SBIR Phase II: Bacteriophage-Based Microbial Gene Therapy Platform for In Situ Engineering of Microbiomes

这个小企业创新研究(SBIR)第二阶段项目的更广泛影响是改善1500万至3000万患有乳糜泻(CD)和其他面筋相关疾病的美国人的健康和生活质量，特别是那些症状管理不善的人。与面筋有关的疾病在全球范围内的总患病率为5%-10%，并且在过去十年中一直在增加。目前，对这些患者唯一有效的治疗方法是坚持严格的无麸质饮食，这无法缓解所有患者的症状，也无法预防意外暴露后的严重胃肠道不适。该项目将推进一种治疗解决方案，以防止与低水平或意外面筋暴露相关的持续症状。这将为旅行时患有CD和非乳糜泻敏感症的人，适应无面筋饮食的新患者，以及尽管坚持无面筋饮食但症状控制不佳的人提供保护。拟议的项目将利用一种新型的基于噬菌体的微生物组工程平台来推进一种产品的开发，以提供对面筋暴露引起的胃肠道不适的保护。为了开发这种治疗性噬菌体产品，将识别能够感染常见肠道细菌(如大肠杆菌)的噬菌体，并对其进行有效的溶原性改造。噬菌体或噬菌体鸡尾酒将被进一步改造以表达治疗方式/蛋白质，并在CD患者的人类器官和小鼠模型中进行测试，以证明疗效。这项拟议的工作将为该平台未来扩展到基于微生物组的广泛应用奠定基础。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 of this Small Business Innovation Research (SBIR) Phase II project is to improve the health and quality of life for the 15-30 million Americans suffering from celiac disease (CD) and other gluten-related disorders, especially those with poor management of symptoms. Gluten-related disorders have a combined global prevalence of 5–10% and have been increasing over the past decade. Currently, the only effective treatment for these patients is adherence to a strict gluten-free diet, which fails to relieve symptoms in all patients and cannot prevent the severe gastrointestinal distress that follows accidental exposure. This project will advance a therapeutic solution to prevent persistent symptoms related to low-level or accidental gluten exposure. This will provide protection for people with CD and non-celiac gluten sensitivity when traveling, new patients adapting to a gluten-free diet, and individuals whose symptoms are poorly controlled despite adherence to a gluten-free diet. The proposed project will leverage a novel bacteriophage-based microbiome engineering platform to advance the development of a product to provide protection from gastrointestinal distress stemming from gluten exposure. To develop this therapeutic phage product, phages capable of infecting common gut bacteria like E. coli will be identified and engineered for efficient lysogenization. The phage or phage cocktail will be further engineered to express therapeutic modalities/proteins and tested in both human organoids derived from patients with CD and mouse models to demonstrate efficacy. The proposed work will provide a foundation for future extension of the platform to a wide range of microbiome-based applications.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.