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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要生物工程的微生物是开发可实现生物治疗产品的有前途的策略将新型代谢活动引入肠道微生物组和消化系统预防和治疗几种与肠道有关的疾病/疾病。 Sanarentero正在发展新型药物排毒细菌（DDB），这是一种生物工程的生物治疗产品可以对癌症患者的化学疗法诱导的肠胃腹泻排毒。成功解决了主要的生物安全问题（即，基因修改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帮助我们产品的监管批准。朝着改进 DDB的安全性概况，我们在产品中引入了遗传生物内疗法开关可以在需要时触发以包含工程的代谢功能。我们的独特遗传生物膜片开关（GBS）不仅旨在防止工程代谢途径基因从指定的环境中逃脱，但也没有执行其功能杀死微生物，以最大程度地减少细胞负担和遗传不稳定性。总体目标项目是建立配备有药物排毒的细菌的活性和安全性在动物模型中提出的遗传生物内膜开关（DDB_GB）。为了实现这一目标，该阶段1 STTR建议的三个特定目标是1）生物工程遗传生物内在切换到DDB； 2）开发DDB_GBS的延迟释放公式改善肠道植物； 3）评估安全性，糖基化功能和 DDB_GBS的生物内在效率。该项目的成功是 - 我们使用安全性开发新型药物排毒方法的方法的概念证据可以在肠道环境中排毒癌症化学治疗药物的功能为了防止癌症患者化学治疗诱导的腹泻。一旦建立了DDB_GB的生物疗法效率，我们将致力于建立 II期SBIR提案的GMP设施中的临床前功效和制造规模。