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候选药物的反应，导致代价高昂的药物开发失败。HemoSher开发了一种生物发现和药物药理筛选的平台技术，通过将人类衍生的血液动力学剪切力应用于共培养的原代人类细胞，在健康和疾病的器官系统中复制人类的生物功能。我们的初始系统复制了人类的血管系统，并能够创造包括血管炎症、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，并识别新的生物标记物和转录途径，以开发药物治疗。完成第一阶段：我们完成第一阶段提案的目标是开发一种更先进的促炎系统，该系统描述人类血管对氧化型低密度脂蛋白(OxLDL)的反应(EC/SMC)，氧化型低密度脂蛋白在血管炎症和动脉粥样硬化中具有广泛公认的作用。我们已经在为我们的客户使用第一阶段先进的炎症系统进行功能分析、靶标验证和击倒实验。问题：目前还没有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通过/不通过的决定。此外，FDA现在要求在药物开发期间必须更彻底地解决血管风险，特别是对于2型抗糖尿病疗法，并且制药业高管和客户已经确认了对预测性血管药理学系统的需求(见支持函)。建议的第二阶段：这项第二阶段SBIR建议的目的是为晚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。上述第一阶段开发的血液剪切血管系统将用于评估各种药物类别的已知药物化合物，这些药物对血管系统具有以下影响：1)直接/预期作用(例如钙通道阻滞剂)，2)积极的多效性作用(例如他汀类药物)和3)消极的多效性作用(例如罗格列酮、万络)，以便建立一个强大的药物相关血管效应数据库。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一个血管特征预测小组(~30个基因)，用于筛选和评分候选化合物的血管药理反应和潜在的安全风险。价值：这一第二阶段SBIR的成功将提供一套预测性工具，用于在人体试验之前评估客户的新药化合物对人体血管的反应。 与公共卫生相关：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，每年用于发现、临床前和临床药物开发的费用为650亿美元。大部分支出被浪费在失败上，主要是因为体外测试和动物模型无法准确预测人类对新候选药物的反应。HemoSher开发了一种生物发现和药物筛选的平台技术，通过将人类衍生的血液动力学剪切力应用于共培养的原代人类细胞，在健康和疾病的器官系统中复制人类的生物功能。HemoSher的专利系统已被证明可以验证已知的FDA批准的药物化合物的有效性、安全性和非靶向效果。这一第二阶段SBIR建议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化合物。

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.