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

这个小企业创新研究（SBIR）第二阶段项目的更广泛的影响/商业潜力将是通过开发用于治疗性细菌菌株在肠道中可靠和可逆定植的技术来推进基于工程细胞的治疗剂在人类肠道中的使用。工程细胞疗法有望成为制药创新的下一个主要驱动力，因为它们具有复杂的行为和模块化设计的潜力。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界面。肠道细菌药物开发的一个关键障碍是缺乏在患者可能拥有的广泛肠道环境中实现可预测定植的策略。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。这项创新将克服这些挑战，并使工程菌细胞作为治疗方法的潜力得以充分实现。SBIR二期项目将开发必要的技术，以实现工程菌菌株在人类肠道的可预测定植和靶向清除。可预测的定殖将通过使用治疗菌株来实现，所述治疗菌株已经被修改为消耗特权益生元底物，所述特权益生元底物可以与菌株一起给药，以通过赋予其竞争优势来精确控制其丰度。为了确保遏制并实现靶向清除，治疗菌株将进一步修饰，使得其仅可以在存在益生元的环境中生长。这将允许在肠道内产生稳健的合成小生境，其可以仅通过施用该益生元控制分子来操纵。此外，为了使这些新技术的商业部署，制造协议将制定，以确保一个完全集成的治疗菌株可以生产足够的数量和稳定的formulation.This奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.