Early Visual Biomarkers of Relapse and Rehabilitation in Multiple Sclerosis
多发性硬化症复发和康复的早期视觉生物标志物
基本信息
- 批准号:10189737
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:4-AminopyridineAccelerationAcuteAddressAffectAnimal ModelAnimalsAnteriorAutologousAxonBackBiological MarkersBone MarrowBrainCaringCerebrospinal FluidChronicClinicalCommunitiesContrast SensitivityDataDemyelinationsDetectionDietary InterventionDiseaseDisease MarkerEarly treatmentEchinomycinEventEvoked PotentialsExperimental Autoimmune EncephalomyelitisFlicker FusionFrequenciesFunctional disorderGlycolysisGoalsHumanIndividualInjectionsInterventionInvestigational TherapiesMagnetic Resonance ImagingMeasuresMediatingMesenchymal Stem CellsModelingMonitorMotorMultiple SclerosisMusMyelinNatureNerveNerve DegenerationNervous System PhysiologyNeural ConductionNeuraxisNeurodegenerative DisordersNeuronsOptic NerveOptic NeuritisOptical Coherence TomographyOutcomeOutcome MeasurePathologyPatientsPharmaceutical PreparationsPhasePreventionPreventiveQuality of lifeRecoveryRehabilitation OutcomeRehabilitation therapyRelapseRetinaRetinal Ganglion CellsSensorySignal TransductionSpeedStress TestsStructureSurrogate MarkersSymptomsTestingTherapeutic EffectThickThinnessTimeTranslatingTranslationsVeteransVisionVisualVisual AcuityVisual PathwaysVisual impairmentclinical practiceclinical translationcognitive functiondisabilityfatty acid metabolismfunctional restorationimmunoregulationimprovedimproved functioningin vivoindividual patientinsightketogenic dietmouse modelmultiple sclerosis patientmultiple sclerosis treatmentmyelinationnerve stem cellneuroinflammationneurological recoveryneuron lossneuroprotectionnovel strategiesnovel therapeuticspre-clinicalpreconditioningpreservationregenerative approachrehabilitation researchrelating to nervous systemremyelinationretinal nerve fiber layerstem cell therapysuccesstooltreatment effecttreatment responsetreatment strategy
项目摘要
Optic neuritis is an associated pathology of MS, and is often the first symptom of the disease. Even in MS
patients without any known episodes of optic neuritis, there is evidence that functional and structural
manifestations of MS in the anterior visual pathway can be detected and monitored in vivo, reflecting disease
activity. These include contrast sensitivity, critical flicker fusion frequency, evoked potentials from the retina
and brain, and inner retinal layer thickness using optical coherence tomography (OCT). Our main purpose is to
establish sensitive biomarkers of visual function that can be made widely available to veterans suffering from
MS for detecting MS relapses, progression and treatment effects. An important secondary rehabilitation goal is
to determine which conventional and new experimental treatment could decrease fluctuation in visual and CNS
function, which are known to impact quality of life, in preclinical animal models of MS.
We will employ two relevant animal models of MS, a MOG-induced experimental autoimmune
encephalomyelitis (EAE) model for chronic MS and PLP-induced EAE to mimic the relapsing-remitting form.
We will also include a heat-induced stress test to trigger fluctuations in visual and CNS function in EAE mice.
We will determine in vivo ocular structural and functional biomarkers and will correlate them with motor-
sensory and cognitive function. Data will be related to ex vivo structural manifestations of MS, namely neuron
loss and demyelination. We propose that the number of remaining neurons and their myelin integrity will
correlate with changes in optic nerve conduction speed, visual acuity and retinal nerve fiber layer thinning. We
will then examine if current treatments using Fingolimod, 4-aminopyridine and a ketogenic diet increase neuro-
axonal electrical activity and decrease functional fluctuation to favor increased rehabilitation. Newer
experimental therapies, derived from compounds hypothesized to mediate the therapeutic effects of
mesenchymal stem cell (MSC) therapy, which targeting improved nerve transduction, will also be tested in the
chronic and relapsing remitting models of MS.
Supported by pilot data results, we will determine with additional rigor that decreased optic nerve conduction
velocity precedes motor-sensory and structural deficits in the EAE model and represents an early marker of
disease activity. Our expected data will provide insights on how impairment of visual function corresponds to
demyelination, retinal thinning and retinal ganglion cell (RGC) loss. We also determine at what time point an
earlier treatment intervention will improve long-term functional and structural outcome. We further expect to
provide convincing data that improvement of neuro-axonal electrical activity and conduction speed represent
promising, new therapeutic avenues with extraordinary clinical impact for restoring function and quality of life.
Clinical translation of these results will help predict MS relapses and rehabilitation in MS patients. We will
provide strong evidence that testing of visual function can be used as a tool to monitor disease activity in MS,
including detection of subclinical episodes of relapse or progression before clinical symptoms develop.
In conclusion, we expect to have obtained conclusive data to determine the nature of early visual biomarkers in
the EAE model and their value in predicting central nervous system outcome. Translation of such biomarkers
to clinical practice would identify veterans with MS in need of further disease modifying agents to optimize
recovery and quality of life.
Optic neuritis is an associated pathology of MS, and is often the first symptom of the disease. Even in MS
patients without any known episodes of optic neuritis, there is evidence that functional and structural
manifestations of MS in the anterior visual pathway can be detected and monitored in vivo, reflecting disease
activity. These include contrast sensitivity, critical flicker fusion frequency, evoked potentials from the retina
and brain, and inner retinal layer thickness using optical coherence tomography (OCT). Our main purpose is to
establish sensitive biomarkers of visual function that can be made widely available to veterans suffering from
MS for detecting MS relapses, progression and treatment effects. An important secondary rehabilitation goal is
to determine which conventional and new experimental treatment could decrease fluctuation in visual and CNS
function, which are known to impact quality of life, in preclinical animal models of MS.
We will employ two relevant animal models of MS, a MOG-induced experimental autoimmune
encephalomyelitis (EAE) model for chronic MS and PLP-induced EAE to mimic the relapsing-remitting form.
We will also include a heat-induced stress test to trigger fluctuations in visual and CNS function in EAE mice.
We will determine in vivo ocular structural and functional biomarkers and will correlate them with motor-
sensory and cognitive function. Data will be related to ex vivo structural manifestations of MS, namely neuron
loss and demyelination. We propose that the number of remaining neurons and their myelin integrity will
correlate with changes in optic nerve conduction speed, visual acuity and retinal nerve fiber layer thinning. We
will then examine if current treatments using Fingolimod, 4-aminopyridine and a ketogenic diet increase neuro-
axonal electrical activity and decrease functional fluctuation to favor increased rehabilitation. Newer
experimental therapies, derived from compounds hypothesized to mediate the therapeutic effects of
mesenchymal stem cell (MSC) therapy, which targeting improved nerve transduction, will also be tested in the
chronic and relapsing remitting models of MS.
Supported by pilot data results, we will determine with additional rigor that decreased optic nerve conduction
velocity precedes motor-sensory and structural deficits in the EAE model and represents an early marker of
disease activity. Our expected data will provide insights on how impairment of visual function corresponds to
demyelination, retinal thinning and retinal ganglion cell (RGC) loss. We also determine at what time point an
earlier treatment intervention will improve long-term functional and structural outcome. We further expect to
provide convincing data that improvement of neuro-axonal electrical activity and conduction speed represent
promising, new therapeutic avenues with extraordinary clinical impact for restoring function and quality of life.
Clinical translation of these results will help predict MS relapses and rehabilitation in MS patients. We will
provide strong evidence that testing of visual function can be used as a tool to monitor disease activity in MS,
including detection of subclinical episodes of relapse or progression before clinical symptoms develop.
In conclusion, we expect to have obtained conclusive data to determine the nature of early visual biomarkers in
the EAE model and their value in predicting central nervous system outcome. Translation of such biomarkers
to clinical practice would identify veterans with MS in need of further disease modifying agents to optimize
recovery and quality of life.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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RANDY H. KARDON其他文献
RANDY H. KARDON的其他文献
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{{ truncateString('RANDY H. KARDON', 18)}}的其他基金
Center for the Prevention and Treatment of Visual Loss
视力丧失预防和治疗中心
- 批准号:
10275482 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Early Visual Biomarkers of Relapse and Rehabilitation in Multiple Sclerosis
多发性硬化症复发和康复的早期视觉生物标志物
- 批准号:
10411975 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Center for the Prevention and Treatment of Visual Loss
视力丧失预防和治疗中心
- 批准号:
10663778 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Diabetic Neuropathy: Function-Structure of Corneal Nerves to Assess Injury-Repair
糖尿病神经病变:角膜神经的功能结构评估损伤修复
- 批准号:
8998985 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Diabetic Neuropathy: Function-Structure of Corneal Nerves to Assess Injury-Repair
糖尿病神经病变:角膜神经的功能结构评估损伤修复
- 批准号:
9293574 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Diabetic Neuropathy: Function-Structure of Corneal Nerves to Assess Injury-Repair
糖尿病神经病变:角膜神经的功能结构评估损伤修复
- 批准号:
10339313 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Diabetic Neuropathy: Function-Structure of Corneal Nerves to Assess Injury-Repair
糖尿病神经病变:角膜神经的功能结构评估损伤修复
- 批准号:
10631891 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Cholinergic Drugs For Reversal Of Visual Deficits In Glaucoma
用于逆转青光眼视力缺陷的胆碱能药物
- 批准号:
8857398 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Cholinergic Drugs For Reversal Of Visual Deficits In Glaucoma
用于逆转青光眼视力缺陷的胆碱能药物
- 批准号:
8466759 - 财政年份:2010
- 资助金额:
-- - 项目类别:
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