2017
Safety and Efficacy of AAV5 Vectors Expressing Human or Canine CNGB3 in CNGB3-Mutant Dogs
Ye GJ, Komáromy AM, Zeiss C, Calcedo R, Harman CD, Koehl KL, Stewart GA, Iwabe S, Chiodo VA, Hauswirth WW, Aguirre GD, Chulay JD. Safety and Efficacy of AAV5 Vectors Expressing Human or Canine CNGB3 in CNGB3-Mutant Dogs. Human Gene Therapy 2017, 28: 197-207. PMID: 29020838, PMCID: PMC5733651, DOI: 10.1089/humc.2017.125.Peer-Reviewed Original ResearchConceptsHuman CNGB3Immune responseHigh dosesT cell immune responsesHigh-dose groupLow-dose groupInherited retinal disorderImmune-mediated toxicitiesHigher vector doseCone photoreceptor functionDifferent dose levelsFocal chorioretinitisRetinal toxicityVisual acuityInflammatory responseAAV vectorsRetinal disordersSubretinal injectionCone functionDose levelsCone photoreceptorsPhotoreceptor functionCNGB3AAV5 vectorVector dose
2014
Preclinical Safety Evaluation of a Recombinant AAV8 Vector for X-Linked Retinoschisis After Intravitreal Administration in Rabbits
Marangoni D, Wu Z, Wiley HE, Zeiss CJ, Vijayasarathy C, Zeng Y, Hiriyanna S, Bush RA, Wei LL, Colosi P, Sieving PA. Preclinical Safety Evaluation of a Recombinant AAV8 Vector for X-Linked Retinoschisis After Intravitreal Administration in Rabbits. Human Gene Therapy 2014, 25: 202-211. PMID: 25211193, PMCID: PMC4275775, DOI: 10.1089/humc.2014.067.Peer-Reviewed Original ResearchConceptsIntravitreal administrationDose groupEye groupClinical trialsOcular inflammatory reactionRs1-KO miceHigh-dose groupPreclinical safety evaluationNew Zealand white rabbitsAdeno-associated viral vectorZealand white rabbitsIrreversible tissue damageNovel gene therapy approachVitreous infiltratesIntraocular inflammationOcular inflammationInflammatory infiltrateOphthalmological examinationEye doseInflammatory cellsIntravitreal routeOcular safetyClinical signsCommon causeHistopathological analysis
2008
Reversal of Blindness in Animal Models of Leber Congenital Amaurosis Using Optimized AAV2-mediated Gene Transfer
Bennicelli J, Wright JF, Komaromy A, Jacobs JB, Hauck B, Zelenaia O, Mingozzi F, Hui D, Chung D, Rex TS, Wei Z, Qu G, Zhou S, Zeiss C, Arruda VR, Acland GM, Dell'Osso LF, High KA, Maguire AM, Bennett J. Reversal of Blindness in Animal Models of Leber Congenital Amaurosis Using Optimized AAV2-mediated Gene Transfer. Molecular Therapy 2008, 16: 458-465. PMID: 18209734, PMCID: PMC2842085, DOI: 10.1038/sj.mt.6300389.Peer-Reviewed Original ResearchConceptsLeber congenital amaurosisAnimal modelsCongenital amaurosisReversal of blindnessRetinal pigment epithelium cellsWeeks of injectionPigment epithelium cellsRPE65 formDose of vectorAppropriate target cellsVisual acuityVisual deficitsHistopathologic analysisAdeno-associated virusERG responsesRPE65 mutationsSubretinal deliveryEpithelium cellsMutant miceMinimal toxicityProtein expressionTarget cellsPupillary responseElectroretinogramAmaurosis
2006
Safety in Nonhuman Primates of Ocular AAV2-RPE65, a Candidate Treatment for Blindness in Leber Congenital Amaurosis
Jacobson SG, Boye SL, Aleman TS, Conlon TJ, Zeiss CJ, Roman AJ, Cideciyan AV, Schwartz SB, Komaromy AM, Doobrajh M, Cheung AY, Sumaroka A, Pearce-Kelling SE, Aguirre GD, Kaushal S, Maguire AM, Flotte TR, Hauswirth WW. Safety in Nonhuman Primates of Ocular AAV2-RPE65, a Candidate Treatment for Blindness in Leber Congenital Amaurosis. Human Gene Therapy 2006, 17: 845-858. PMID: 16942444, DOI: 10.1089/hum.2006.17.845.Peer-Reviewed Original ResearchConceptsLeber congenital amaurosisOptic nerveGood Laboratory Practice safety studiesCongenital amaurosisObserved adverse effect levelSafety studiesRPE65-mutant dogsSingle intraocular injectionVector-injected eyesHeterogeneous disease groupNormal cynomolgus monkeysAdverse effect levelFuture human trialsGene transfer trialsDose-dependent mannerHigh vector dosesPresurgical recordingsRetinal histopathologyInjected eyeControl eyesIntraocular injectionRetinal injuryCentral retinaThickness abnormalitiesClinical examinationSafety of Recombinant Adeno-Associated Virus Type 2–RPE65 Vector Delivered by Ocular Subretinal Injection
Jacobson SG, Acland GM, Aguirre GD, Aleman TS, Schwartz SB, Cideciyan AV, Zeiss CJ, Komaromy AM, Kaushal S, Roman AJ, Windsor EA, Sumaroka A, Pearce-Kelling SE, Conlon TJ, Chiodo VA, Boye SL, Flotte TR, Maguire AM, Bennett J, Hauswirth WW. Safety of Recombinant Adeno-Associated Virus Type 2–RPE65 Vector Delivered by Ocular Subretinal Injection. Molecular Therapy 2006, 13: 1074-1084. PMID: 16644289, DOI: 10.1016/j.ymthe.2006.03.005.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, Genetically ModifiedBlindnessCarrier ProteinsCis-trans-IsomerasesDependovirusDogsDose-Response Relationship, DrugDrug-Related Side Effects and Adverse ReactionsEye ProteinsFemaleGenetic TherapyGenetic VectorsInjections, IntralesionalMaleOptic Atrophy, Hereditary, LeberRatsRats, Sprague-DawleyRecombinant ProteinsRetinaTissue DistributionConceptsRPE65-mutant dogsLeber congenital amaurosisMonths postinjectionHuman trialsBiodistribution studiesVector dosesHigh vector dosesOcular examinationRetinal histopathologyInjected eyeOptic nerveDose-response resultsModerate inflammationNormal ratsTraumatic lesionsDose efficacyVisual centersSubretinal injectionRPE65 geneSystemic toxicityVirus typeCongenital amaurosisOcular deliveryPostinjectionDoses