Engineered probiotic for the treatment of autoimmune diseases

用于治疗自身免疫性疾病的工程益生菌

基本信息

批准号：
10561101
负责人：
ROBERT A BRITTON
金额：
$ 68.23万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2023-03-20 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10561101
关键词：
16S ribosomal RNA sequencing Acids Address Affect Animal Model Anti-Inflammatory Agents Autoimmune Diseases Bacteria Biodistribution Biological Assay Biological Products Biological Response Modifier Therapy Biomedical Engineering Blood Caring Cells Cessation of life Chromosomes Circulation Clinical Clinical Trials Collagen Arthritis Disease Dose Drug Kinetics Electrophysiology (science)Engineered Probiotics Engineering Enteral Enzyme-Linked Immunosorbent Assay Epithelium Flow Cytometry Functional disorder Gastrointestinal tract structure Genes Goals Histology Human Immunohistochemistry Immunomodulators In Vitro Injections Intestinal permeability Intestines Joints Lactobacillus reuteri Marketing Mass Spectrum Analysis Mediating Memory Modeling Multiple Sclerosis National Institute of Allergy and Infectious Disease Nature Oral Oral Administration Organoids Pathology Patient Care Patients Peptides Persons Pharmaceutical Preparations Phase Population Potassium Channel Probiotics Production Property Rattus Recombinants Research Project Grants Rheumatoid Arthritis Rodent Safety Second Messenger Systems Severities Symptoms T memory cell T-Cell Activation T-Cell Proliferation T-Lymphocyte TNF gene Testing Therapeutic Tissues Venoms Western Blotting Work adduct analog bone capsule chronic autoimmune disease compliance behavior cytokine disability dysbiosis gut microbiome healthy volunteer immune modulating agents immunogenicity immunoregulation improved in vivo lymphoid organ multidisciplinary nonhuman primate novel novel therapeutic intervention novel therapeutics pilot trial prevent pristane induced arthritis probiotic therapy promoter radiological imaging recombinant peptide response side effect therapeutic evaluation treatment strategy

项目摘要

PROJECT SUMMARY Approximately 50 million people suffer from one or more autoimmune diseases in the US alone. Over the last decades, the discovery of biologics has considerably improved the care for patients with autoimmune diseases. However, current treatments require weekly or more frequent injections and this can lead to missed doses and to poor patient compliance, especially in the younger population, resulting is inconsistent or sub- therapeutic drug levels. Since many of the therapeutics on the market or being developed to treat rheumatoid arthritis (RA), multiple sclerosis, and other T lymphocyte-mediated chronic autoimmune diseases are biologics, we propose a novel bioengineering approach for the non-invasive delivery of recombinant peptides in autoimmune diseases. More specifically, we propose to produce an immunomodulatory peptide by a probiotic for oral administration to treat RA. As our immunomodulator, we have chosen a recombinant analog of ShK, a small venom peptide that blocks Kv1.3 channels and thus inhibits the activation of human and rat effector memory T lymphocytes. As a probiotic, we have selected Lactobacillus reuteri LJ01, a well-characterized probiotic that survives transit through the gastrointestinal tract. In preliminary work, we have introduced an ShK analog in L. reuteri to generate LrS235 that secretes a functionally active peptide upon induction, resulting in the block of Kv1.3 channels and the inhibition of human TEM cell proliferation in vitro and in a reduction of clinical severity in a small pilot trial using the collagen-induced arthritis rat model of RA. Through this project, we will define the pharmacokinetics, biodistribution, and efficacy of ShK-235 produced by LrS235 in preventing and treating rat models of RA (Specific Aim 1) and we will define and optimize the efficacy and safety of our probiotic based gut delivery (Specific Aim 2). At the end of this project, we will have established proof-of-concept for a new therapeutic strategy for the treatment of RA and other autoimmune diseases mediates by effector memory T lymphocytes through the oral delivery of a probiotic engineered to secrete an immunomodulatory Kv1.3 blocking venom peptide.

项目概要仅在美国就有大约 5000 万人患有一种或多种自身免疫性疾病。超过过去几十年，生物制剂的发现大大改善了自身免疫性疾病患者的护理疾病。然而，目前的治疗需要每周或更频繁地注射，这可能会导致错过剂量和患者依从性差，特别是在年轻人群中，导致不一致或次要的结果治疗药物水平。由于市场上或正在开发的许多疗法用于治疗类风湿关节炎（RA）、多发性硬化症和其他 T 淋巴细胞介导的慢性自身免疫性疾病是生物制剂，我们提出了一种新的生物工程方法，用于非侵入性地递送重组肽自身免疫性疾病。更具体地说，我们建议通过益生菌生产免疫调节肽用于口服治疗 RA。作为我们的免疫调节剂，我们选择了 ShK 的重组类似物，这是一种小毒液肽，可以阻断 Kv1.3 通道并因此抑制人和大鼠效应记忆 T 淋巴细胞的激活。作为益生菌，我们选择了罗伊氏乳杆菌 LJ01，这是一种特性良好的益生菌，可在运输过程中存活下来。胃肠道。在前期工作中，我们在罗伊氏乳杆菌中引入了 ShK 类似物来生成 LrS235 诱导后分泌功能活性肽，导致 Kv1.3 通道阻断和在一项小型试点试验中，体外抑制人 TEM 细胞增殖并降低临床严重程度胶原诱导的RA关节炎大鼠模型。通过这个项目，我们将确定 ShK-235 的药代动力学、生物分布和功效 LrS235 在预防和治疗 RA 大鼠模型中的作用（具体目标 1），我们将定义和优化我们基于益生菌的肠道输送的功效和安全性（具体目标 2）。在这个项目结束时，我们将拥有为治疗 RA 和其他自身免疫性疾病的新治疗策略建立了概念验证疾病是由效应记忆 T 淋巴细胞通过口服益生菌介导的分泌免疫调节 Kv1.3 阻断毒液肽。