Optical imaging in the development of molecularly targeted AAV for cardiac regeneration after myocardial infarction

光学成像在开发用于心肌梗塞后心脏再生的分子靶向 AAV 中

基本信息

  • 批准号:
    10395499
  • 负责人:
  • 金额:
    $ 40.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-04-01 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

The overarching goal of this proposal is to engineer novel, multifunctional drug and gene delivery systems that can target therapies to particular cells and intracellular compartments and also monitor delivery and determine therapeutic efficacy through the integration of advanced imaging technologies. To pursue this goal, this multi-PI application proposes to leverage existing strengths within UVA including: expertise in using advanced biomedical imaging techniques to assess ischemic heart disease in animal models and re-engineering recombinant adeno-associated vectors (rAAV) (French), screening molecular libraries in vivo to identify specific peptides capable of targeting diseased tissue (Kelly) so that the capsid surface displays specific peptides capable of targeting gene delivery to diseased tissue (Dasa). Not only will the targeting peptides validated during this project be used to develop a novel AAV-based cardiac gene delivery system, future applications include labeling the cardiotropic peptides with fluorophores and/or radiotracers to create contrast agents for the molecular imaging of ischemic heart disease. Similarly, the same cardiotropic peptides may prove valuable in targeting novel therapeutic agents directly to the heart after intravenous (iv) injection. In preliminary studies, the two PIs have already demonstrated the robustness and utility of the interdisciplinary technologies needed to achieve the following specific aims: 1) Validate additional peptides specific for the infarct border zone by evaluating their specificity with in vivo optical imaging and ex vivo confocal microscopy. 2) Optimize the cardiac gene delivery system by grafting cardiotropic peptide ligands into the AAV9 capsid for the selective delivery of expression cassettes driven by a cardiac-specific promoter. 3) Demonstrate the utility of the cardiac-targeted AAV gene delivery system by overexpressing the TTK protein kinase and down-regulating Meis1 transcription factor in the heart after myocardial infarction, then use advanced imaging techniques to quantify the therapeutic effect on LV remodeling. The development of this cardiac-targeted gene delivery system will establish a foundation for future research efforts including the engineering and evaluation of cardiac-targeted nanoparticles and liposomes as multifunctional platforms to facilitate not only the molecular imaging of ischemic heart disease, but also the targeted delivery of novel small molecule therapies. This proposal takes a multidisciplinary approach that makes extensive use of biomedical imaging, thus spanning the fields of radiology, cardiology, molecular imaging and molecular virology. The combined research/development project will result in: a) new targeting peptides that interact specifically with cardiomyocytes in vivo, b) new AAV-based systems for cardiac gene delivery with considerable potential for both pre-clinical research and translation to clinical applications, c) insights into the mechanism(s) of action for a novel gene therapy with clear potential for translational medicine.
该提案的总体目标是设计新颖的多功能药物和基因递送系统 它可以将治疗靶向特定的细胞和细胞内区室,还可以监测递送, 通过整合先进的成像技术来确定治疗效果。为了追求这一目标, 该多PI应用程序建议利用UVA内部的现有优势,包括: 先进的生物医学成像技术,以评估缺血性心脏病的动物模型和再造 重组腺相关载体(rAAV)(法国),体内筛选分子文库,以确定特异性 能够靶向病变组织的肽(Kelly),从而使衣壳表面显示特异性肽 能够将基因递送到患病组织(Dasa)。不仅靶向肽将在 该项目将用于开发一种新的基于AAV的心脏基因递送系统,未来的应用包括 用荧光团和/或放射性示踪剂标记所述亲心肽,以产生用于所述细胞的造影剂。 缺血性心脏病的分子成像类似地,相同的心肌肽可能在以下方面证明是有价值的: 在静脉内(iv)注射后将新的治疗剂直接靶向心脏。在初步研究中, 两个PI已经证明了所需的跨学科技术的鲁棒性和实用性, 实现以下具体目标: 1)通过用以下方法评价它们的特异性,筛选对梗塞边缘区特异的另外的肽: 体内光学成像和离体共焦显微镜。 2)通过在AAV 9中植入心脏肽配体优化心脏基因递送系统 用于选择性递送由心脏特异性启动子驱动的表达盒的衣壳。 3)通过过表达靶向心脏的AAV基因递送系统, 心肌梗死后TTK蛋白激酶与Meis 1转录因子表达下调 梗死,然后使用先进的成像技术来量化对LV重塑的治疗效果。 这种心脏靶向基因递送系统的开发将为未来的研究奠定基础 包括心脏靶向纳米颗粒和脂质体的工程设计和评估在内的努力, 多功能平台,不仅有助于缺血性心脏病的分子成像, 新型小分子疗法的靶向递送。该提案采取多学科方法, 生物医学成像的广泛使用,从而跨越放射学、心脏病学、分子成像和 分子病毒学联合研究/开发项目将产生:a)新的靶向肽, 在体内与心肌细胞特异性相互作用,B)用于心脏基因递送新的基于AAV的系统, 临床前研究和转化为临床应用的巨大潜力,c)对 具有明确转化医学潜力的新型基因治疗的作用机制。

项目成果

期刊论文数量(0)
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Brent A French其他文献

Pharmacologic immunomodulation via adenosine 2a receptor stimulation improves LV remodeling and systolic strain in regions adjacent to the infarct as assessed by cardiac MRI
  • DOI:
    10.1186/1532-429x-18-s1-o73
  • 发表时间:
    2016-01-27
  • 期刊:
  • 影响因子:
  • 作者:
    Ya-Jian Cheng;Elie R Chemaly;Yikui Tian;Frederick H Epstein;Brent A French
  • 通讯作者:
    Brent A French
2093 CMR reveals that cardiac-specific overexpression of the inducible form of nitric oxide synthase induces Left Ventricular Hypertrophy in wild-type mice after AAV-Mediated direct gene transfer
  • DOI:
    10.1186/1532-429x-10-s1-a362
  • 发表时间:
    2008-10-22
  • 期刊:
  • 影响因子:
  • 作者:
    Konkal MR Prasad;Ronald J Beyers;Yaqin Xu;Frederick H Epstein;Brent A French
  • 通讯作者:
    Brent A French
2091 Manganese enhanced mri demonstrates a predominant role for nNOS, not eNOS, in modulating L-Type calcium channel flux in the heart
  • DOI:
    10.1186/1532-429x-10-s1-a360
  • 发表时间:
    2008-10-22
  • 期刊:
  • 影响因子:
  • 作者:
    Moriel H Vandsburger;Brent A French;Patrick A Helm;Christopher M Kramer;Frederick H Epstein
  • 通讯作者:
    Frederick H Epstein
Detection of increased coronary microvascular permeability with MRI T1 mapping and gadolinium-labeled albumin
  • DOI:
    10.1186/1532-429x-18-s1-w3
  • 发表时间:
    2016-01-27
  • 期刊:
  • 影响因子:
  • 作者:
    Sophia X Cui;Brent A French;Frederick H Epstein
  • 通讯作者:
    Frederick H Epstein

Brent A French的其他文献

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{{ truncateString('Brent A French', 18)}}的其他基金

Optical imaging in the development of molecularly targeted AAV for cardiac regeneration after myocardial infarction
光学成像在开发用于心肌梗塞后心脏再生的分子靶向 AAV 中
  • 批准号:
    9903440
  • 财政年份:
    2019
  • 资助金额:
    $ 40.38万
  • 项目类别:
Highly Specific and Efficient Vectors for Targeting Pancreatic Cancer
用于靶向胰腺癌的高度特异性和高效的载体
  • 批准号:
    8775439
  • 财政年份:
    2014
  • 资助金额:
    $ 40.38万
  • 项目类别:
Multi-parameter CMR of post-MI Left Ventricular Remodeling in Gene Modified Mice
基因修饰小鼠 MI 后左心室重构的多参数 CMR
  • 批准号:
    8504366
  • 财政年份:
    2013
  • 资助金额:
    $ 40.38万
  • 项目类别:
Multi-parameter CMR of post-MI Left Ventricular Remodeling in Gene Modified Mice
基因修饰小鼠 MI 后左心室重塑的多参数 CMR
  • 批准号:
    8858407
  • 财政年份:
    2013
  • 资助金额:
    $ 40.38万
  • 项目类别:
Multi-parameter CMR of post-MI Left Ventricular Remodeling in Gene Modified Mice
基因修饰小鼠 MI 后左心室重塑的多参数 CMR
  • 批准号:
    8685318
  • 财政年份:
    2013
  • 资助金额:
    $ 40.38万
  • 项目类别:
Multi-parameter CMR of post-MI Left Ventricular Remodeling in Gene Modified Mice
基因修饰小鼠 MI 后左心室重塑的多参数 CMR
  • 批准号:
    9065605
  • 财政年份:
    2013
  • 资助金额:
    $ 40.38万
  • 项目类别:
Inflammation and Oxidative Stress in Hyperglycemic Exacerbation of Infarct Size
梗塞面积高血糖恶化中的炎症和氧化应激
  • 批准号:
    8495393
  • 财政年份:
    2009
  • 资助金额:
    $ 40.38万
  • 项目类别:
Inflammation and Oxidative Stress in Hyperglycemic Exacerbation of Infarct Size
梗塞面积高血糖恶化中的炎症和氧化应激
  • 批准号:
    7900419
  • 财政年份:
    2009
  • 资助金额:
    $ 40.38万
  • 项目类别:
Inflammation and Oxidative Stress in Hyperglycemic Exacerbation of Infarct Size
梗塞面积高血糖恶化中的炎症和氧化应激
  • 批准号:
    7730598
  • 财政年份:
    2009
  • 资助金额:
    $ 40.38万
  • 项目类别:
Inflammation and Oxidative Stress in Hyperglycemic Exacerbation of Infarct Size
梗塞面积高血糖恶化中的炎症和氧化应激
  • 批准号:
    8284413
  • 财政年份:
    2009
  • 资助金额:
    $ 40.38万
  • 项目类别:

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