Genetic Biocontainment Switch to Improve the Safety of Drug Detoxifying Bacteria in Preventing Chemotherapy-induced Diarrhea

项目摘要 生物工程微生物是一种很有前途的策略，可以开发活的生物制品， 将新的代谢活性引入肠道微生物组和消化系统， 预防和治疗几种肠道相关疾病/病症。Sanarenegro正在开发 新型药物解毒细菌（DDB），这是一种生物工程活生物制品， 可解毒导致癌症患者化疗引起腹泻的肠道毒性药物。 成功解决重大生物安全问题（即，转基因的传播 微生物进入人类和环境）将使我们的产品更具竞争力， 将提高临床适应性，并有助于我们产品的监管批准。为改善 DDB的安全性，我们正在我们的产品中引入一种遗传生物控制开关， 可以在需要时被触发以包含工程代谢功能。我们独特 基因生物遏制开关（GBS）不仅旨在防止工程代谢 途径基因逃离指定的环境，但也执行其功能， 杀死微生物以最小化细胞负担和遗传不稳定性。的总体目标 项目是建立药物解毒细菌的活性和安全性， 在动物模型中提出了遗传生物遏制开关（DDB_GBS）。为了实现这一目标， 第一阶段STTR提案的三个具体目标是：1）生物工程遗传 生物防护转换为DDB; 2）开发DDB_GBS的延迟释放制剂 用于改善肠移植;和3）评价安全性、糖基化功能，和 DDB_GBS的生物遏制效率。这个项目的成功证明了-- 概念证据，我们的方法开发新的药物解毒细菌的安全性， 可以在肠道环境中解毒癌症化疗药物的功能 用于预防癌症患者化疗引起的腹泻。一旦 DDB_GBS的生物防护效率已经建立，我们将致力于建立 临床前疗效和GMP设施中的生产规模扩大，用于II期SBIR提案。

PROJECT SUMMARY Bioengineered microbes are a promising strategy to develop live biotherapeutic products that can introduce novel metabolic activities into the gut microbiome and digestive system for the prevention and treatment of several gut-related diseases/disorders. Sanarentero is developing novel drug detoxifying bacteria (DDB), which is a bioengineered live biotherapeutic product that can detoxify gut-toxic drugs causing chemotherapy-induced diarrhea in cancer patients. Successfully addressing a major biosafety concern (i.e., the transmission of genetically modified microbes into humans and environments) will make our product much more competitive since it will improve clinical adaptability and aid the regulatory approval of our product. Towards improving the safety profile of DDB, we are introducing a genetic biocontainment switch in our product that can be triggered to contain the engineered metabolic function as and when needed. Our unique genetic biocontainment switch (GBS) not only is designed to prevent the engineered metabolic pathway genes to escape from a designated environment but also performs its function without killing the microbes to minimize the cellular burden and genetic instability. The overall goal of the project is to establish the activity and safety of drug detoxifying bacteria equipped with the proposed genetic biocontainment switch (DDB_GBS) in an animal model. To achieve this goal, the three specific aims of this phase 1 STTR proposal are 1) to bioengineer genetic biocontainment switch into DDB; 2) to develop a delayed-release formulation of DDB_GBS for improved intestinal engraftment; and 3) to evaluate the safety, glycosylation function, and biocontainment efficiency of DDB_GBS. The success of this project is the proof-of- concept evidence of our approach for developing novel drug detoxifying bacteria with a safety feature that can detoxify cancer chemotherapeutic drugs in the gut environment towards preventing chemotherapeutic-induced diarrhea in cancer patients. Once the biocontainment efficiency of DDB_GBS is established, we will work on establishing the preclinical efficacy and manufacturing scale-up in the GMP facility for a phase II SBIR proposal.