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

这一i-Corps项目的广泛影响/商业潜力正在解决有效预防措施以降低与微生物组有关的疾病风险的未得到满足的需求。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病有关，但目前缓解微生物组中特定微生物威胁的技术极其有限和不发达。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，而靶向预防的空间几乎仍然是空的。这种方法既低成本又可推广，是在微生物组中进行有针对性的干预的一个例子，为患者和医生提供了更好地管理与微生物组有关的疾病风险的机构。这个i-Corps项目是基于开发一种大规模并行工程噬菌体的新方法，以针对复杂微生物群落中的特定细菌。这条管道确定哪些突变驱动噬菌体的活性和特异性，并使用一种新的高通量方法将精心挑选的突变纳入复杂的噬菌体鸡尾酒中，以及数千个用户设计的变体，以精确消除目标细菌。与传统的开发噬菌体鸡尾酒的方法相比，这种方法的吞吐量提高了近四个数量级。这种方法已被用来制造噬菌体鸡尾酒，以消除肠道微生物群中与不同疾病的发展密切相关的细菌。针对并清除这些细菌为管理风险和将肠道微生物群推向健康状态提供了一个优雅的解决方案。该奖项反映了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 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.