2023
Development of neural repair therapy for chronic spinal cord trauma: soluble Nogo receptor decoy from discovery to clinical trial
Howard E, Strittmatter S. Development of neural repair therapy for chronic spinal cord trauma: soluble Nogo receptor decoy from discovery to clinical trial. Current Opinion In Neurology 2023, 36: 516-522. PMID: 37865850, PMCID: PMC10841037, DOI: 10.1097/wco.0000000000001205.Peer-Reviewed Original ResearchConceptsSpinal cord injuryChronic cervical spinal cord injuryCervical spinal cord injuryRecent clinical trialsCentral nervous systemClinical trialsAnimal studiesNeural repairChronic spinal cord injuryIncomplete spinal cord injuryTraumatic spinal cord injuryAdult mammalian central nervous systemContusion spinal cord injuryTreatment-naïve patientsSpinal cord traumaMammalian central nervous systemNeural repair therapiesUpper extremity strengthNonhuman primate studiesReceptor 1 pathwayNeurological recoveryNeurological deficitsCord traumaMedical therapyChronic stageSoluble Nogo-Receptor-Fc decoy (AXER-204) in patients with chronic cervical spinal cord injury in the USA: a first-in-human and randomised clinical trial
Maynard G, Kannan R, Liu J, Wang W, Lam T, Wang X, Adamson C, Hackett C, Schwab J, Liu C, Leslie D, Chen D, Marino R, Zafonte R, Flanders A, Block G, Smith E, Strittmatter S. Soluble Nogo-Receptor-Fc decoy (AXER-204) in patients with chronic cervical spinal cord injury in the USA: a first-in-human and randomised clinical trial. The Lancet Neurology 2023, 22: 672-684. PMID: 37479373, PMCID: PMC10410101, DOI: 10.1016/s1474-4422(23)00215-6.Peer-Reviewed Original ResearchMeSH KeywordsAdultCervical CordDouble-Blind MethodFemaleHumansMaleSpinal Cord InjuriesTreatment OutcomeConceptsUpper extremity motor scoreSpinal cord injuryChronic spinal cord injuryTreatment-related adverse eventsAdverse eventsDay 169Intrathecal dosesCord injuryClinical trialsAmerican Spinal Injury Association Impairment Scale (AIS) gradeCervical traumatic spinal cord injuryChronic cervical spinal cord injuryCommon treatment-related adverse eventsCervical spinal cord injurySevere spinal cord injuryTraumatic spinal cord injuryPost-hoc subgroup analysesPersistent neurological deficitsDouble-blind comparisonKey secondary objectiveNational InstituteOpen labelAdvancing Translational SciencesPlacebo groupNeurological deficits
2022
Rabphilin3A reduces integrin-dependent growth cone signaling to restrict axon regeneration after trauma
Sekine Y, Kannan R, Wang X, Strittmatter SM. Rabphilin3A reduces integrin-dependent growth cone signaling to restrict axon regeneration after trauma. Experimental Neurology 2022, 353: 114070. PMID: 35398339, PMCID: PMC9555232, DOI: 10.1016/j.expneurol.2022.114070.Peer-Reviewed Original ResearchConceptsAxon regenerationModerate spinal cord contusion injurySpinal cord contusion injuryTraumatic spinal cord injuryAdult mammalian central nervous systemGrowth conesRetinal ganglion cell axonsOptic nerve crushSpinal cord crush injuryGanglion cell axonsSpinal cord injuryMammalian central nervous systemCentral nervous systemCorticospinal axon regenerationContusion injuryAxonal sproutingCrush injuryNerve crushAxonal growth conesCord injuryAxon sproutingCell axonsProximal bodyNervous systemNeural repairTranslational PET Imaging of Spinal Cord Injury with the Serotonin Transporter Tracer [11C]AFM
Fang H, Rossano S, Wang X, Nabulsi N, Kelley B, Fowles K, Ropchan J, Strittmatter SM, Carson RE, Huang Y. Translational PET Imaging of Spinal Cord Injury with the Serotonin Transporter Tracer [11C]AFM. Molecular Imaging And Biology 2022, 24: 560-569. PMID: 35020138, PMCID: PMC9550197, DOI: 10.1007/s11307-021-01698-7.Peer-Reviewed Original ResearchConceptsSpinal cord injurySpinal cordHealthy ratsHuman spinal cordCord injurySerotonin transporterRat modelRodent modelsPET imagingTranslational PET imagingSCI rat modelIntact spinal cordSpinal cord caudalRodent spinal cordSerotonin transporter tracerUse of PETCervical uptakeSERT changesSCI animalsSCI patientsPresynaptic serotonin transporterCord caudalAxon damageSerotonin systemSERT radioligand
2020
Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury
Wang X, Zhou T, Maynard GD, Terse PS, Cafferty WB, Kocsis JD, Strittmatter SM. Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury. Brain 2020, 143: 1697-1713. PMID: 32375169, PMCID: PMC7850069, DOI: 10.1093/brain/awaa116.Peer-Reviewed Original ResearchConceptsPrimate spinal cord injurySpinal cord injuryCord injuryFemale African green monkeysTreatment-related adverse eventsChronic neurological deficitsNogo receptor 1Left motor cortexRecovery of functionPreclinical rodent modelsSpinal cord injury animalsAfrican green monkeysRaphespinal fibersAdverse eventsCervical cordNeurological deficitsSurgical complicationsCNS traumaTreatment cessationCorticospinal axonsLumbar catheterInjury animalsNeural recoverySpontaneous feedingLateral hemisection
2019
A proteolytic C-terminal fragment of Nogo-A (reticulon-4A) is released in exosomes and potently inhibits axon regeneration
Sekine Y, Lindborg JA, Strittmatter SM. A proteolytic C-terminal fragment of Nogo-A (reticulon-4A) is released in exosomes and potently inhibits axon regeneration. Journal Of Biological Chemistry 2019, 295: 2175-2183. PMID: 31748413, PMCID: PMC7039549, DOI: 10.1074/jbc.ra119.009896.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsExosomesFemaleHEK293 CellsHumansMice, Inbred C57BLNerve RegenerationNogo ProteinsProtein Structure, SecondaryProteolysisSpinal Cord InjuriesConceptsMembrane-associated proteinsRecombinant protein expressionMatrix-associated proteinOligodendrocyte plasma membraneProteolytic C-terminal fragmentsRegeneration assaysC-terminal fragmentPlasma membraneNeurite outgrowth inhibitor NogoAxonal regenerationExosomal releaseDiffusible inhibitorC-terminalSiRNA knockdownCleavage siteCultured cellsLong fragmentPrimary cortical neuron culturesCentral nervous system traumaExosomesEnzyme inhibitor treatmentExosomal fractionSpinal cord crush injuryCerebral cortex neuronsProteinPlexina2 and CRMP2 Signaling Complex Is Activated by Nogo-A-Liganded Ngr1 to Restrict Corticospinal Axon Sprouting after Trauma
Sekine Y, Algarate PT, Cafferty WBJ, Strittmatter SM. Plexina2 and CRMP2 Signaling Complex Is Activated by Nogo-A-Liganded Ngr1 to Restrict Corticospinal Axon Sprouting after Trauma. Journal Of Neuroscience 2019, 39: 3204-3216. PMID: 30804090, PMCID: PMC6788813, DOI: 10.1523/jneurosci.2996-18.2019.Peer-Reviewed Original ResearchConceptsCNS traumaNeural repairMouse cervical spinal cordSpinal cord traumaCervical spinal cordNon-neuronal cellsInteraction of NogoAxon growth inhibitionAxonal guidance mechanismsNeurological recoveryAxonal sproutingCNS pathwaysCord traumaFunctional recoveryAxon sproutingSpinal cordNgR1 functionUnilateral pyramidotomyAxon regenerationAdult traumaNgR1TraumaAxon growthNogoCytoplasmic mediators
2018
Human neuroepithelial stem cell regional specificity enables spinal cord repair through a relay circuit
Dell’Anno M, Wang X, Onorati M, Li M, Talpo F, Sekine Y, Ma S, Liu F, Cafferty WBJ, Sestan N, Strittmatter SM. Human neuroepithelial stem cell regional specificity enables spinal cord repair through a relay circuit. Nature Communications 2018, 9: 3419. PMID: 30143638, PMCID: PMC6109094, DOI: 10.1038/s41467-018-05844-8.Peer-Reviewed Original ResearchConceptsHuman neuroepithelial stem cellsNeuroepithelial stem cellsSpinal cord injury recoverySpinal cord injury resultsNeural stem cell transplantationStem cell transplantationSpinal cord repairOptimal cell typeStem cellsGrafted neuronsPersistent disabilityFunctional recoveryTherapeutic optionsCell transplantationHost axonsInjury resultsSpinal cordRobust engraftmentImmunodeficient miceInjury recoveryAnatomical sitesNeural elementsSpecific marker proteinsTransplantationAdherent conditionsThe nociceptin receptor inhibits axonal regeneration and recovery from spinal cord injury
Sekine Y, Siegel CS, Sekine-Konno T, Cafferty WBJ, Strittmatter SM. The nociceptin receptor inhibits axonal regeneration and recovery from spinal cord injury. Science Signaling 2018, 11 PMID: 29615517, PMCID: PMC6179440, DOI: 10.1126/scisignal.aao4180.Peer-Reviewed Original ResearchConceptsSpinal cord injuryCord injuryAxonal regenerationMid-thoracic spinal cordTraumatic spinal cord injuryPartial neurological recoveryTraumatic CNS injuryDorsal hemisectionNeurological recoveryPeptide nociceptinCNS injuryAxon sproutingORL1 agonistSelective blockadeSpinal cordLocomotor functionNociceptin receptorAxon regenerationNeural repairPrimary neuronsNgR1 proteinAxonal growthNull miceMRNA expressionORL1Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration
Sekine Y, Lin-Moore A, Chenette DM, Wang X, Jiang Z, Cafferty WB, Hammarlund M, Strittmatter SM. Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration. Cell Reports 2018, 23: 415-428. PMID: 29642001, PMCID: PMC5937716, DOI: 10.1016/j.celrep.2018.03.058.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsCaenorhabditis elegansCaenorhabditis elegans ProteinsCentral Nervous SystemFemaleGene Regulatory NetworksGenomeMiceMice, Inbred C57BLMice, KnockoutNerve RegenerationOptic NerveRab GTP-Binding ProteinsRecovery of FunctionRetinal Ganglion CellsRNA InterferenceRNA, Small InterferingSpinal Cord InjuriesSuppressor of Cytokine Signaling ProteinsConceptsAxonal regenerationCentral nervous system axonal regenerationRetinal ganglion cell axon regenerationGreater motor functionOptic nerve crushCerebral cortical neuronsSpinal cord traumaNeurological recoveryCord traumaNerve crushCNS injuryAxonal regrowthCortical neuronsMotor functionAxon regenerationReceptor bindingComprehensive functional screenAdult mammalsInjuryMultiple pathwaysExpression profilesIdentifies pathwaysSignificant overlapPathwayFunction screen
2017
Regulation of axonal regeneration by the level of function of the endogenous Nogo receptor antagonist LOTUS
Hirokawa T, Zou Y, Kurihara Y, Jiang Z, Sakakibara Y, Ito H, Funakoshi K, Kawahara N, Goshima Y, Strittmatter SM, Takei K. Regulation of axonal regeneration by the level of function of the endogenous Nogo receptor antagonist LOTUS. Scientific Reports 2017, 7: 12119. PMID: 28935984, PMCID: PMC5608707, DOI: 10.1038/s41598-017-12449-6.Peer-Reviewed Original ResearchConceptsSpinal cord injuryOptic nerve crushAxonal regenerationMotor recoveryNerve crushNeural repairRetinal ganglion cell axonal regenerationAdult mammalian central nervous systemIntrinsic motor recoverySpontaneous neural repairAxonal growth inhibitorsMammalian central nervous systemCentral nervous systemNon-permissive environmentLevel of functionUntreated miceFunctional recoveryCord injuryReceptor antagonistNeuronal overexpressionNervous systemGenetic deletionViral overexpressionCrushInhibitors
2016
Rewiring the spinal cord: Direct and indirect strategies
Dell’Anno M, Strittmatter SM. Rewiring the spinal cord: Direct and indirect strategies. Neuroscience Letters 2016, 652: 25-34. PMID: 28007647, PMCID: PMC5466898, DOI: 10.1016/j.neulet.2016.12.002.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsCell DifferentiationHumansNeural Stem CellsNeurogliaNeuronsSpinal CordSpinal Cord InjuriesSpinal Cord RegenerationSynaptic TransmissionConceptsSpinal cordNeural stem cellsNeural stem cell-derived neuronsTransplanted neural stem cellsNeural stem cell transplantationAdult central nervous systemLong-distance axonsNeutralization of myelinRecipient spinal cordStem cell transplantationSpinal cord injuryStem cell-derived neuronsCentral nervous systemCell-derived neuronsIntrinsic regenerative capacityPoor intrinsic regenerative capacityStem cellsNeurologic recoveryAxonal sproutingSecondary complicationsCell transplantationCord injuryAxonal regenerationGlial cellsAdult brainInhibition of Poly-ADP-Ribosylation Fails to Increase Axonal Regeneration or Improve Functional Recovery after Adult Mammalian CNS Injury
Wang X, Sekine Y, Byrne AB, Cafferty WB, Hammarlund M, Strittmatter SM. Inhibition of Poly-ADP-Ribosylation Fails to Increase Axonal Regeneration or Improve Functional Recovery after Adult Mammalian CNS Injury. ENeuro 2016, 3: eneuro.0270-16.2016. PMID: 28032120, PMCID: PMC5187389, DOI: 10.1523/eneuro.0270-16.2016.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsBenzimidazolesCells, CulturedCerebral CortexDisease Models, AnimalFemaleIsoenzymesMaleMice, 129 StrainMice, Inbred C57BLMice, TransgenicMotor ActivityNerve RegenerationOptic Nerve InjuriesPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsRecovery of FunctionSpinal Cord InjuriesThoracic VertebraeConceptsOptic nerve crush injuryNerve crush injuryThoracic spinal cordAxonal regenerationSpinal cordDorsal hemisectionCrush injuryFunctional recoveryPARP inhibitorsMotor function recoveryRecovery of functionPoly (ADP-ribose) polymeraseClinical PARP inhibitorsNeurological recoveryShort hairpin RNACNS traumaCNS injuryFunction recoveryAxonal regrowthSystemic administrationPharmacodynamic actionAxon regenerationTraumatic damageTherapeutic efficacyNeurological traumaSCISSOR—Spinal Cord Injury Study on Small molecule-derived Rho inhibition: a clinical study protocol
Kopp MA, Liebscher T, Watzlawick R, Martus P, Laufer S, Blex C, Schindler R, Jungehulsing GJ, Knüppel S, Kreutzträger M, Ekkernkamp A, Dirnagl U, Strittmatter SM, Niedeggen A, Schwab JM. SCISSOR—Spinal Cord Injury Study on Small molecule-derived Rho inhibition: a clinical study protocol. BMJ Open 2016, 6: e010651. PMID: 27466236, PMCID: PMC4964175, DOI: 10.1136/bmjopen-2015-010651.Peer-Reviewed Original ResearchConceptsSpinal cord injurySystemic inflammatory response syndromeNeuropathic painHeterotopic ossificationMotor complete spinal cord injuryPrimary safety end pointEnd pointOpen-label pilot trialImproved motor recoveryPrimary safety analysisSafety end pointSecondary end pointsSerious adverse eventsSevere gastrointestinal bleedingInflammatory response syndromeSecondary outcome assessmentsWarrants clinical investigationAnti-inflammatory drugsClinical study protocolClinical trial protocolGood clinical practiceRho inhibitionDeclaration of HelsinkiGastroduodenal bleedingGastrointestinal bleeding
2015
Comprehensive Corticospinal Labeling with mu-crystallin Transgene Reveals Axon Regeneration after Spinal Cord Trauma in ngr1−/− Mice
Fink KL, Strittmatter SM, Cafferty WB. Comprehensive Corticospinal Labeling with mu-crystallin Transgene Reveals Axon Regeneration after Spinal Cord Trauma in ngr1−/− Mice. Journal Of Neuroscience 2015, 35: 15403-15418. PMID: 26586827, PMCID: PMC4649010, DOI: 10.1523/jneurosci.3165-15.2015.Peer-Reviewed Original ResearchMeSH KeywordsAmidinesAnalysis of VarianceAnimalsAxonsBiotinCrystallinsDextransDisease Models, AnimalFunctional LateralityGene Expression RegulationGlial Fibrillary Acidic ProteinGPI-Linked ProteinsLuminescent ProteinsMiceMice, Inbred C57BLMice, TransgenicMu-CrystallinsMyelin ProteinsNerve RegenerationNogo Receptor 1Pyramidal TractsReceptors, Cell SurfaceRecovery of FunctionSpinal Cord InjuriesConceptsCorticospinal tractCST axonsTransgenic miceMotor tractsDextran amineFunctional deficitsSpinal cordAxon regenerationSpinal Cord Injury StudySpontaneous axon regenerationSpinal cord traumaNogo receptor 1Permanent functional deficitsPersistent functional deficitsBilateral pyramidotomyDorsal hemisectionMidthoracic cordCord traumaMotor pathwaysAdult CNSCST regenerationInjury studiesLesion siteRegenerating fibersNeural repairGene-Silencing Screen for Mammalian Axon Regeneration Identifies Inpp5f (Sac2) as an Endogenous Suppressor of Repair after Spinal Cord Injury
Zou Y, Stagi M, Wang X, Yigitkanli K, Siegel CS, Nakatsu F, Cafferty WB, Strittmatter SM. Gene-Silencing Screen for Mammalian Axon Regeneration Identifies Inpp5f (Sac2) as an Endogenous Suppressor of Repair after Spinal Cord Injury. Journal Of Neuroscience 2015, 35: 10429-10439. PMID: 26203138, PMCID: PMC4510284, DOI: 10.1523/jneurosci.1718-15.2015.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsDisease Models, AnimalGene Knockdown TechniquesImmunohistochemistryInositol Polyphosphate 5-PhosphatasesMiceMice, Inbred C57BLMice, KnockoutNerve RegenerationPhosphoric Monoester HydrolasesRecovery of FunctionReverse Transcriptase Polymerase Chain ReactionSpinal Cord InjuriesConceptsSpinal cord injuryCord injuryEndogenous suppressorAxon regenerationNonoverlapping substrate specificityGenome-wide scaleHigh-throughput functional screensFunctional recoveryAxonal regenerationCNS axon repairSpinal cord injury researchDorsal hemisection injuryMammalian genesPI3K/AKT/mTOR pathwayCNS axon growthAKT/mTOR pathwayLipid phosphataseCorticospinal tract axonsCNS axon regenerationAdult mammalian CNSFunctional screenSubstrate specificityNovel suppressorShRNA resultsINPP5FPlasticity of Intact Rubral Projections Mediates Spontaneous Recovery of Function after Corticospinal Tract Injury
Siegel CS, Fink KL, Strittmatter SM, Cafferty WB. Plasticity of Intact Rubral Projections Mediates Spontaneous Recovery of Function after Corticospinal Tract Injury. Journal Of Neuroscience 2015, 35: 1443-1457. PMID: 25632122, PMCID: PMC4308593, DOI: 10.1523/jneurosci.3713-14.2015.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDesigner DrugsFunctional LateralityGene Expression RegulationGlial Fibrillary Acidic ProteinLocomotionMaleMiceMice, Inbred C57BLMice, TransgenicMuscle StrengthMyelin ProteinsNeuronal PlasticityNogo ProteinsPsychomotor DisordersPyramidal TractsRaphe NucleiRecovery of FunctionSpinal Cord InjuriesStereotyped BehaviorTime FactorsConceptsSpinal cord injurySpontaneous functional recoveryFunctional recoverySpontaneous recoveryIncomplete spinal cord injuryCorticospinal tract lesionsWeeks of lesionCorticospinal tract injuryNogo receptor 1Nucleus raphe magnusTract injuryRubrospinal projectionsTract lesionsCord injuryRaphe magnusCircuit rearrangementsAdult CNSCircuit plasticityLocomotor functionAdult micePharmacogenetic toolsRed nucleusRubral projectionReceptor 1Extensive sprouting
2014
Human NgR-Fc Decoy Protein via Lumbar Intrathecal Bolus Administration Enhances Recovery from Rat Spinal Cord Contusion
Wang X, Yigitkanli K, Kim CY, Sekine-Konno T, Wirak D, Frieden E, Bhargava A, Maynard G, Cafferty WB, Strittmatter SM. Human NgR-Fc Decoy Protein via Lumbar Intrathecal Bolus Administration Enhances Recovery from Rat Spinal Cord Contusion. Journal Of Neurotrauma 2014, 31: 1955-1966. PMID: 24964223, PMCID: PMC4245872, DOI: 10.1089/neu.2014.3355.Peer-Reviewed Original ResearchConceptsSpinal cord injuryTraumatic spinal cord injurySpinal cord contusionNeurological recoveryCord contusionRat spinal cord contusionSpinal contusion injuryLumbar intrathecal spaceLumbar spinal cordContinuous intracerebroventricular infusionRodent SCI modelsPercentage of ratsRaphespinal axonsContusion injuryAdministration regimenSCI modelContinuous infusionCord injuryIntracerebroventricular infusionIntrathecal spaceSpinal cordPreclinical modelsEffective treatmentWalking tasksClinical testingDiffusion Tensor Imaging as a Predictor of Locomotor Function after Experimental Spinal Cord Injury and Recovery
Kelley BJ, Harel NY, Kim CY, Papademetris X, Coman D, Wang X, Hasan O, Kaufman A, Globinsky R, Staib LH, Cafferty WB, Hyder F, Strittmatter SM. Diffusion Tensor Imaging as a Predictor of Locomotor Function after Experimental Spinal Cord Injury and Recovery. Journal Of Neurotrauma 2014, 31: 1362-1373. PMID: 24779685, PMCID: PMC4120934, DOI: 10.1089/neu.2013.3238.Peer-Reviewed Original ResearchConceptsSpinal cord injuryDiffusion tensor imagingCord injuryAxonal integrityLocomotor functionExperimental spinal cord injuryTraumatic spinal cord injuryFemale Sprague-Dawley ratsTensor imagingFractional anisotropyFunctional recovery assessmentSpinal cord contusionLimited functional recoveryLong-term disabilityQuantitative diffusion tensor imagingRodent SCI modelsSprague-Dawley ratsSpinal cord morphologyWhite matter pathologyCaudal spinal cordWhite matter integrityInjury epicenterMidthoracic laminectomyCord contusionPrimary outcome
2013
The current state-of-the-art of spinal cord imaging: Applications
Wheeler-Kingshott CA, Stroman PW, Schwab JM, Bacon M, Bosma R, Brooks J, Cadotte DW, Carlstedt T, Ciccarelli O, Cohen-Adad J, Curt A, Evangelou N, Fehlings MG, Filippi M, Kelley BJ, Kollias S, Mackay A, Porro CA, Smith S, Strittmatter SM, Summers P, Thompson AJ, Tracey I. The current state-of-the-art of spinal cord imaging: Applications. NeuroImage 2013, 84: 1082-1093. PMID: 23859923, PMCID: PMC4371134, DOI: 10.1016/j.neuroimage.2013.07.014.Peer-Reviewed Original Research