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

这一小型企业创新研究(SBIR)第二阶段项目的更广泛影响/商业潜力将是通过开发使用治疗性细菌菌株对肠道进行可靠和可逆定植的技术，促进基于工程细胞的疗法在人体肠道中的使用。工程细胞疗法由于其复杂的行为和模块化设计的潜力，有望成为药物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，因为它是我们身体与外来遗传物质的天然接口。肠道细菌药物开发的一个关键障碍是缺乏在患者可以容纳的广泛肠道环境中实现可预测的定植的策略。此外，目前还不存在按需清除治疗菌株以确保安全性的工具。拟议的创新将克服这些挑战，并使工程细菌细胞作为治疗方法的潜力得到充分实现。这项SBIR第二阶段项目将开发必要的技术，以实现工程细菌菌株对人类肠道的可预测定植和有针对性的清除。可预测的定植将通过使用一种治疗性菌株来实现，这种菌株经过改造，可以消耗一种特权的益生菌底物，这种底物可以与该菌株一起服用，通过给予它竞争优势来精确控制其丰度。为了确保遏制和靶向清除，治疗性菌株将被进一步修饰，使其只能在存在益生素的环境中生长。这将允许在肠道内产生一个强大的合成生态位，仅通过给药这种益生菌控制分子就可以操纵它。此外，为了实现这些新技术的商业部署，将开发制造方案，以确保能够生产足够数量的完全整合的治疗菌株并稳定地配制。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.