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

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
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

DAVID V SCHAFFER其他文献

DAVID V SCHAFFER的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:
Molecular Engineering of Bioactive Hydrogels
生物活性水凝胶的分子工程
  • 批准号:
    7471860
  • 财政年份:
    2008
  • 资助金额:
    $ 22.46万
  • 项目类别:
Molecular Engineering of Bioactive Hydrogels
生物活性水凝胶的分子工程
  • 批准号:
    7595085
  • 财政年份:
    2008
  • 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:

相似海外基金

Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
  • 批准号:
    MR/Z503605/1
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Research Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
  • 批准号:
    2402691
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Standard Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
  • 批准号:
    2336167
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
  • 批准号:
    24K12150
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
  • 批准号:
    2341428
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
  • 批准号:
    DE240100561
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Discovery Early Career Researcher Award
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
  • 批准号:
    10065645
  • 财政年份:
    2023
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Collaborative R&D
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
  • 批准号:
    23K09542
  • 财政年份:
    2023
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
  • 批准号:
    23K07552
  • 财政年份:
    2023
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
  • 批准号:
    23K07559
  • 财政年份:
    2023
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了