Novel extra cellular RNA-based combinatorial RNA inhibition therapy

基于细胞外RNA的新型组合RNA抑制疗法

基本信息

  • 批准号:
    9128780
  • 负责人:
  • 金额:
    $ 100万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-08-01 至 2018-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): RNA molecules are secreted in extracellular spaces (exRNAs) and act as endocrine signals altering the phenotypes of cancer cells. In this application we will focus on the class of small non-codingRNAs named microRNAs. We propose an innovative therapeutic concept: the depletion of oncogenic microRNAs from malignant cells by enhancing their secretion as exRNAs or blocking suppressor microRNAs' delivery in extracellular space by blocking secretion mechanisms. Our main goal is to develop new strategies using combined miRNA and siRNA to maximize therapeutic benefit by affecting the production of exRNAs. Our proposal centers on the identification and targeting of specific tumor-derived exRNA and exosomes leading to novel therapies and improved therapeutic outcomes. In UH2 phase of the grant, using ovarian cancer (OC) cell lines and cells derived from OC patient tumors, we will identify novel exRNA-based cancer therapeutic lead candidates by siRNA library genome-wide screening based on secretion measurements, by small RNA deep sequencing in "paired" samples from tumors, plasma and ascites from the same patient, and by functional studies for the lead exRNA candidates. In the UH3 phase, we will achieve pre-clinical optimization by testing the exRNA lead(s) identified in the UH2 for antitumor efficacy in well-established OC murine orthotopic models and their safety using well-established preclinical protocols. The aims in exploratory UH2 phase are designed to identify and validate the function of novel exRNA therapeutic candidates for pre- clinical studies. In UH3 phase, we will formulate the methods for the validation of the assays to determine the activity, pharmacology in tissue and plasma to establish dosage schedules in animal models for the design of rational anti-tumor approaches. Using our nanoliposomal delivery technology, we will also conduct target modulation and efficacy studies to generate clear evidence regarding the safety of exRNA-based therapeutic candidates in the proposed dose range. Our approach, by using a new category of regulatory exRNAs- miRNAs, could substantially enhance therapeutic efficacy for cancer treatment. We will also demonstrate, for the first time, the use of nanoliposome-siRNA-exRNA targeting to generate a synergistic boosting effect for treatment of cancers. While we are focusing on OC due to the high mortality associated with this malignancy, our findings have applications for any type of cancer. This proposal brings synergistic capabilities of scientists working for over a decade in the fields of miRNA (Dr. Calin), siRNA (Dr. Sood), nanoparticle delivery (Dr. Lopez-Berestein), and exosome biology (Dr. O'Halloran). The team has the expertise and synergistic drive to achieve novel exRNA therapeutic development by performing highly innovative research, and has developed RNA-based therapies in the past.
描述(由申请人提供):RNA分子分泌在细胞外间隙(exRNA)中,并作为改变癌细胞表型的内分泌信号。在这个应用程序中,我们将集中在一类小的非编码RNA称为microRNA。我们提出了一个创新的治疗概念:通过增强其作为exRNA的分泌或通过阻断分泌机制阻断抑制性microRNA在细胞外空间的递送来消除恶性细胞中的致癌microRNA。我们的主要目标是开发新的策略,使用组合的miRNA和siRNA通过影响exRNA的产生来最大化治疗益处。我们的建议集中在识别和靶向特定的肿瘤来源的exRNA和外泌体,从而导致新的疗法和改善的治疗结果。在授权的UH 2阶段,使用卵巢癌(OC)细胞系和来自OC患者肿瘤的细胞,我们将通过基于分泌测量的siRNA文库全基因组筛选,通过来自同一患者的肿瘤、血浆和腹水的“配对”样品中的小RNA深度测序,以及通过对前导exRNA候选物的功能研究,鉴定新的基于exRNA的癌症治疗先导候选物。在UH 3阶段,我们将使用完善的临床前方案,通过检测UH 2中鉴定的exRNA前导序列在完善的OC小鼠原位模型中的抗肿瘤疗效及其安全性,实现临床前优化。探索性UH 2阶段的目的旨在鉴定和验证用于临床前研究的新型exRNA治疗候选物的功能。在UH 3阶段,我们将制定用于验证测定的方法,以确定组织和血浆中的活性、药理学,从而在动物模型中建立给药方案,以设计合理的抗肿瘤方法。使用我们的纳米脂质体递送技术,我们还将进行靶向调节和功效研究,以产生关于在拟议剂量范围内基于exRNA的治疗候选物的安全性的明确证据。我们的方法,通过使用一类新的调节exRNAs-miRNA,可以大大提高癌症治疗的疗效。我们还将首次证明使用纳米脂质体-siRNA-exRNA靶向产生治疗癌症的协同增效作用。虽然我们专注于OC由于与这种恶性肿瘤相关的高死亡率,但我们的研究结果适用于任何类型的癌症。这项提议带来了在miRNA(Calin博士)、siRNA(Sood博士)、纳米颗粒递送(Lopez-Berestein博士)和外泌体生物学(O 'Halloran博士)领域工作了十多年的科学家的协同能力。该团队拥有专业知识和协同动力,通过进行高度创新的研究来实现新的exRNA治疗开发,并在过去开发了基于RNA的疗法。

项目成果

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George A Calin其他文献

George A Calin的其他文献

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{{ truncateString('George A Calin', 18)}}的其他基金

Small molecule inhibitors of oncogenic miR-21
致癌 miR-21 的小分子抑制剂
  • 批准号:
    10081975
  • 财政年份:
    2020
  • 资助金额:
    $ 100万
  • 项目类别:
miR-155 targeted therapeutics for precision medicine in lung cancer
miR-155靶向治疗用于肺癌精准医疗
  • 批准号:
    10225382
  • 财政年份:
    2018
  • 资助金额:
    $ 100万
  • 项目类别:
miR-155 targeted therapeutics for precision medicine in lung cancer
miR-155靶向治疗用于肺癌精准医疗
  • 批准号:
    10460112
  • 财政年份:
    2018
  • 资助金额:
    $ 100万
  • 项目类别:
miR-155 targeted therapeutics for precision medicine in lung cancer
miR-155靶向治疗用于肺癌精准医疗
  • 批准号:
    9755389
  • 财政年份:
    2018
  • 资助金额:
    $ 100万
  • 项目类别:
miR-155 targeted therapeutics for precision medicine in lung cancer
miR-155靶向治疗用于肺癌精准医疗
  • 批准号:
    9976985
  • 财政年份:
    2018
  • 资助金额:
    $ 100万
  • 项目类别:
HPV Communication to Microenvironment via Exosomes
HPV 通过外泌体与微环境通讯
  • 批准号:
    8843659
  • 财政年份:
    2013
  • 资助金额:
    $ 100万
  • 项目类别:
Novel extra cellular RNA-based combinatorial RNA inhibition therapy
基于细胞外RNA的新型组合RNA抑制疗法
  • 批准号:
    8711594
  • 财政年份:
    2013
  • 资助金额:
    $ 100万
  • 项目类别:
Novel extra cellular RNA-based combinatorial RNA inhibition therapy
基于细胞外RNA的新型组合RNA抑制疗法
  • 批准号:
    8962199
  • 财政年份:
    2013
  • 资助金额:
    $ 100万
  • 项目类别:
Novel extra cellular RNA-based combinatorial RNA inhibition therapy
基于细胞外RNA的新型组合RNA抑制疗法
  • 批准号:
    8582255
  • 财政年份:
    2013
  • 资助金额:
    $ 100万
  • 项目类别:
MicroRNAs and other non-coding RNAs in Colorectal Metastasis
结直肠转移中的 MicroRNA 和其他非编码 RNA
  • 批准号:
    7653452
  • 财政年份:
    2009
  • 资助金额:
    $ 100万
  • 项目类别:

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