Creating a predictive vascular system for early development

为早期发育创建预测性血管系统

基本信息

批准号：
8203043
负责人：
Brett R Blackman
金额：
$ 296.31万
依托单位：
HEMOSHEAR THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8203043
关键词：
Address Adhesions Adverse effects Agreement Animal Model Atherosclerosis Bioinformatics Biological Assay Biological Markers Biological Process Blood Vessels Boxing Categories Cells Clinical Clinical Drug Development Coculture Techniques Collaborations Complement Complications of Diabetes Mellitus Computer Simulation Consultations Custom Data Data Set Databases Decision Making Detection Development Disease Dose Drug Compounding Drug Delivery Systems Drug Industry Drug vehicle End Point Assay Endothelium Exhibits Expenditure FDA approved Failure Gene Expression Genes Genome Genomics Human Human Genome In Vitro Individual Industry Inflammatory Informatics Lead Legal patent Letters Lipoproteins Marketing Methods Modeling Molecular Molecular Profiling Outcome Pathway interactions Permeability Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacotherapy Phase Phase I Clinical Trials Phosphorylation Preclinical Drug Development Preclinical Drug Evaluation Quality Control RNA Relative Risks Risk Rofecoxib Role Safety Sampling Scientist Screening procedure Signal Transduction Small Business Innovation Research Grant Smooth Muscle Smooth Muscle Myocytes Staging System TNF gene Technology Testing Time Training Validation Vascular System atherogenesis body system channel blockers chemokine cytokine diabetic drug candidate drug development drug discovery drug testing falls hemodynamics in vitro Assay knock-down large-scale database monocyte new technology novel oxidized low density lipoprotein pre-clinical prospective research study response rosiglitazone shear stress success therapy design tool trend vascular inflammation wasting

项目摘要

DESCRIPTION (provided by applicant): The frequent inability of in vitro assays and animal models to accurately predict human response to a new drug candidate results in costly drug development failures. HemoShear has developed a platform technology for biodiscovery and drug pharmacology screening that replicates human biological function in healthy and diseased organ systems by applying human-derived hemodynamic shear stress forces to primary human cells in co-culture. Our initial system replicates the human vascular system and enables the creation of disease conditions including vascular inflammation, early atherogenesis and diabetic complications. Our novel technology is being deployed for customers to investigate the cellular and molecular mechanisms of human vascular inflammation and the identification of novel biomarkers and transcriptional pathways for development of drug therapies. Completed Phase I: The objective of our completed Phase I proposal was to develop a more advanced pro-inflammatory system that profiles the human vascular response (EC/SMC) to oxidized low density lipoprotein (oxLDL), which has a widely recognized role in vascular inflammation and atherosclerosis. We are already using the Phase I advanced inflammatory system for functional assays, target validation and knock-down experiments for our customers. The Problem: There does not exist an in vitro human vascular pharmacology system that can guide pharma and biotech in making key go-/no-go decisions in drug discovery and development. Furthermore, the FDA now requires that vascular risk must be more "thoroughly addressed during drug development, especially for Type 2 anti-diabetic therapies," and the need for a predictive vascular pharmacology system has been confirmed by pharma industry executives and customers (see Letters of Support). Proposed Phase II: The purpose of this Phase II SBIR proposal is to develop a predictive vascular pharmacology system for late-stage drug discovery and preclinical drug development. The HemoShear vascular system, developed in Phase I above, will be used to evaluate known drug compounds across a broad range of drug classes that have the following effects on the vasculature: 1) direct/intended effect (e.g. Ca channel blockers), 2) positive pleiotropic effect (e.g. statins) and 3) negative pleiotropic effect (e.g. rosiglitazone, Vioxx), in order to create a robust database of drug-related vascular effect profiles. We will use proprietary bioinformatics methods to develop a vascular signature predictor panel (~30 genes) from whole genome data sets that can be used for screening and scoring candidate compounds for vascular pharmacology response and potential safety risk. Value: Success of this Phase II SBIR will provide a predictive set of tools with which to assess human vascular response of customers' novel drug compounds, prior to human studies. PUBLIC HEALTH RELEVANCE: Over 90% of drugs that enter Phase I clinical trials ultimately fail because of lack of efficacy or adverse effects. It is estimated that $65bln is spent annually in discovery, pre-clinical and clinical drug development. Much of that expenditure is wasted on failure, largely because of the inability of in vitro assays and animal models to accurately predict human response to a new drug candidate. HemoShear has developed a platform technology for biodiscovery and drug screening that replicates human biological function in healthy and diseased organ systems by applying human-derived hemodynamic shear stress forces to primary human cells in co-culture. HemoShear's patented system has been shown to validate efficacy, safety and off-target effects of known, FDA-approved drug compounds. The purpose of this Phase II SBIR proposal is to develop a predictive vascular pharmacology system to assess new drug compounds in late-stage drug discovery and preclinical drug development.

描述（由申请人提供）：体外测定和动物模型的频繁无力准确预测人类对新药候选药物的反应会导致昂贵的药物发育失败。 Heamshear开发了一种用于生物发现和药物药理学筛查的平台技术，该技术通过将人类衍生的血液动力学剪切应力应用于共培养的原代人细胞，从而在健康和患病的器官系统中复制人类生物学功能。我们的初始系统复制了人类血管系统，并能够创建包括血管炎症，早期动脉粥样硬化和糖尿病并发症在内的疾病状况。我们的新技术正在部署，以研究人类血管炎症的细胞和分子机制，并鉴定新的生物标志物和用于开发药物疗法的转录途径。完成的I期：我们完成的I期建议的目的是开发一种更先进的促炎系统，该系统将人血管反应（EC/SMC）介绍到氧化的低密度脂蛋白（OXLDL）中，该系统在血管炎症和动脉粥样硬化中具有广泛认可的作用。我们已经在使用I期高级炎症系统来为客户提供功能测定，目标验证和击倒实验。问题：不存在体外人体血管药理学系统，该系统可以指导药物和生物技术在药物发现和发育中做出关键/无需决定。此外，FDA现在要求“在药物开发期间，尤其是对于2型抗糖尿病疗法，必须更彻底地解决血管风险”，并且药物行业的高管和客户已经确认了对预测性血管药理学系统的需求（请参阅支持信）。提出的II期：该II期SBIR提案的目的是开发一种用于后期药物发现和临床前药物开发的预测血管药理学系统。 The HemoShear vascular system, developed in Phase I above, will be used to evaluate known drug compounds across a broad range of drug classes that have the following effects on the vasculature: 1) direct/intended effect (e.g. Ca channel blockers), 2) positive pleiotropic effect (e.g. statins) and 3) negative pleiotropic effect (e.g. rosiglitazone, Vioxx), in order to create a robust database of与药物有关的血管效应谱。我们将使用专有生物信息学方法从整个基因组数据集中开发一个血管签名预测板（〜30个基因），可用于筛查和评分候选化合物，以实现血管药理学反应和潜在安全风险。价值：此II阶段SBIR的成功将提供一组预测性的工具，用于在人类研究之前评估客户新型药物化合物的人类血管反应。公共卫生相关性：超过90％的药物进入I期临床试验最终由于缺乏功效或不良影响而失败。据估计，每年在发现，临床前和临床药物开发中花费65美元。大部分支出浪费在失败上，这主要是因为体外测定和动物模型无法准确预测人类对新药候选者的反应。 Hemoshear开发了一种用于生物发现和药物筛查的平台技术，该技术通过将人类衍生的血液动力学剪切应力在共培养的原代人细胞中应用于健康和患病器官系统中的人类生物学功能。已显示出血际的专利系统可以验证已知的，FDA批准的药物化合物的功效，安全性和脱靶作用。该II期SBIR提案的目的是开发一种预测性血管药理学系统，以评估晚期药物发现和临床前药物开发中的新药物化合物。