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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：
DAVID V SCHAFFER
金额：
$ 22.46万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
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：
https://reporter.nih.gov/project-details/9353802
关键词：
Address Adult Anatomy Animal Model Animals Apoptosis Astrocytoma Biodistribution Biological Blood - brain barrier anatomy Brain Neoplasms Cancer Model Capsid Proteins Cells Clinic Clinical Clinical Trials Dependovirus Development Diagnosis Diffuse Directed Molecular Evolution Disease Distal Engineering Essential Genes Evolution Excision Familial Lipoprotein Lipase Deficiency Future Gene Delivery Gene Library Generations Genetic Genetic Enhancement Glioblastoma Glioma Growth Hemophilia A Herpesviridae Human Immunocompromised Host In Vitro Individual Injectable Injection of therapeutic agent Intervention Leber&apos s amaurosis Libraries Malignant Neoplasms Mediating Medical Mendelian disorder Modeling Molecular Molecular Virology Mus Neoplasm Metastasis Neuraxis Oncolytic Operative Surgical Procedures Patients Pre-Clinical Model Primary Brain Neoplasms Property Protein Engineering Radiation Recovery Safety Series Suicide System Therapeutic Time Tissues Treatment Efficacy Tropism Tumor Initiators Vaccinia Variant Viral Viral Genome Viral Vector Virus Work Xenograft Model Xenograft procedure adeno-associated viral vector antiangiogenesis therapy base brain parenchyma cancer immunotherapy cancer therapy chemotherapy clinical translation conventional therapy experience extracellular gene therapy immune checkpoint blockade improved in vivo in vivo Model mouse model neoplastic cell next generation novel novel strategies outcome forecast particle response success targeted delivery targeted treatment therapeutic gene therapeutic target therapy resistant trafficking transgene expression tumor tumor growth tumor progression vector virtual

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