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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）：体外试验和动物模型经常无法准确预测人类对候选新药的反应，导致药物开发失败，代价高昂。HemoShear开发了一种用于生物发现和药物药理学筛选的平台技术，通过将人源性血液动力学剪切应力应用于共培养的原代人体细胞，在健康和患病器官系统中复制人体生物学功能。我们的初始系统复制了人类血管系统，并能够创建疾病条件，包括血管炎症，早期动脉粥样硬化和糖尿病并发症。我们的新技术正在为客户部署，以研究人类血管炎症的细胞和分子机制，并识别用于开发药物疗法的新型生物标志物和转录途径。完成第一阶段：我们完成的I期研究的目的是开发一种更先进的促炎系统，该系统可以描述人体血管对氧化低密度脂蛋白（oxLDL）的反应（EC/SMC），氧化低密度脂蛋白在血管炎症和动脉粥样硬化中具有广泛的作用。我们已经在使用Phase I先进的炎症系统为我们的客户进行功能测定、靶点验证和敲除实验。问题：目前还不存在一个体外人体血管药理学系统，可以指导制药和生物技术在药物发现和开发中做出关键的去/不去决定。此外，FDA现在要求必须“在药物开发期间更彻底地解决血管风险，特别是对于2型抗糖尿病治疗”，并且制药行业高管和客户已经证实了对预测血管药理学系统的需求（见支持信）。拟议的第二阶段：该II期SBIR提案的目的是为后期药物发现和临床前药物开发开发一个预测性血管药理学系统。在上述I期开发的HemoShear血管系统将用于评价对血管系统具有以下影响的广泛药物类别中的已知药物化合物：1）直接/预期效果（例如Ca通道阻滞剂），2）正多效性作用（例如他汀类药物）和3）负多效性作用（例如罗格列酮、万络），以创建药物相关血管效应特征的稳健数据库。我们将使用专有的生物信息学方法，从全基因组数据集开发血管特征预测因子组（约30个基因），可用于筛选和评分血管药理学反应和潜在安全性风险的候选化合物。数值：该II期SBIR的成功将提供一套预测工具，用于在人体研究之前评估客户的新型药物化合物的人体血管反应。公共卫生相关性：超过90%进入I期临床试验的药物最终因缺乏疗效或不良反应而失败。据估计，每年有650亿美元用于发现，临床前和临床药物开发。大部分支出都浪费在失败上，主要是因为体外试验和动物模型无法准确预测人类对新药候选物的反应。HemoShear开发了一种用于生物发现和药物筛选的平台技术，通过将人源性血液动力学剪切应力应用于共培养的原代人体细胞，在健康和患病器官系统中复制人体生物学功能。HemoShear的专利系统已被证明可以验证FDA批准的已知药物化合物的有效性、安全性和脱靶效应。该II期SBIR提案的目的是开发预测性血管药理学系统，以评估后期药物发现和临床前药物开发中的新药化合物。