SBIR Phase I: An Engineering Platform for Adaptive Medicines

这项小企业创新研究（SBIR）项目的更广泛影响/商业潜力是开发一种基于细胞的平台技术，该技术可以感知炎症部位，并通过产生抗炎因子来治疗自身免疫性疾病。有80多种自身免疫性疾病，超过2350万美国人受到影响。自身免疫性疾病是美国女性发病的头号原因，也是65岁以下女性死亡的十大原因之一。据估计，仅在美国，这些疾病每年造成的医疗负担就超过1000亿美元。目前对自身免疫性疾病的治疗对一些患者是有效的，但大多数患者要么没有反应，要么变得难治性。此外，标准药物会导致全身免疫抑制，这可能导致严重和慢性的副作用。因此，市场对消炎药的需求很大，这种药物可以在局部炎症部位起作用，并根据病情的严重程度在适当的时间给予“适当的剂量”。如果成功，本提案中开发的适应性细胞治疗平台将作为现有生物制剂的下一代治疗的基础。这个SBIR一期项目提出开发一种基于细胞的技术，该技术可以定位炎症部位，感知炎症信号，并触发抗炎剂的释放。近年来在合成生物学和细胞疗法方面取得的实质性技术和临床进展使这类产品的发展成为可能。目标是设计和优化合成基因回路，以编程细胞局部感知炎症信号，如tnf α，并释放抗tnf药物。该计划是将这些电路引入成体干细胞中，这种干细胞已经在许多针对自身免疫性疾病的临床试验中安全使用，并且已经有了完善的商业开发路径。这些工程细胞将在培养中进行测试，以显示对不同水平的TNFalpha的输入/输出反应，然后在小鼠疾病模型中进行测试。如果成功，主要候选药物将在第二阶段申请中进一步开发。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) project is to develop a cell-based platform technology that can sense inflammatory sites and respond by producing anti-inflammatory factors to treat autoimmune diseases. There are more than 80 types of autoimmune disease with more than 23.5 million Americans affected. Autoimmune diseases are the number one cause of morbidity for women in the U.S., and one of the top 10 causes of death for women under 65 years old. The annual healthcare burden of these diseases is estimated at more than $100 billion in the U.S. alone. Current treatments for autoimmune diseases are effective for some patients, but a majority either do not respond or become refractory. Furthermore, standard drugs result in systemic immune suppression, which can cause severe and chronic side effects. Hence, there is substantial market need for anti-inflammatory drugs that can act locally at the site of inflammation, and deliver the "right dose at the right time" depending on the severity of the flare. If successful, the adaptive cell therapy platform being developed in this proposal will serve as the basis for a next-generation therapy to existing biologics.This SBIR Phase I project proposes to develop a cell-based technology that localizes to a site of inflammation, senses inflammatory signals, and triggers the release of anti-inflammatory agents. The substantial technical and clinical progress made in recent years in synthetic biology and cell therapies is enabling development of this type of product. The goal is to design and optimize synthetic gene circuits to program cells to locally sense inflammatory signals such as TNFalpha and release anti-TNF drugs. The plan is to introduce these circuits into adult stem cells that have been used safely in numerous clinical trials against autoimmune diseases and have a well-established commercial development path. The engineered cells will be tested in culture to show input/output response to different levels of TNFalpha, and then tested in mouse models of disease. If successful, lead candidates will be further developed in a Phase II application.