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

基因生物防护开关提高药物解毒细菌预防化疗引起的腹泻的安全性

• 批准号: 10698718
• 负责人: Tsz Yan Clement Chan
• 金额: $ 40万
• 依托单位: SANARENTERO LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698718
• 关键词: Address; Animal Model; Antineoplastic Agents; BAY 54-9085; Bacteria; Biological Response Modifier Therapy; Biomedical Engineering; Body Weight; CRISPR/Cas technology; Cancer Patient; Cells; Chemicals; Chemotherapy-Oncologic Procedure; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Development; Devices; Diarrhea; Disease; Dose; Dose Limiting; Drug Formulations; Drug Metabolic Detoxication; Drug usage; Encapsulated; Engineering; Engraftment; Ensure; Environment; Environmental Pollution; Enzymes; Erlotinib; Escherichia coli; Evaluation; Excision; Feces; Fluorescence; Freeze Drying; Funding; Genes; Genetic; Glucose; Glucuronosyltransferase; Goals; Grant; Green Fluorescent Proteins; Health; Human; Inbred F344 Rats; Intestines; Investments; Large Intestine; Malignant Neoplasms; Market Research; Measures; Medical; Metabolic; Metabolic Pathway; Microbe; Nitrogen; Oral Administration; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Plants; Plasma; Prevention; Process; Quality of life; Reproducibility; SN-38; Safety; Sampling; Signal Transduction; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Structure; System; Texas; Therapeutic; Toxic effect; Tyrosine Kinase Inhibitor; Universities; Work; capsule; chemotherapeutic agent; chemotherapy; commensal bacteria; commercialization; cytotoxic; design; experience; flexibility; gastrointestinal; gastrointestinal system; glucosidase; glycosylation; glycosyltransferase; gut colonization; gut microbiome; improved; in vitro testing; innovation; irinotecan; manufacturing scale-up; medication safety; metabolic engineering; microbial; novel; novel strategies; novel therapeutics; overexpression; pre-clinical; preclinical efficacy; prevent; response; scale up; side effect; success; transmission process

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.

项目总结 生物工程微生物是开发活的生物治疗产品的一种很有前途的策略，可以 将新的代谢活动引入肠道微生物群和消化系统，以 预防和治疗几种与肠道有关的疾病/紊乱。Sanarentero正在开发 新型药物解毒菌(DDB)，是一种生物工程活生物治疗产品， 能解毒引起癌症患者化疗所致腹泻的肠道毒性药物。 成功地解决了一个主要的生物安全问题(即，转基因生物的传播 微生物进入人体和环境)将使我们的产品更具竞争力，因为它 将提高临床适应性，并有助于我们产品的监管批准。迈向进步 为了提高DDB的安全性，我们在我们的产品中引入了一种基因生物遏制开关 可在需要时触发以包含工程代谢功能。我们独一无二的 基因生物遏制开关(GBS)的设计不仅是为了防止工程代谢 途径基因从指定的环境中逃脱，但也在没有 杀死微生物，将细胞负担和遗传不稳定性降至最低。该计划的总体目标 该项目是建立活性和安全性的药物解毒菌配备 在动物模型中提出了遗传生物抑制开关(DDB_GBS)。为了实现这一目标， 这一第一阶段STTR提案的三个具体目标是：1)生物工程基因 生物包结改用DDB；2)研制DDB_GBS缓释制剂 用于改善肠道植入；以及3)评估安全性、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- 我们开发安全的新型药物解毒菌的方法的概念证据 可在肠道环境中对癌症化疗药物进行解毒的功能 预防癌症患者化疗引起的腹泻。一旦 确定了DDB_GBS的生物遏制效率，我们将致力于建立 第二阶段SBIR方案的GMP设施的临床前疗效和生产规模扩大。