SBIR Phase II: An omics-based computational drug design and discovery platform for next generation microbiome therapeutics

这一小型企业创新研究(SBIR)第二阶段项目的更广泛/商业影响集中在人体肠道微生物群，即驻留在胃肠道中的复杂和动态的微生物群落。肠道微生物群影响多种人类疾病，如2型糖尿病和炎症性肠病。在美国，这些疾病总共困扰着1.2亿人，每年花费在患者治疗上的费用超过5800亿美元。目前对其中许多疾病的标准治疗具有不同的疗效和严重的副作用。作为治疗难治性疾病的新一代药物，人们越来越有兴趣使用微生物组疗法，即包含活细菌的疗法来调节肠道微生物群。然而，该行业目前缺乏一种可靠的方法来系统和成本效益地开发有效的微生物组疗法。具体地说，微生物组治疗开发的最大障碍是缺乏将早期研究转化为药物发现和开发的预测性临床前模型。拟议的项目旨在通过开发一个首个此类计算平台来解决微生物组治疗学使用的障碍，作为第一个综合的、计算的、药物设计和发现平台。目前，微生物组疗法的发展是基于一系列实验和统计步骤，这些步骤在经验和迭代过程中确定目标治疗候选的潜在微生物菌株。因此，这种方法需要大量的体外和体内迭代实验，这大大增加了开发计划的长度和成本。这些挑战导致了低效和不可预测的微生物组治疗开发过程，限制了可以拯救全球数百万人生命的有效微生物组疗法的数量。该项目通过可靠且经济高效地确定适用于各种适应症的候选治疗方法来应对这些挑战。该平台可以取代目前在药物发现阶段迭代和不可预测的开发过程。该平台的效用将通过开发新的2型糖尿病候选治疗药物并在临床前研究中验证这些候选药物的有效性来展示。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/commercial impact of this Small Business Innovation Research (SBIR) Phase II project focuses on the human gut microbiome, the complex and dynamic community of microorganisms residing in the gastrointestinal tract. The gut microbiome influences a variety of human diseases, such as Type 2 Diabetes and inflammatory bowel disease. Collectively, these diseases afflict more than 120 million people and cost more than $580 billion in patient treatments in the US annually. The current standard care of treatments for many of these diseases have variable efficacy and serious side effects. There is increasing interest in modulating the gut microbiome using microbiome therapeutics, i.e., therapeutics comprising living bacteria, as a new generation of drugs for difficult-to-treat diseases. However, the industry currently lacks a reliable approach to systematically and cost-effectively developing effective microbiome therapeutics. Specifically, the largest barrier to microbiome therapeutic development is the lack of predictive preclinical models to translate early-stage research into drug discovery and development.The proposed project seeks to address the barrier to the use of microbiome therapeutics by developing a first-of-its-kind computational platform, as the first comprehensive, computational, drug design and discovery platform. Currently, the development of microbiome therapeutics is based on a series of experimental and statistical steps that identify the potential microbial strains for target therapeutic candidates in an empirical and iterative process. As a result, this approach requires extensive iterative in vitro and in vivo experiments, which substantially increase the length and cost of the development programs. These challenges have resulted in an inefficient and unpredictable microbiome therapeutic development process, limiting the number of efficacious microbiome therapeutics that could save millions of lives worldwide. This project addresses these challenges by reliably and cost-effectively identifying therapeutic candidates for a wide range of indications. This platform could replace the current iterative and unpredictable development process in the drug discovery stage. The utility of the platform will be demonstrated by developing new therapeutic candidates for Type 2 Diabetes and validating the efficacy of these candidates in preclinical studies.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.