Molecular and Gene TherapiesMolecular and Gene Therapies Ex vivo gene therapiesEx vivo gene therapies

Genetically modified progenitor or Genetically modified progenitor or stem cellsstem cells

Stem cells and lymphocytes seem Stem cells and lymphocytes seem to know where to goto know where to go

In vivo gene therapyIn vivo gene therapy Viral vectorsViral vectors Non-viral vectors for gene deliveryNon-viral vectors for gene delivery

Novel Remyelination Novel Remyelination StrategiesStrategies

Cell transplantationCell transplantation Schwann cellsSchwann cells Oligodendroglia precursorOligodendroglia precursor

O2A cells remyelinate axonsO2A cells remyelinate axons Stem cells produce O2AStem cells produce O2A

Olfactory ensheathing gliaOlfactory ensheathing glia Adult autograftAdult autograft Fetal heterograftsFetal heterografts nasal mucosanasal mucosa

Stem cell transplantsStem cell transplants Embryonic stem cellsEmbryonic stem cells Fetal stem cells (neural, Fetal stem cells (neural,

umbilical cord blood)umbilical cord blood) Adult stem cells (bone Adult stem cells (bone

marrow, neural,& skin)marrow, neural,& skin)

Stimulation of remyelinationStimulation of remyelination M1 antibodiesM1 antibodies

Germ cell line IgM kappa Germ cell line IgM kappa auto-antibody that stimulate auto-antibody that stimulate oligodendroglia to proliferate oligodendroglia to proliferate and to myelinate axonsand to myelinate axons

IgM kappa antibodies may act IgM kappa antibodies may act as signaling moleculesas signaling molecules

M1 belongs in the same class M1 belongs in the same class of molecules as IN-1, the of molecules as IN-1, the antibody that binds Nogoantibody that binds Nogo

NeuregulinsNeuregulins Neuregulin regulates neural Neuregulin regulates neural

precursor growth and the precursor growth and the oligodendrocyte conversionoligodendrocyte conversion

Progenitor CellsProgenitor Cells

Neurosphere

Nestin stain BRDU stain

Cell Loss and ReplacementCell Loss and Replacement Cell Loss Cell Loss

Primary Cell LossPrimary Cell Loss Secondary Necrosis Secondary Necrosis

Central hemorrhagic necrosis Central hemorrhagic necrosis leaves rim of white matterleaves rim of white matter

Wallerian degenerationWallerian degeneration ApoptosisApoptosis

Neuronal apoptosis in gray Neuronal apoptosis in gray matter at 48 hoursmatter at 48 hours

Oligodendroglial apoptosis in Oligodendroglial apoptosis in white matter at 2 weekswhite matter at 2 weeks

Cystic degenerationCystic degeneration Syringomyelia Syringomyelia Chronic myelopathyChronic myelopathy

Muscle AtrophyMuscle Atrophy

Replacing lost cellsReplacing lost cells Endogenous stem cellsEndogenous stem cells

Ependymal cells = stem cells Ependymal cells = stem cells of the spinal cordof the spinal cord

Ependymal scaffolding Ependymal scaffolding support axonal growthsupport axonal growth

Cell Replacement TherapiesCell Replacement Therapies Embryonic stem cellsEmbryonic stem cells NRPs and GRPsNRPs and GRPs Intrathecal stem cellIntrathecal stem cell Systemic stem cellSystemic stem cell Fetal neuronal transplants Fetal neuronal transplants

into muscle to prevent into muscle to prevent atrophyatrophy

Stem cell therapies to reverse Stem cell therapies to reverse muscle atrophymuscle atrophy

SolutionsSolutions Each clinical trial has a limited Each clinical trial has a limited

probability of successprobability of success To increase odds of clinical To increase odds of clinical

trial success, we must:trial success, we must: Do systematic preclinical Do systematic preclinical

studies to establish and studies to establish and optimize therapies for clinical optimize therapies for clinical trialstrials

Create a spinal cord injury Create a spinal cord injury clinical trial networkclinical trial network

Randomize a larger percent of Randomize a larger percent of SCI patients to the best SCI patients to the best experimental therapies in experimental therapies in comparison with best standard comparison with best standard therapiestherapies

The Program at RutgersThe Program at Rutgers Establish and disseminate Establish and disseminate

well-standardized models & well-standardized models & outcome measuresoutcome measures

Sharing databasesSharing databases SCICure Consortium to share SCICure Consortium to share

spinal cord injury dataspinal cord injury data NGEL gene chip to share NGEL gene chip to share

gene expression datagene expression data Standardized cell transplant Standardized cell transplant

(stem cells, precursor cells, (stem cells, precursor cells, olfactory ensheathing glia)olfactory ensheathing glia)

Training workshopsTraining workshops Annual SCI clinical trial Annual SCI clinical trial

symposia for scientists and symposia for scientists and cliniciansclinicians