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

小型企业创新研究(SBIR)项目的更广泛影响/商业潜力是，通过开发控制患者体内肠道微生物丰度的工具，利用工程肠道微生物的力量治疗疾病。基础技术平台利用对胃肠道状况做出反应的工程肠道细菌，在适当的剂量和时间将新的治疗活动输送到肠道中的特定部位。这个SBIR项目将通过精确控制肠道中工程化细菌的数量来提高这些基于细胞的疗法的可靠性。这种控制是确保不同患者饮食和微生物群一致治疗效果的关键。工程菌已被用于将抗炎蛋白输送到肠道，以治疗患有炎症性肠病(IBD)模型的小鼠。IBD是一种慢性疾病，无法治愈，对当前治疗的应答率很低，仅在美国就影响了140万美国人，每年花费63亿美元。除了解决将IBD疗法推向临床的关键剩余挑战外，这一SBIR项目还将使工程肠道细菌能够更广泛地应用于治疗其他疾病，如心脏病、肥胖症和结直肠癌。这个SBIR第一阶段项目建议开发第一种通过工程治疗微生物实现肠道可靠定植的方法。可靠的定植将通过将生长在控制分子上的能力工程到一种治疗菌株来实现，这种控制分子对人类来说是安全的，很少被其他肠道细菌消耗，也不会被肠道组织吸收。首先，所有被怀疑参与控制分子生长的基因将被系统地从自然分离株中移除，以确定哪些是必需的。接下来，这些基因将被转移到一个非消耗菌株，以引入在控制分子上生长的能力。最后，这种新的工程菌株被改造成在对照分子上生长，将被引入到拥有人类微生物区系的小鼠中，并将测试通过喂食对照分子来获得这些小鼠可靠定植的能力。该项目将利用对管理微生物区系结构的机制的最新见解，开发当前基于细胞的治疗方法中缺失的一个关键工具，以实现更可预测的治疗结果。

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.