In Vivo Directed Evolution of Adeno-Associated Virus Vectors for Glioblastoma Multiforme Tumor-Initiating Cells
多形性胶质母细胞瘤肿瘤起始细胞腺相关病毒载体的体内定向进化
基本信息
- 批准号:9353802
- 负责人:
- 金额:$ 22.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-16 至 2019-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAnatomyAnimal ModelAnimalsApoptosisAstrocytomaBiodistributionBiologicalBlood - brain barrier anatomyBrain NeoplasmsCancer ModelCapsid ProteinsCellsClinicClinicalClinical TrialsDependovirusDevelopmentDiagnosisDiffuseDirected Molecular EvolutionDiseaseDistalEngineeringEssential GenesEvolutionExcisionFamilial Lipoprotein Lipase DeficiencyFutureGene DeliveryGene LibraryGenerationsGeneticGenetic EnhancementGlioblastomaGliomaGrowthHemophilia AHerpesviridaeHumanImmunocompromised HostIn VitroIndividualInjectableInjection of therapeutic agentInterventionLeber&aposs amaurosisLibrariesMalignant NeoplasmsMediatingMedicalMendelian disorderModelingMolecularMolecular VirologyMusNeoplasm MetastasisNeuraxisOncolyticOperative Surgical ProceduresPatientsPre-Clinical ModelPrimary Brain NeoplasmsPropertyProtein EngineeringRadiationRecoverySafetySeriesSuicideSystemTherapeuticTimeTissuesTreatment EfficacyTropismTumor InitiatorsVacciniaVariantViralViral GenomeViral VectorVirusWorkXenograft ModelXenograft procedureadeno-associated viral vectorantiangiogenesis therapybasebrain parenchymacancer immunotherapycancer therapychemotherapyclinical translationconventional therapyexperienceextracellulargene therapyimmune checkpoint blockadeimprovedin vivoin vivo Modelmouse modelneoplastic cellnext generationnovelnovel strategiesoutcome forecastparticleresponsesuccesstargeted deliverytargeted treatmenttherapeutic genetherapeutic targettherapy resistanttraffickingtransgene expressiontumortumor growthtumor progressionvectorvirtual
项目摘要
Summary
Glioma, the most common brain tumor in adults, develops as a result of aberrant growth and invasion of
astrocytic tumor cells. Even with aggressive treatment, survival is very poor and is attributed to the presence
of therapy-resistant tumor-initiating cells (TICs), which are highly migratory and invasive and thus render
complete surgical tumor removal impossible. Engineering therapies that target glioma tumor cells and TICs
may enable enhanced efficacy and as a result longer clinical survival times in patients afflicted with this
disease. Accordingly, this proposal is focused on the development of gene therapy strategies for glioblastoma
multiforme (GBM), an aggressive form of glioma, based on the targeting of GBM tumor cells and TICs.
Adeno-associated virus (AAV) has emerged as a safe and promising vector for gene delivery
applications. However, viral vectors in general, and AAV in particular, do not display strong intrinsic cell tropism
for glioma cells in the central nervous system (CNS), and in addition they experience a number of delivery and
transport barriers for systemic delivery to clinical GBM, including biodistribution to the CNS, the blood brain
barrier, and intraparenchymal and intratumoral transport to the primary and diffuse secondary tumors. Thus, it
is highly desirable to develop vectors that can be systemically delivered and that are capable of overcoming
these delivery barriers.
We propose to engineer the coat proteins of AAV to target delivery to glioma tumor cells and TICs to
greatly enhance delivery efficiency and reduce any biological off-target effects. We hypothesize that AAV
directed evolution, a strategy we originally developed and have successfully employed to enhance viral vector
properties, can be implemented to engineer AAV vectors in vivo for enhanced and potentially selective tropism
for GBM tumor cells and TICs. Specifically, we propose to harness (1) a mouse model based on the
xenografting of primary cultured, patient-derived GBM TICs that accurately represents the hallmarks of GBM,
(2) highly diverse AAV vector libraries, and (3) a sophisticated directed evolution strategy that includes a
stringent in vivo selection selective for viral particles that can localize to the CNS and transduce GBM tumor
cells and TICs. We have successfully recovered viral genomes from the first round of evolution, highlighting the
potential of this strategy. We also propose to characterize the resulting engineered AAV vectors by studying
their tropism and biodistribution, essential gene delivery properties for clinical implementation.
Furthermore, we propose to evaluate the therapeutic potential of engineered AAVs by delivering two
promising therapeutic genes that can hamper tumor progression and extend the survival of our animal models,
or that offer promise in future exploration of cancer immunotherapies. This blend of molecular virology, protein
engineering, and a translationally accurate animal model will therefore enable the engineering of enhanced
genetic delivery systems for the treatment of glioblastoma multiforme and in the future potentially other
cancers.
总结
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)
Genome-wide activation screens to increase adeno-associated virus production.
全基因组激活筛选以增加与腺相关的病毒产生。
- DOI:10.1016/j.omtn.2021.06.026
- 发表时间:2021-12-03
- 期刊:
- 影响因子:0
- 作者:Barnes CR;Lee H;Ojala DS;Lewis KK;Limsirichai P;Schaffer DV
- 通讯作者:Schaffer DV
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DAVID V SCHAFFER其他文献
DAVID V SCHAFFER的其他文献
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{{ truncateString('DAVID V SCHAFFER', 18)}}的其他基金
Biology and Biotechnology of Cell and Gene Therapy
细胞和基因治疗生物学和生物技术
- 批准号:
10090424 - 财政年份:2021
- 资助金额:
$ 22.46万 - 项目类别:
Engineering AAV Vectors to Evade Antibody Neutralization
设计 AAV 载体以逃避抗体中和
- 批准号:
7849654 - 财政年份:2007
- 资助金额:
$ 22.46万 - 项目类别:
Engineering AAV Vectors to Evade Antibody Neutralization
设计 AAV 载体以逃避抗体中和
- 批准号:
7442123 - 财政年份:2007
- 资助金额:
$ 22.46万 - 项目类别:
Engineering AAV Vectors to Evade Antibody Neutralization
设计 AAV 载体以逃避抗体中和
- 批准号:
7208807 - 财政年份:2007
- 资助金额:
$ 22.46万 - 项目类别:
Engineering AAV Vectors to Evade Antibody Neutralization
设计 AAV 载体以逃避抗体中和
- 批准号:
7626787 - 财政年份:2007
- 资助金额:
$ 22.46万 - 项目类别:
Engineering AAV Vectors to Evade Antibody Neutralization
设计 AAV 载体以逃避抗体中和
- 批准号:
7851669 - 财政年份:2007
- 资助金额:
$ 22.46万 - 项目类别:
Engineering Novel AAV Vectors for Retinal Gene Therapy
用于视网膜基因治疗的新型 AAV 载体工程
- 批准号:
7268010 - 财政年份:2006
- 资助金额:
$ 22.46万 - 项目类别:
Engineering Novel AAV Vectors for Retinal Gene Therapy
用于视网膜基因治疗的新型 AAV 载体工程
- 批准号:
7149417 - 财政年份:2006
- 资助金额:
$ 22.46万 - 项目类别:
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