血管新生抑制因子之臨床運用課件

血管新生抑制因子之臨床運用血管新生抑制因子之臨床運用血管新生抑制因子之臨床運用Angiogenesistheprocessofgrowingnewbloodvessels

playsanimportantroleinphysiologicalprocesssuchasfetaldevelopment,woundhealing,andmenstrualcycleparticipatesinpathologicalconditionssuchastumorigenesis,retinopathy,andarthritis.血管新生抑制因子之臨床運用Tumordevelopmentstages血管新生抑制因子之臨床運用Clinicalapplicationof

angiogenesisinhibitorscancer/metastasiscorneaangiogenesischoroidalneovascularizationrheumatoidarthritis血管新生抑制因子之臨床運用Dr.Folkman'sWaronCancer

PioneeronangiogenesisandtumorsuppressionTreatcanceraschronicdisease!血管新生抑制因子之臨床運用NPCcalreticulin1--4171--18020-6xHis-vasostatinExpressionandpurificationofvasostatinABkDa30-vasostatin血管新生抑制因子之臨床運用Vasostatininducedendothelialapoptosis血管新生抑制因子之臨床運用Vasostatinperturbedtubeformation血管新生抑制因子之臨床運用InhibitionofneovascularizationinCAMPBSVS血管新生抑制因子之臨床運用Summary(I)VasostatinspecificallyinducesapoptosisinendothelialcellsVasostatininhibitsangiogenesisinvitroandinvivo血管新生抑制因子之臨床運用Topicalapplicationofvasostatinfortreatmentofneovascularizationineyes血管新生抑制因子之臨床運用Angiogenesiscausesproblemsineyes**血管新生抑制因子之臨床運用Modelsfor

eyeneovascularization

corneaangiogenesis

implantationofbFGF-containingpolymerintocornea

choroidalneovascularization

laser-inducedphotocoagulation血管新生抑制因子之臨床運用Excellentstabilityofvasostatin血管新生抑制因子之臨床運用ExperimentalSchemeVSeyedropeyedrop血管新生抑制因子之臨床運用TopicalapplicationofVSeyedropreducedcorneaangiogenesis血管新生抑制因子之臨床運用TopicalapplicationofVSeyedropreducedcorneaangiogenesisMolecularVision2005;11:28-35血管新生抑制因子之臨床運用Corneaiseasy.Howaboutretina?**血管新生抑制因子之臨床運用Choroidalneovascularization

/MaculardegenerationChoroidalneovascularization(CNV)istheprimarycauseforvisionlossinpatientswithmaculardegeneration血管新生抑制因子之臨床運用InductionofchoroidalneovscularizationphotoreceptorsandRPEdamagelaserfreeradicalproduction3-6weeksFluoresceinangiography血管新生抑制因子之臨床運用ExperimentalScheme0 7 14 21 28 35 42(day)Eyedrops(n=12,threetimesdaily)LaserFAGanalysis血管新生抑制因子之臨床運用PBSeyedropControlVSeyedropTopicalapplicationofVSreducedtheincidenceofCNV血管新生抑制因子之臨床運用VSeyedropreducedtheareaofCNV血管新生抑制因子之臨床運用Summary(II)RepeatedinjectionofvasostatinretardedthetumorgrowthandenhancedsurvivalEyedropcontainingvasostatineffectivelyinhibitedneovascularizationineyeswithoutsignificantadverseeffects血管新生抑制因子之臨床運用Proteinworksgreat,buttediousandlabor-intensive

Howaboutgenedelivery?Whatnon-viralpolymertobeused?血管新生抑制因子之臨床運用vasostatinAAAACMVHAGenedeliveryschemePVPpolymerpoly-(N-vinylpyrrolidone)DNA-PVPcomplexIMinjection血管新生抑制因子之臨床運用kDa453121PBSpCMV3pCMV3-VS

-tubulinHA21HAPBSpCMV3pCMV3-VSkDaCellextractsCulturedsupernatantsVSgenedeliveryinmusclecells血管新生抑制因子之臨床運用kDa-21.5PVP-vectorPVP-VSABHAcalreticulinIMinjectionofvasostatinPVPpolymercomplexledtosystemicvasostatinexpressionExperimentalEyeResearch81(2005)673–679血管新生抑制因子之臨床運用IntramuscularVSgenedeliveryreducedtheincidenceofCNVsalinePVP-VSPVP-vectorExperimentalEyeResearch81(2005)673–679血管新生抑制因子之臨床運用****IntramuscularVSgenedeliveryreducedtheextentofCNV血管新生抑制因子之臨床運用HistologicalanalysisofCNVafterintramuscularVSgenedeliveryABPVP+vectorPVP+VS血管新生抑制因子之臨床運用Summary(III)IntramuscularvasostatingenedeliveryincreasedcirculatingvasostatinlevelsandsuppressedtumorgrowthSystemicvasostatingenedeliverypotentlyinhibitedneovascularizationineyeswithoutsignificantadverseeffects血管新生抑制因子之臨床運用Systemicanti-angiogenictherapyworkswell,butmayhaveadverseeffectonphysiologicalprocesses

Canweachievenon-invasive,localgenedeliveryineyes?血管新生抑制因子之臨床運用LTUE1AE1BE2E3E4E3deletionAd5genomevasostatinCMVpromoterAATAAASV40polyAAdenovirusGeneDeliverySystemPurificationbyCsClgradientultracentrifugation1x1012pfu/mlluciferase血管新生抑制因子之臨床運用day1day7day14day21day28day35Durationofadenovirus-mediatedluciferaseexpressionaftersubconjunctivalinjection血管新生抑制因子之臨床運用ExperimentalScheme0 7 14 21 28 35 42(day)Subconjuntivalinjection(1x109pfu)LaserFAG&ERGanalysis血管新生抑制因子之臨床運用SuppressionofCNVby

subconjunctivalinjectionofAd-VSControlAd-GFPAd-VS血管新生抑制因子之臨床運用SuppressionofCNVby

subconjunctivalinjectionofAd-VS血管新生抑制因子之臨床運用Summary(IV)Subconjunctivalinjectionofadenovirusvectorsleadstosustainedtransgeneexpressioninconjunctivaregionfor28daysSubconjunctivalinjectionofAd-VSeff