SBIR Phase II: An Innovative Full-Thickness Human Skin Model for Increased Throughput Screening in Drug Discovery

该小企业创新研究（SBIR）二期项目建议开发一种高通量分析方法，结合能够准确识别和表征DNA损伤的3d皮肤模型。在药物开发过程中，迫切需要改进遗传毒性检测方法以进行安全性筛选。通常筛选药物化合物的过程昂贵、耗时，而且往往不能提供对体内行为的准确描述。该项目的第一阶段开发了一种全层皮肤模型，可用于一系列毒理学分析。II期将通过将荧光报告结构纳入96孔皮肤模型来解决当前遗传毒性分析的局限性，以创建高通量和准确区分基因毒素类别的分析。这项研究的更广泛的影响是开发一种比现有替代方案更丰富、更准确和高通量的遗传毒性筛选。准确的体外分析的发展不仅减少了对动物试验的需求，而且还可以通过更好地预测人体反应来降低临床试验中患者的风险。在药物开发过程中，毒性已成为导致产品失败的主要原因之一。这种检测方法能够在开发过程的早期识别和消除有害化合物，可以显著降低成本，加快药物开发的时间。除了这些对药物和化学筛选的直接贡献外，该试验提供的机制数据将为DNA损伤的基础科学研究提供有价值的工具。

This Small Business Innovation Research (SBIR) Phase II project proposes to develop a high-throughput assay incorporating 3-D skin models capable of accurately identifying and characterizing DNA damage. There is an urgent need for improved genotoxicity assays for safety screening in drug development. The process by which drug compounds are usually screened is expensive, time-consuming, and often does not provide an accurate depiction of in vivo behavior. Phase I of this project developed a full-thickness skin model that can be used in a range of toxicological assays. Phase II will address the limitations of current genotoxicity assays by incorporating fluorescent reporter constructs into the 96-well skin model to create an assay that is high-throughput and accurately distinguishes between classes of genotoxins. The broader impacts of this research are to develop a genotoxicity screen that is more informative, accurate, and high-throughput than existing alternatives. Development of accurate in vitro assays not only reduces the need for animal testing, but can also reduce the risk to patients included in clinical trials by providing better predictions of the human response. Toxicity has become one of the leading reasons for product failure during drug development. The ability for this assay to identify and eliminate harmful compounds earlier in the development process could significantly reduce the costs and accelerate the timeline of drug development. In addition to these direct contributions for drug and chemical screening, the mechanistic data provided by this assay will provide a valuable tool for basic science research into DNA damage.