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

SBIR 第二阶段：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: 1831185
• 负责人: Weston Whitaker
• 金额: $ 75万
• 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: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1831185&HistoricalAwards=false
• 关键词: SBIR; Phase; II; Establishing; Synthetic

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project will be to advance the use of engineered cell-based therapeutics in the human gut through the development of technologies for the reliable and reversible colonization of the gut with therapeutic bacterial strains. Engineered cellular therapeutics are poised to become the next major driver of pharmaceutical innovation due to their potential for sophisticated behavior and modular design. The gut is an ideal entry point for deploying engineered therapeutic cells, as it serves as our body's natural interface with foreign genetic material. A key impediment to bacterial drug development for the gut is the lack of strategies for achieving predictable colonization across the wide range of gut environments that patients can harbor. Furthermore, tools for on-demand clearance of therapeutic strains to ensure safety do not currently exist. The proposed innovation will overcome these challenges and allow the potential of engineered bacterial cells as therapies to be fully realized.This SBIR Phase II project will develop the technologies necessary to achieve predictable colonization of, and targeted clearance from, the human gut by engineered bacterial strains. Predictable colonization will be achieved through the use of a therapeutic strain that has been modified to consume a privileged prebiotic substrate that can be dosed alongside the strain to precisely control its abundance by giving it a competitive advantage. To ensure containment and enable targeted clearance, the therapeutic strain will be further modified such that it only can grow in environments where the prebiotic is present. This will allow for the generation of a robust synthetic niche within the gut that can be manipulated solely through the administration of this prebiotic control molecule. In addition, to enable the commercial deployment of these novel technologies, manufacturing protocols will be developed to ensure that a fully integrated therapeutic strain can be produced in sufficient quantities and stably formulated.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这项小型企业创新研究（SBIR）II期项目的更广泛的影响/商业潜力将是通过开发具有治疗细菌菌株的可靠和可逆肠道化的技术来推动人类肠道中的基于工程的基于细胞的治疗剂的使用。由于其具有复杂行为和模块化设计的潜力，工程性的细胞疗法有望成为制药创新的下一个主要驱动力。肠道是部署工程治疗细胞的理想切入点，因为它是我们人体与外来遗传物质的自然界面。肠道药物开发的关键障碍是缺乏在患者可以携带的各种肠道环境中实现可预测定植的策略。此外，用于按需清除治疗菌株的工具以确保安全目前不存在。提出的创新将克服这些挑战，并允许设计的细菌细胞作为疗法的全面实现。该SBIR II期项目将开发出通过工程细菌菌株实现可预测的人类肠道和靶向清除所必需的技术。可以通过使用修饰的治疗菌株来实现可预测的定殖，以消耗特权的益生元底物，可以与菌株一起剂量，以通过赋予其竞争优势来精确控制其丰度。为了确保遏制和实现靶向清除，将进一步修改治疗菌株，以便它只能在存在益生元的环境中生长。这将允许在肠道内产生可靠的合成生态位，仅通过该益生元对照分子的给药就可以操纵。此外，为了实现这些新技术的商业部署，将制定制造协议，以确保可以以足够数量的数量生产完全集成的治疗菌株。该奖项反映了NSF的法定任务，并认为通过使用该基金会的知识分子和更广泛的影响来评估的支持，可以通过评估来进行评估。