Non-viral Reprogramming of Intervertebral Disc Cells for the treatment of Discogenic back pain
椎间盘细胞非病毒重编程治疗椎间盘源性背痛
基本信息
- 批准号:9911144
- 负责人:
- 金额:$ 36.77万
- 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:2019-09-20 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdolescenceAdultAnimal ModelAutomobile DrivingBehaviorBiologicalBiomedical EngineeringBlood VesselsBrachyury proteinCanis familiarisCatabolismCell Culture TechniquesCellsCellularityChronicChronic low back painClinicalClinical TrialsCognitionCommunitiesControl GroupsDNADataDevelopmentDiseaseDog DiseasesDrug AddictionEconomic BurdenEndothelial CellsEngineeringExtracellular MatrixFOXF1 geneFailureFibroblastsFibrosisFunctional disorderGAG GeneGene ProteinsGenerationsGeneticGenomeGlycosaminoglycansGoalsHealthHeightHumanHyperalgesiaIn SituIn VitroInflammationInflammatoryInjuryIntervertebral disc structureLeadLow Back PainMagnetic Resonance ImagingMechanicsMedicalMethodsModelingMusNerveOperative Surgical ProceduresOpioidPainPathologicPathologyPatientsPhasePhase TransitionPhenotypePublic HealthPuncture procedureQuality of lifeResearchResearch PersonnelResearch PriorityRodent ModelSocietiesSomatic CellSpeedStem cellsStructureSystemTechnologyTherapeuticTherapeutic EffectTissuesTransfectionTranslatingTranslational ResearchTreatment EfficacyUnited States National Institutes of HealthValidationVertebral columnVeterinariansViral VectorWorkaddictionclinically relevantcytotoxicitydiscogenic painextracellularextracellular vesiclesgene therapyhealinghuman diseaseimprovedin vivoin vivo Modelinflammatory paininnovationinterdisciplinary approachintervertebral disk degenerationminimally invasivemouse modelmultidisciplinarynanoneurotrophic factornovelnucleus pulposusopioid epidemicoptimal treatmentspain behaviorpain modelpain patientpain reliefpain symptompre-clinicalprogramsprotein expressionreduce symptomsrestorationsocioeconomicsspontaneous painstemstem cell therapytooltranscription factortranslational approachtranslational model
项目摘要
Project Summary/Abstract
Chronic low back pain exerts a significant socio-economic burden on society and is a major contributor to the
growing opioid crisis. Last year, NIH “launched the HEAL (Helping to End Addiction Long-term) initiative, an
aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis”.
This enormous burden is largely because studies have failed to target the underlying mechanisms associated
with pain generation. Intervertebral disc (IVD) degeneration is strongly associated with the pathophysiology of
low back pain and identifying non-addictive minimally invasive treatments for discogenic back pain (DBP) is a
research priority. Pathological IVD changes include extracellular matrix (ECM) breakdown, inflammation and
aberrant nerve/vascular ingrowth which have been shown to significantly correlate with pain. Therefore the
optimal therapy for DBP would target both structural restoration and reduce the symptoms of pain. Yet current
strategies involving the use of stem cells or gene therapy are faced with a number of challenges which include
failure of stem cells to adapt to the harsh IVD microenvironment, the use of viral vectors and unwarranted DNA
deletions within the host genome. Furthermore clinicians do not have access to clinically relevant tools or
technologies that could directly help treat the underlying disease in patients with DBP. There is a critical need
for a biological non-addictive strategy that addresses these limitations. Our goal is to use novel cellular
reprogramming technologies to alter the innate cell phenotype of native diseased IVD cells to a healthy
extracellular producing and anti-catabolic/inflammatory phenotype in human in vitro cell culture and in vivo
models of DBP. Non-viral delivery for transporting genetic cargo into the cell such as engineered extracellular
vesicles (EVs) or tissue nano-transfection (TNT) offer safe and minimally invasive methods for reprogramming
somatic cells and recent work by the investigators has demonstrated successful reprogramming of adult
fibroblasts into endothelial cells in vivo mouse models. We propose using these innovative non-viral delivery
systems to deliver genetic cargo to IVDs in vitro and in vivo. The first specific aim (R61 Phase 1 Aim 1) focuses
on the effects of EV or TNT delivery of transcription factors on diseased human nucleus pulposus cells and
tissue in vitro examining changes in ECM and catabolic, inflammatory and pain markers. The second aim (R61
Phase 1 Aim 2) investigates the effects of EV or TNT delivery of transcription factors in mouse IVD puncture
models of DBP assessing changes in disc structure/function, pain, cognition and cytotoxicity. These studies
are both significant and highly innovative because they combine a unique multi-disciplinary team of medical
and veterinary clinicians, spine biologists, neuroscientists, biomedical engineers, and a biostatistician to
interrogate the use of these novel concepts and technologies to treat DBP. The broader impacts of this
proposal and transition to the R33 portion involve assessing this strategy in clinically relevant
chondrodystrophic dogs that develop DBP spontaneously followed by clinical trials in patient dogs with DBP.
项目总结/文摘
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Non-viral Gene Delivery Methods for Bone and Joints.
- DOI:10.3389/fbioe.2020.598466
- 发表时间:2020
- 期刊:
- 影响因子:5.7
- 作者:Gantenbein B;Tang S;Guerrero J;Higuita-Castro N;Salazar-Puerta AI;Croft AS;Gazdhar A;Purmessur D
- 通讯作者:Purmessur D
Non-viral reprogramming of human nucleus pulposus cells with FOXF1 via extracellular vesicle delivery: an in vitro and in vivo study.
- DOI:10.22203/ecm.v041a07
- 发表时间:2021-01-19
- 期刊:
- 影响因子:3.1
- 作者:Tang S;Salazar-Puerta A;Richards J;Khan S;Hoyland JA;Gallego-Perez D;Walter B;Higuita-Castro N;Purmessur D
- 通讯作者:Purmessur D
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Natalia Higuita-Castro其他文献
Natalia Higuita-Castro的其他文献
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{{ truncateString('Natalia Higuita-Castro', 18)}}的其他基金
Novel non-viral reprogramming strategies to treat Discogenic back pain via engineered extracellular vesicles
通过工程细胞外囊泡治疗椎间盘源性背痛的新型非病毒重编程策略
- 批准号:
10446202 - 财政年份:2022
- 资助金额:
$ 36.77万 - 项目类别:
Novel non-viral reprogramming strategies to treat Discogenic back pain via engineered extracellular vesicles
通过工程细胞外囊泡治疗椎间盘源性背痛的新型非病毒重编程策略
- 批准号:
10606527 - 财政年份:2022
- 资助金额:
$ 36.77万 - 项目类别:
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