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Engineering non-proliferating-but-active (NPBA) probiotic for breast-cancer gene therapy

用于乳腺癌基因治疗的工程非增殖但有活性（NPBA）益生菌

基本信息

批准号：
10350147
负责人：
RUSSELL C HOVEY
金额：
$ 20.66万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-02 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10350147
关键词：
Address Antibiotics Attenuated Autolysis BRCA1 gene Bacteria Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Breast Cancer cell line Breast Cancer gene Breast Cancer therapy CD47 gene Cell Line Cell membrane Cells Clustered Regularly Interspaced Short Palindromic Repeats Cytosol DNA DNA delivery Data Development Disease Drug Delivery Systems Drug resistance Duct (organ) structure ERBB2 gene Effectiveness Engineering Environment Escherichia coli Essential Genes Estrogen Antagonists Face Foundations Future Gene Amplification Gene Delivery Gene Expression Genes Growth Heel Hydrogels Infection Invaded Label Lead Listeria monocytogenes Mammalian Cell Measures Membrane Metabolism Methods Molecular Molecular Target Monoclonal Antibodies Oncogenic Organ PIK3CA gene Pathway interactions Patients Penetration Pharmaceutical Preparations Phenotype Probiotics Proteins Proteome RNA Recombinants Research Resistance Site Solid Neoplasm Stress System Systemic Therapy T cell response T-Lymphocyte TP53 gene Testing Therapeutic Tissues Treatment Efficacy Work Yersinia pestis antagonist anti-cancer aqueous biomaterial compatibility cancer cell cancer immunotherapy cancer therapy crosslink cytotoxic delivery vehicle design drug development effective therapy gene repair gene therapy genome editing in vivo information processing innovation loss of function mutation malignant breast neoplasm nanobodies novel strategies novel therapeutics public health relevance side effect therapeutic protein tool tumor

项目摘要

PROJECT SUMMARY Engineering non-proliferating-but-active (NPBA) probiotic for breast-cancer gene therapy A major breast-cancer treatment challenge is the debilitating effects of systemic therapies. To create more tolerable and effective therapies against breast cancer, considerable effort is being directed to using CRISPR- Cas to target the molecular origins of the disease. However, current methods face multiple challenges in delivering CRISPR-Cas to breast cancer cells, including low penetration of solid tumors, low delivery amount, and small size of CRISPR-Cas. To address the challenges, we will engineer a new kind of CRISPR-Cas delivery vehicle for breast cancer cells using non-proliferating-but-active (NPBA) probiotic. Our preliminary work demonstrates that the NPBA probiotic conduct metabolism, move in aqueous environments, and does not proliferate. We ultimately envisage that the NPBA probiotic can be introduced into the breast ducts or tumors to migrate towards cancer cells and then deliver a CRISPR-Cas construct that targets specific oncogenic mechanisms. Hence, this proposal aims to engineer these NPBA probiotic to deliver genes or proteins to breast cancer cells. Our team will leverage expertise in gene expression control, bacterial information processing, molecular tools, and breast cancer models. We will pursue two parallel aims that correspond to the engineering and testing of the NPBA Escherichia coli Nissle 1917. 1) Enable NPBA probiotics to invade mammalian cells before delivering CRISPR-Cas. This aim will establish the basic CRISPR-Cas-delivery function of the NPBA probiotics. 2) Enhance the invasion and CRISPR-Cas delivery efficacy of the NPBA probiotic in silencing the ErbB2 oncogene of breast cancer cells. This project will create a new paradigm that uses non-proliferating-but- active probiotics for effective and specific delivery of CRISPR-Cas to cancer cells. Our work will also form the foundation for using the NPBA probiotics to target various oncogenic and proliferative pathways of cancer cells. Future work may also investigate any dispersion of the NPBA probiotics into the surrounding tissues and throughout the host.

项目总结