Gene and Stem Cell-Based Treatment for Tendinopathy

Project SummaryTendinopathy is a common chronic tendon disorder that affectsof individuals overyears oldIt is characterized by painswellingloss of functionand impaired performanceThere is currently no cure for tendinopathySpontaneous repair or treatment typically leads to scar formationresulting in a weakened tissue with reduced function and mechanical properties that may ultimately rupture with further useOur previous and preliminary studies show that reprogramming tendon stem progenitor cellsTSPCsderived from aged donors to increase their levels of CITEDTSPCCITEDreverses the age induced changes in the stem cells and enhances their reparative efficacy in rat models of tendon ruptureMoreoverintra tendinous injection of aged TSPCCITEDinto the diseased tendon mitigated disease progression and relieved pain in a rat modelHoweveracquisition of TSPCs from patients is not feasible due to concerns regarding donor site morbidityAdiposederived stem cellsADSCshave multiple lineage differentiation potentialincluding that of tendonand is a patient friendly source of mesenchymal stem cellsMSCsOf interestour pilot study suggests that CITEDreprogramming may exert a similar effect on ADSCs as in TSPCsIn additionaged ADSCs transferred with CITEDADSCCITEDand injected into the supraspinatus tendon of healthy recipients can survive for at leastdaysTogetherthese findings led us to propose and test the hypothesis that aged ADSCs transferred with CITEDADSCCITEDexert an enhanced therapeutic effect on mitigating tendinopathy pathology and relieving tendinopathy related painADSCs and TSPCs isolated from aged and young Fischer rats ubiquitously expressing green fluorescence proteinGFPwill be subjected to gene transfer of CITEDADSCCITEDor TSPCCITEDor vector controlADSCV or TSPCVAdult non GFP expressing Fischer rats subjected to overuse treadmill running at a stage of moderate tendinopathy will be subjected to one intra tendon injection of aged ADSCCITEDat two dosagesor injected with aged ADSCVyoung ADSCVaged TSPCsCITEDaged TSPCVand young TSPCV all as controlsA sham placebo grouprats placed on treadmill without running and injected with a vehicle with no cellswill serve as an additional controlAtweeks after injectionsupraspinatus tendons will be dissected and subjected to assays forhistologic evaluationimmunohistochemistry for tendon phenotypic proteinsandmechanical property testingWe will also evaluatepain behaviorsandpainrelated pathogenic changes in the tendon and in the dorsal root ganglionDRGUpon successful completion of Phase I studiesusing larger animal modelsi erabbit model of collagenase induced tendinopathyin Phase II studieswe willfinalize the quality control protocoloptimize dose and treatment frequencyAnimal models in Phase II studies will include tendinopathy of other commonly affected tendonsincluding the Achilles and patellar tendonsand these tendons will be the primary focus of future clinical trialsProject NarrativeTendinopathy is a common chronic tendon disorder representing a significant clinical problem that currently has no cure or effective treatmentThis project will determine the therapeutic effect of a novel geneand stem cell based therapeutic approach on mitigating tendinopathy pathology and relieving pain in a clinically relevant rat model of tendinopathySuccessful completion of the proposed studies will lead to future studies in larger animal models of tendinopathy and human clinical trials