SBIR Phase I: Establishing a Synthetic Niche to Reliably Colonize the Human Gut with Engineered Bacterial Therapeutics

SBIR 第一阶段：建立一个合成生态位，用工程细菌疗法可靠地定殖人类肠道

• 批准号: 1648230
• 负责人: Weston Whitaker
• 金额: $ 22.5万
• 依托单位: Novome Biotechnologies, Inc.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2017-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1648230&HistoricalAwards=false
• 关键词: SBIR; Phase; Establishing; Synthetic; Niche; SBIR; Phase; Establishing; Synthetic; Niche

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) project is to harness the power of engineered gut microbes for treating disease through the development of tools for controlling their abundance in patients. The underlying technology platform utilizes engineered gut bacteria that respond to gastrointestinal conditions to deliver new therapeutic activities to specific sites in the gut at the appropriate dose and time. This SBIR project will improve the reliability of these cell-based therapies by allowing for precise control over the abundance of engineered bacteria in the gut. Such control is key to ensuring a consistent therapeutic effect across different patient diets and microbiomes. Engineered bacteria have been used to deliver anti-inflammatory proteins to the gut to treat mice with a model of inflammatory bowel disease (IBD). IBD is a chronic disease with no cure and low response rates to current treatments, affecting 1.4 million Americans at an annual cost of $6.3 billion in the US alone. In addition to solving a critical remaining challenge in bringing this IBD therapy to the clinic, this SBIR project will enable broader application of engineered gut bacteria to treat additional diseases such as heart-disease, obesity and colorectal cancer. This SBIR Phase I project proposes to develop the first means of achieving reliable colonization of the gut by an engineered therapeutic microbe. Reliable colonization will be accomplished by engineering into a therapeutic strain the ability to grow on a control molecule that is safe for humans to consume, is rarely consumed by other gut bacteria, and will not be absorbed by the intestinal tissue. First, all genes that are suspected to be involved in growth on the control molecule will be systematically removed from a natural isolate to determine those that are required. Next, these genes will be transferred to a non-consuming strain to introduce the ability to grow on the control molecule. Finally, this newly engineered strain that was modified to grow on the control molecule will be introduced into mice that harbor a human microbiota, and the ability to get reliable colonization of these mice by feeding the mice the control molecule will be tested. This project will employ recent insights into the mechanisms governing microbiota structure to develop a key missing tool from current cell-based therapeutic approaches to achieve more predictable therapeutic outcomes.

这项小型企业创新研究（SBIR）项目的更广泛的影响/商业潜力是利用工程肠道微生物的力量来治疗疾病，通过开发控制患者丰富的工具。底层技术平台利用工程的肠道细菌对胃肠道疾病做出反应，以适当的剂量和时间为肠道的特定部位提供新的治疗活动。该SBIR项目将通过允许对肠道中的丰富性细菌进行精确控制，从而提高这些基于细胞的疗法的可靠性。这种控制是确保在不同患者饮食和微生物中保持一致的治疗作用的关键。工程细菌已用于将抗炎蛋白输送到肠道上，以使用炎症性肠病模型（IBD）治疗小鼠。 IBD是一种慢性疾病，对当前治疗方法没有治愈和低反应率，仅在美国就影响了140万美国人，每年63亿美元的成本。除了解决将这种IBD疗法带到诊所中的重要剩余挑战之外，该SBIR项目还将使工程肠道细菌更广泛地应用，以治疗其他疾病，例如心脏病，肥胖和结肠直肠癌。该SBIR I期项目提议开发第一种通过工程治疗微生物实现肠道可靠殖民化的方法。可靠的定植将通过工程化成治疗性菌株来实现，该菌株能够在对对照分子上生长的能力，该对照分子安全食用，很少被其他肠道细菌消耗，并且不会被肠道组织吸收。首先，所有涉嫌参与对照分子生长的基因将系统地从天然分离株中去除以确定所需的基因。接下来，这些基因将被转移到非消耗菌株中，以引入对照分子上生长的能力。最后，这种新设计的菌株被修饰以在对照分子上生长，将引入具有人类微生物群的小鼠，并通过喂养对照分子的小鼠来获得这些小鼠可靠定植的能力。该项目将采用对涉及微生物群结构的机制的最新见解，以从当前基于细胞的治疗方法中开发出关键的缺失工具，以实现更可预测的治疗结果。