Brain Tumor Stem Cell-targeted Gene Therapy

脑肿瘤干细胞靶向基因治疗

基本信息

  • 批准号:
    7294274
  • 负责人:
  • 金额:
    $ 7.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-09-28 至 2009-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma Multiforme (GBM) is a lethal brain tumor that typically causes death within two years after initial diagnosis. GBM accounts for 25% of all primary brain tumors in adults. Despite improvements in precise surgical de-bulking, radiation, and drug therapy, the prognosis for GBM patients has not significantly changed in decades. Novel therapies are therefore desperately needed. Recent studies have revealed that similar to leukemia, a glioma is a heterogeneous tumor comprised of differentiated tumor cells and cancerous progenitor cells known as "brain tumor stem cells" (BTSCs). It has been demonstrated that BTSCs account for a minor fraction of total tumor cells, but are the only cells within the tumor mass that are capable of tumor renewal and tumor recurrence. These findings have significance because they suggest that novel therapy should be designed to selectively target BTSC, rather than conventional approaches that target the bulk tumor mass. We have discovered the BTSCs may be invisible to the immune system because they lack expression of cell surface receptors needed for both innate and adaptive immune-mediated killing. Treatment of BTSCs with interferon gamma (INF-?) restores their immunogenicity and susceptibility to being killed. We are moving forward with our Sleeping Beauty (SB) Transposon plasmid-based gene transfer system for treatment of brain tumors with INF-? gene therapy. In contrast to conventional plasmid DNA vectors, SB mediates sustained gene expression in glioma cells and therefore has potent anti- tumor efficacy. In parallel, we will develop and test a novel BTSC-targeted plasmid delivery vector by conjugating polyethylenimine (PEI) transfection reagent with anti-CD133 antibody because BTSCs express the CD133 receptor but their daughter cells do not. PEI/DNA/CD133mAb complexes will be used to deliver a potent suicide gene into an improved, invasively growing mouse model of GBM alone, or in combination with SB-mediated INF-? gene therapy. We contend that the combination of BTSC-targeted cell death with sustained INF-? mediated immune stimulation will provide a breakthrough in brain tumor immunotherapy by evoking an immune response that eliminates residual BTSCs. This project will initiate the commercialization of these two drugs for GBM therapy. In Aim1, we will develop and optimize BTSC-targeted gene delivery by perfecting PEI/DNA/CD133mAb complexes. These experiments will be done in vitro using human GBM tumor samples to produce a targeted drug for a phase I clinical trial. In Aim 2, the efficacy of SB-mediated INF-? gene therapy and BTSC-targeted suicide gene therapy will be evaluated in vivo in preparation for large animal studies and eventual IND application. Completion of these studies is crucial to accelerate commercialization of SB and BTSC-targeted gene therapy vectors, in order to meet our goal of providing safe and effective gene therapy for treatment of patients with fatal brain tumors. There is currently no effective therapy for patients with glioblastoma, a lethal brain tumor that accounts for 25% of primary brain tumors in adults. Most patients die within two years after diagnosis and over 10, 000 people die each year from glioblastoma in the United States alone. In this project we will develop and begin to commercialize a novel form of gene therapy that is intended to destroy rare "tumor stem cells", which are the cells that ultimately kill glioblastoma patients.
描述(由申请人提供):多形性胶质母细胞瘤(GBM)是一种致命的脑肿瘤,通常在最初诊断后两年内导致死亡。GBM占成人原发性脑肿瘤的25%。尽管精确的手术切除、放疗和药物治疗有了进步,但几十年来GBM患者的预后并没有显著改变。因此,迫切需要新的治疗方法。最近的研究表明,与白血病类似,胶质瘤是由分化的肿瘤细胞和称为“脑肿瘤干细胞”(BTSCs)的癌前细胞组成的异质性肿瘤。研究表明,BTSCs仅占肿瘤细胞总数的一小部分,但却是肿瘤团块中唯一具有肿瘤更新和肿瘤复发能力的细胞。这些发现具有重要意义,因为它们表明应该设计新的治疗方法来选择性地靶向BTSC,而不是传统的靶向大块肿瘤的方法。我们发现BTSCs可能对免疫系统是不可见的,因为它们缺乏先天和适应性免疫介导杀伤所需的细胞表面受体的表达。用干扰素γ (INF-?)治疗BTSCs可恢复其免疫原性和被杀死的易感性。我们正在推进睡美人(SB)转座子质粒基因转移系统,用于INF-?基因治疗。与传统的质粒DNA载体相比,SB在胶质瘤细胞中介导持续的基因表达,因此具有强大的抗肿瘤功效。同时,我们将开发和测试一种新的btsc靶向质粒传递载体,通过偶联聚乙烯亚胺(PEI)转染试剂与抗CD133抗体,因为btsc表达CD133受体,但它们的子细胞不表达。PEI/DNA/CD133mAb复合物将被用于将一个有效的自杀基因传递到单独的、侵袭性生长的GBM小鼠模型,或与sb介导的INF-?基因治疗。我们认为btsc靶向细胞死亡与持续的INF-?介导的免疫刺激将通过唤起消除残留BTSCs的免疫反应,为脑肿瘤免疫治疗提供突破。该项目将启动这两种药物用于GBM治疗的商业化。在Aim1中,我们将通过完善PEI/DNA/CD133mAb复合物来开发和优化btsc靶向基因递送。这些实验将在体外使用人类GBM肿瘤样本进行,以生产用于I期临床试验的靶向药物。在Aim 2中,sb介导的INF-?基因疗法和btsc靶向自杀基因疗法将在体内进行评估,为大型动物研究和最终的IND应用做准备。这些研究的完成对于加速SB和btsc靶向基因治疗载体的商业化至关重要,以实现我们为致命脑肿瘤患者提供安全有效的基因治疗的目标。胶质母细胞瘤是一种致命的脑肿瘤,占成人原发性脑肿瘤的25%,目前尚无有效的治疗方法。大多数患者在确诊后两年内死亡,仅在美国每年就有超过1万人死于胶质母细胞瘤。在这个项目中,我们将开发并开始商业化一种新型的基因疗法,旨在破坏罕见的“肿瘤干细胞”,这种细胞最终会杀死胶质母细胞瘤患者。

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)
Transposon-based interferon gamma gene transfer overcomes limitations of episomal plasmid for immunogene therapy of glioblastoma.
基于转座子的干扰素γ基因转移克服了附加型质粒在胶质母细胞瘤免疫基因治疗中的局限性。
  • DOI:
    10.1038/sj.cgt.7701045
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    6.4
  • 作者:
    Wu,A;Oh,S;Ericson,K;Demorest,ZL;Vengco,I;Gharagozlou,S;Chen,W;Low,WC;Ohlfest,JR
  • 通讯作者:
    Ohlfest,JR
{{ 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 }}

John R Ohlfest其他文献

John R Ohlfest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('John R Ohlfest', 18)}}的其他基金

Discovery and Validation of Tumor Immunoevasion Mechanisms
肿瘤免疫逃避机制的发现和验证
  • 批准号:
    8166119
  • 财政年份:
    2011
  • 资助金额:
    $ 7.43万
  • 项目类别:
Oxygen as a master immunologic switch
氧气作为主要免疫开关
  • 批准号:
    8183092
  • 财政年份:
    2011
  • 资助金额:
    $ 7.43万
  • 项目类别:
Understanding and enhancing mechanisms of priming in cancer immunotherapy
了解和增强癌症免疫治疗的启动机制
  • 批准号:
    8305867
  • 财政年份:
    2010
  • 资助金额:
    $ 7.43万
  • 项目类别:
Understanding and enhancing mechanisms of priming in cancer immunotherapy
了解和增强癌症免疫治疗的启动机制
  • 批准号:
    7953371
  • 财政年份:
    2010
  • 资助金额:
    $ 7.43万
  • 项目类别:
Concurrent Immune Stimulation and Inhibition of Angiogenesis for Glioma Therapy
神经胶质瘤治疗中同时免疫刺激和血管生成抑制
  • 批准号:
    7384288
  • 财政年份:
    2007
  • 资助金额:
    $ 7.43万
  • 项目类别:
Concurrent Immune Stimulation and Inhibition of Angiogenesis for Glioma Therapy
神经胶质瘤治疗中同时免疫刺激和血管生成抑制
  • 批准号:
    7490563
  • 财政年份:
    2007
  • 资助金额:
    $ 7.43万
  • 项目类别:
Brain Tumor Stem Cell-targeted Gene Therapy
脑肿瘤干细胞靶向基因治疗
  • 批准号:
    7221638
  • 财政年份:
    2006
  • 资助金额:
    $ 7.43万
  • 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:
    $ 7.43万
  • 项目类别:
    Research 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:
    $ 7.43万
  • 项目类别:
    Standard 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:
    $ 7.43万
  • 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:
    $ 7.43万
  • 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:
    $ 7.43万
  • 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:
    $ 7.43万
  • 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:
    $ 7.43万
  • 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:
    $ 7.43万
  • 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:
    $ 7.43万
  • 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:
    $ 7.43万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了