Designer Probiotics for the treatment of intestinal infection and inflammation

用于治疗肠道感染和炎症的设计师益生菌

• 批准号: 10004029
• 负责人: Wendy S. Garrett
• 金额: $ 73.34万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004029
• 关键词: Address; Anthrax disease; Antibiotics; Bacteria; Bacterial Adhesins; Bacterial Proteins; Bacterial Toxins; Botulism; Cells; Clinical Trials; Clostridium difficile; Colitis; Colorectal Cancer; Communicable Diseases; Cytosol; Data; Development; Disease; Drug Delivery Systems; Drug Targeting; Engineered Probiotics; Engineering; Enteral; Escherichia coli; Escherichia coli EHEC; Exhibits; Gastrointestinal tract structure; Genetic Engineering; Hemolytic-Uremic Syndrome; Human; Immune checkpoint inhibitor; Immunologist; Immunosuppressive Agents; In Situ; Infection; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Intervention; Intestinal Mucosa; Intestines; Laboratories; Laboratory Study; Malignant Neoplasms; Mammalian Cell; Mediating; Medical Oncologist; Mus; Pathogenesis; Physicians; Plant Roots; Positioning Attribute; Precision Medicine Initiative; Prevention; Probiotics; Proteins; Route; Shiga Toxin; Site; Solid Neoplasm; Specificity; Stains; Study models; System; Testing; Therapeutic; Treatment Efficacy; Type III Secretion System Pathway; United States National Institutes of Health; Virulence; Virulence Factors; Work; base; beneficial microorganism; cost; cost effective; cytokine; design; enteric infection; enteropathogenic Escherichia coli; flexibility; gastrointestinal infection; gut microbiome; inflammatory disease of the intestine; innovation; interest; microbiome; nanobodies; nanomachine; nanoparticle; novel; novel therapeutics; pathogenic bacteria; programs; side effect; synthetic biology; targeted agent; targeted delivery; working group

Project Summary New drug delivery platforms are vitally needed for the targeted delivery of high-specificity therapeutics to sites of disease in order to maximize therapeutic efficacy while limiting off-target side effects. The majority of efforts currently underway for the development of such targeted drug delivery systems are focused on the development of synthetic nanoparticles, materials which are costly to produce, store, and distribute. Here, we propose to develop cost-effective, self-replicating and flexible, programmable designer probiotics for the targeted delivery of therapeutics directly to sites of disease. We propose to utilize a synthetic biology approach to genetically engineer a widely and safely administered probiotic, Escherichia coli Nissle 1917, to express a nanomachine that can secrete therapeutic payloads into the intestinal milieu. These designer bacteria will be equipped with a type 3 secretion system modified to secrete proteins into the intestinal lumen rather than their innate target, the cytosol of mammalian cells. As proof of concept and towards the development of these designer probiotics as therapeutics, we will engineer these designer probiotics to secrete a new class of well- documented therapeutic biomolecules of exquisite specificity, single domain antibodies, also referred to as VHH. We will focus on the delivery of VHH multimers that exhibit profound neutralizing activity, VHH-based neutralizing agents (VNAs), which inhibit the activity of essential bacterial toxins or proinflammatory cytokines. Furthermore, we will investigate the potential of these strains as novel therapeutic paradigms for the treatment of both intestinal infections and inflammation disorders. Specifically, we will investigate the efficacy of these strains in the prevention of treatment of Clostridium difficile infections (CDI), hemolytic uremic syndrome (HUS) and inflammatory bowel disease (IBD). We appreciate that there might be some concern regarding the administration of genetically modified bacteria as therapeutics. However, as we enter the `era of the microbiome,' it seems extremely likely that such interventions are to become an integral component of the armamentarium utilized to treat infections and inflammatory disorders, particularly those rooted in the gastrointestinal tract, especially because of the high likelihood that such agents can overcome many issues associated with the wide-spread usages of antibiotics and systemic immunosuppressive agents. While efforts here are specifically devoted towards the development of these designer probiotics for the treatment of CDI, HUS, and IBD, once established as a therapeutic paradigm, this designer probiotic platform can be extended to treat a variety of intestinal based diseases. For example, the designer probiotics could be programmed to deliver a variety of protein-based therapeutic payloads, including cytokines, such as IL-10, that suppress intestinal inflammation or VNAs designed to target essential exposed virulence proteins of enteric bacterial pathogens, e.g., adhesins or essential components of virulence factor delivery systems.

项目总结

项目成果

PROT3EcT, engineered Escherichia coli for the targeted delivery of therapeutics.

PROT3EcT，工程大肠杆菌，用于靶向治疗。

• DOI: 10.1016/j.molmed.2023.07.007
• 发表时间: 2023
• 期刊: Trends in molecular medicine
• 影响因子: 13.6
• 作者: González-Prieto,Coral;Lynch,JasonP;Lesser,CammieF
• 通讯作者: Lesser,CammieF

Rationale redesign of type III secretion systems: toward the development of non-pathogenic E. coli for in vivo delivery of therapeutic payloads.

• DOI: 10.1016/j.mib.2017.10.011
• 发表时间: 2018-03
• 期刊: Current opinion in microbiology
• 影响因子: 5.4
• 作者: González-Prieto C;Lesser CF
• 通讯作者: Lesser CF

Engineered Escherichia coli for the in situ secretion of therapeutic nanobodies in the gut.

工程大肠杆菌用于在肠道中原位分泌治疗性纳米抗体。

• DOI: 10.1016/j.chom.2023.03.007
• 发表时间: 2023
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Lynch,JasonP;González-Prieto,Coral;Reeves,AnaliseZ;Bae,Sena;Powale,Urmila;Godbole,NehaP;Tremblay,JacquelineM;Schmidt,FlorianI;Ploegh,HiddeL;Kansra,Vikram;Glickman,JonathanN;Leong,JohnM;Shoemaker,CharlesB;Garrett,WendyS
• 通讯作者: Garrett,WendyS

Emerging strategies for engineering Escherichia coli Nissle 1917-based therapeutics.

• DOI: 10.1016/j.tips.2022.02.002
• 发表时间: 2022-09
• 期刊: TRENDS IN PHARMACOLOGICAL SCIENCES
• 影响因子: 13.8
• 作者: Lynch, Jason P.;Goers, Lisa;Lesser, Cammie F.
• 通讯作者: Lesser, Cammie F.

Citrobacter rodentium(ϕStx2dact), a murine infection model for enterohemorrhagic Escherichia coli.

• DOI: 10.1016/j.mib.2021.11.013
• 发表时间: 2022-03
• 期刊: CURRENT OPINION IN MICROBIOLOGY
• 影响因子: 5.4
• 作者: Thorpe, Cheleste M.;Pulsifer, Amanda R.;Osburne, Marcia S.;Vanaja, Sivapriya Kailasan;Leong, John M.
• 通讯作者: Leong, John M.