I-Corps: Tackling Microbiome-Associated Diseases with Precision Editing

该I-Corps项目的更广泛影响/商业潜力正在解决对有效抗菌药物的未满足需求，以降低与微生物组相关的疾病风险。越来越多的证据表明，微生物组中的特定细菌与急性疾病和慢性疾病有关，但目前减轻微生物组中特定微生物威胁的技术非常有限且不发达。在美国，微生物组相关疾病的筛查和治疗的总目标市场超过180亿美元，靶向药物的空间几乎仍然是空的。这种方法既成本低又可扩展，并提供了微生物组中靶向干预措施的实用性的一个例子，以帮助患者和医生更好地管理与微生物组相关的疾病风险。 这个I-Corps项目是基于开发一种新的方法，用于噬菌体的大规模并行工程，以靶向复杂微生物群落中的特定细菌。该管道确定了哪些突变驱动了噬菌体的活性和特异性，并使用一种新的高通量方法将策划的突变与数千种用户设计的变体结合在复杂的噬菌体混合物中，以精确消除靶向细菌。与开发噬菌体鸡尾酒的传统方法相比，这种方法代表了近四个数量级的吞吐量增加。这种方法已被用来创建噬菌体鸡尾酒，消除肠道微生物组中与不同疾病发展密切相关的细菌。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值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 I-Corps project is addressing an unmet need for effective prophylactics to reduce the risk of diseases associated with the microbiome. Growing evidence has associated specific bacteria in the microbiome with both acute conditions and chronic illnesses, but current technologies to mitigate specific microbial threats in the microbiome are extremely limited and underdeveloped. The total addressable market in the US for screening and therapeutics for microbiome-associated diseases exceeds 18 billion USD and the space for targeted prophylactics has remained virtually empty. This approach is both low-cost and scalable and presents an example of the utility of targeted interventions in the microbiome to give agency to patients and physicians for better management of the risk of diseases associated with the microbiome. This I-Corps project is based on the development of a novel approach for massively parallel engineering of bacteriophages to target specific bacteria in complex microbial communities. This pipeline determines which mutations drive activity and specificity in phages and uses a new high throughput method to incorporate curated mutations in complex phage cocktails with thousands of user-designed variants to precisely eliminate targeted bacteria. Compared to traditional approaches for developing phage cocktails, this approach represents increased throughput by nearly four orders of magnitude. This approach has been leveraged to create phage cocktails that eliminate bacteria in the gut microbiome strongly associated with the development of different diseases. Targeting and removing these bacteria presents an elegant solution to manage risk and move the gut microbiome towards a healthy state.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.