Targeted Exosome-Associated AAV-Mediated Gene Therapy to Eliminate Metastatic Neuroendocrine Cancers
靶向外泌体相关 AAV 介导的基因治疗可消除转移性神经内分泌癌
基本信息
- 批准号:9907789
- 负责人:
- 金额:$ 24.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffinityAnimal ModelAnimalsApoptosisBindingBiodistributionBiological MarkersBiological Response Modifier TherapyBioluminescenceBiomanufacturingBioreactorsBypassCancer BurdenCancer PatientCancer cell lineCarcinoid TumorCell DeathCellsCessation of lifeClinicClinical TrialsCloningCoupledCytosolDataDependovirusDiagnosisDiarrheaDrug KineticsElectron MicroscopeEndocrine systemEnergy MetabolismEngineeringEnzymesExcisionFlow CytometryFlushingFutureGene DeliveryGene ProteinsGenesGoalsHeart failureHormone secretionHormonesIgG1ImpairmentIn VitroInner mitochondrial membraneIslet Cell TumorIslets of LangerhansLegal patentLightLiverLuciferasesLungMalignant - descriptorMalignant Carcinoid SyndromeMalignant NeoplasmsMaximum Tolerated DoseMediatingMembrane PotentialsMetastatic Neoplasm to the LiverMitochondriaModelingMonoclonal AntibodiesMorphologyMusNamesNeoplasm MetastasisNeoplasmsNervous system structureNeuroendocrine TumorsNeurosecretory SystemsNormal CellOctreotideOperative Surgical ProceduresPancreasPatientsPeptide ReceptorPharmaceutical PreparationsPlayPropertyProteinsProtonsQuality of lifeRadiation therapyResistanceRhodopsinRoleSDZ RADSSTR2 geneSafetySchemeSignal TransductionSourceSurfaceSurvival RateSystemTechniquesTechnologyTherapeuticTherapeutic EffectTimeTranslationsTreatment EfficacyWestern BlottingXenograft procedureanti-cancerbasecancer cellcancer therapychemotherapyclinical efficacyconfocal imagingexosomeexpression vectorgene therapyimaging systemimprovedin vivoin vivo imaging systeminnovationlight gatedluciferinmedullary thyroid carcinomamitochondrial membranemouse modelneuroendocrine cancernoveloptogeneticspre-clinicalpromoterprotein expressionresponseside effectsomatostatin receptor 2subcutaneoustargeted treatmenttherapeutic genetransmission processtumortumor growth
项目摘要
ABSTRACT
Neuroendocrine (NE) malignancies are hormone secreting neoplasms that arise from endocrine and nervous
system. Multiple NE tumors (NETs) have been diagnosed, such as pancreatic neuroendocrine cancers,
medullary thyroid cancers, and pulmonary neuroendocrine carcinoids. Most NE cancer patients are metastatic
at the time of initial diagnosis which makes the complete resections via surgery impossible. The current
chemotherapies, including Octreotide, Sunitinib, Everolimus and peptide receptor, have marginal curative
benefits and severe side effects. Thus, an effective targeted therapy is critical for patients with metastatic NE
cancers.
We have recently developed a novel technique, named “mitochondrial chemo-optogenetics”, by expressing a
heterologous light-gated channelrhodopsin protein in the IMM of cancer cells, and depolarizing IMM potentials
and inducing cell death by using luciferase-luciferin bioluminescence as the endogenous light source. Our
preliminary data showed that this new mitochondrial gene therapy caused substantial NE cancer cell death in
vitro and stopped NE tumor growth and even reduced tumor size in a subcutaneous NE cancer xenograft mouse
model. Additionally, we have built an innovative NE cancer-targeted gene delivery platform by tagging our new
anti-somatostatin receptor 2 (SSTR2) monoclonal antibody (mAb) to the surface of exosome.
However, a targeted gene therapy, such as mAb-Exo-AAV carrying our mitochondrial chemo-optogenetics
therapeutic gene, is urgently needed to achieve substrate-induced mitochondrial depolarization and selective
elimination of cancer cells in vivo. Moreover, the therapeutic efficacy of the gene therapy in metastatic a model
is essential because most diagnosed NE cancer patients are metastatic. The specific objective of this application
is to develop, produce and evaluate an innovative NE cancer-targeted mitochondrial gene therapy to selectively
destroy and eliminate NETs in vivo. The following two specific aims over a 12-month period are propose.
Aim 1: To develop, produce and characterize the NE-cancer targeted mitochondrial gene therapy. A high-quality
anti-SSTR2 mAb-Exo-AAV will be constructed by cloning a cancer promoter (cfos) and the fused blue light-
producing luciferase and light-gated rhodopsin gene, i.e. cfos-NLuc-2A-ABCB-CoChR (~3.3 kb), into the
engineered pAAV-MCS promoterless expression vector, and produced using our stirred-tank bioreactor-based
exosome-AAV biomanufacturing platform and surface tagging technology. The anti-SSTR2 mAb-Exo-AAV will
then be evaluated for its cancer specific targeting and in vitro anti-cancer efficacy.
Aim 2: To evaluate the therapeutic values of the mitochondrial gene therapy using preclinical NET metastatic
animal model. Most NE cancer patients are initially diagnosed with metastases and have already developed
carcinoid syndrome. Therefore we will evaluate the maximal tolerated dose (MTD), pharmacokinetics (PK), anti-
NET efficacy, and liver metastases reduction of the developed gene therapy using metastatic model.
摘要
项目成果
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