Creating a predictive vascular system for early 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新药的反应，导致昂贵的药物开发失败。hemshear开发了一种生物发现和药物药理筛选的平台技术，通过在共培养的原代人细胞中应用源自人类的血流动力学剪切力，在健康和患病器官系统中复制人类生物功能。我们的初始系统复制了人类血管系统，并能够创造疾病条件，包括血管炎症、早期动脉粥样硬化和糖尿病并发症。我们的新技术正被客户用于研究人类血管炎症的细胞和分子机制，以及用于开发药物治疗的新型生物标志物和转录途径的鉴定。完成I期：我们完成I期提案的目的是开发一种更先进的促炎系统，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。我们已经在为客户使用I期先进炎症系统进行功能分析、靶标验证和敲除实验。问题：目前还没有一个体外的人体血管药理学系统，可以指导制药公司和生物技术公司在药物发现和开发过程中做出关键的决定。此外，FDA现在要求血管风险必须“在药物开发过程中更彻底地解决，特别是2型抗糖尿病治疗”，并且对预测性血管药理学系统的需求已经得到制药行业高管和客户的确认（见支持信）。拟议的II期：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预测性血管药理学系统。在上述I期开发的hemshear血管系统将用于评估已知的药物化合物，这些药物对血管系统具有以下影响：1)直接/预期作用（例如Ca通道阻滞剂），2)阳性多效作用（例如他汀类药物）和3)负多效作用（例如罗格列酮，万络），以便创建一个与药物相关的血管作用概况的强大数据库。我们将使用专有的生物信息学方法从全基因组数据集中开发血管特征预测面板（约30个基因），可用于筛选和评分候选化合物的血管药理学反应和潜在安全风险。价值：该II期SBIR的成功将提供一套预测性工具，用于在人体研究之前评估客户新型药物化合物的人体血管反应。

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.