Novel Nanoligomer-Based Therapeutics for Inflammatory Bowel Disease

基于纳米低聚物的新型炎症性肠病治疗方法

基本信息

批准号：
10764688
负责人：
Prashant Nagpal
金额：
$ 5.5万
依托单位：
SACHI BIOWORKS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-06 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10764688
关键词：
Affect Anaerobic Bacteria Animals Anti-Inflammatory Agents Autoimmune Diseases Bacteria Bacterial Genome Bacteroides Binding Binding Proteins Blood Cells Chronic Clostridium Colitis Colon Complex DNA Development Disease Disease Progression Engineered Probiotics Environment Environmental Risk Factor Family Functional disorder Gastrointestinal tract structure Gene Cluster Genes Genetic Genetic Engineering Genetic Models Goals Health Care Costs Histology Human Immune response In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-10 Intestines Literature Messenger RNA Microbe Mus Nucleic Acids Patients Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Phase Polysaccharides Population Process Production Proteins Quality of life Recurrent disease Regulatory T-Lymphocyte Research Research Personnel Role Small Business Innovation Research Grant Standardization Testing Therapeutic Therapeutic Intervention Therapeutic immunosuppression Tissues Transplantation Volatile Fatty Acids Work cancer risk colorectal cancer risk commercialization cytokine design design,build,test dysbiosis efficacy study genetic variant gut bacteria gut inflammation gut microbiome gut microbiota immunological status immunoregulation improved in vitro Assay in vivo indexing individualized medicine inflammatory marker interest microbial microbiome microbiome therapeutics mouse model nanoparticle new technology novel novel strategies personalized medicine preservation response standard of care success targeted treatment tool

项目摘要

PROJECT SUMMARY—Sachi Bioworks has developed a platform to rapidly generate Nanoligomers, a novel family of nanoparticle-bound, modified nucleic acid oligomers that up- or down-regulate the expression of selected proteins by binding to targeted DNA or mRNA. In preliminary work, Sachi demonstrated the ability to selectively target and alter the expression of immunomodulatory proteins produced by > 30 human gut anaerobes, which suggests Nanoligomers could be developed as a potential therapy for inflammatory bowel disease (IBD) or other conditions promoted by inflammatory processes in the gut microbiota. In this Phase I SBIR, Sachi proposes to apply this platform to rapidly design and build Nanoligomers to target Biosynthetic Gene Clusters (BGCs) in gut microbial strains that produce immunomodulatory metabolites and then test these Nanoligomers in vitro and in vivo to establish proof-of-concept to support further development as either a standardized or personalized treatment for IBD. Aim 1. Design and build Nanoligomers to target BGCs in six gut bacteria known to produce metabolites involved in anti-inflammatory or inflammatory processes in the intestine. Based on the literature on IBD and gut microbiota, Sachi identified 14 metabolites of interest encoded in BGCs in 6 species of bacteria (Table 3, Research Strategy). In this aim, Sachi will use the platform to a) design and build Nanoligomers to target each of these BGCs, b) conduct in vitro assays to assess the ability of each Nanoligomer to up- or down-regulate production of the target metabolite in the relevant bacteria, and c) assess the immunomodulatory effects of lysates from Nanoligomer-treated bacteria on human peripheral blood mononuclear cells (PBMCs). Milestones and Success Criteria: 1) Design, build, and test at least 42 Nanoligomers (three per metabolite) and 2) Select the two Nanoligomers from that group that produce the greatest change in PBMC cytokine expression (thresholds: ≤ 50% of wild-type expression of pro-inflammatory cytokines or ≥ 200% increase in anti-inflammatory cytokines). Exploratory: Characterize change in metabolite production in response to Nanoligomer treatment. Aim 2. Characterize immunomodulatory and inflammatory effects of the Nanoligomers in vivo. To assess the effects of the Nanoligomers on immunomodulation and markers of inflammation and provide proof-of concept in the more complex setting of a live animal intestine, Sachi will evaluate the effect of the top two Nanoligomers from Aim 1 and one missense Nanoligomer on the gut microbiome and immune responses in mouse models of chronic colitis and genetic IBD. Sachi will assess the effects on histology in colon tissue and cytokine production in the colon and blood. Milestones and Success Criteria: Inhibitory Nanoligomers will produce ≥ 50% decrease in pro-inflammatory cytokines compared to missense Nanoligomer and activating Nanoligomers will produce ≥ 200% increase in anti-inflammatory cytokines compared to missense Nanoligomer. Exploratory: Characterize change in the Disease Activity Index and Mouse Histology Colitis Index in Nanoligomer-treated mice to inform the design of subsequent efficacy studies.

项目摘要——Sachi Bioworks 开发了一个快速生成纳米低聚物的平台，纳米低聚物是一种新型的纳米低聚物。纳米颗粒结合的修饰核酸寡聚物家族，可上调或下调以下表达：在初步工作中，Sachi 展示了通过与目标 DNA 或 mRNA 结合来选择蛋白质的能力。选择性靶向并改变超过 30 种人类肠道产生的免疫调节蛋白的表达厌氧菌，这表明纳米低聚物可以开发为炎症性肠病的潜在疗法疾病（IBD）或由肠道微生物群炎症过程促进的其他病症在第一阶段。 SBIR，Sachi 提议应用该平台快速设计和构建针对生物合成基因的纳米低聚物肠道微生物菌株中产生免疫调节代谢物的簇 (BGC)，然后测试这些代谢物纳米低聚物在体外和体内建立概念验证以支持进一步开发 IBD 的标准化或个性化治疗目标 1. 设计和构建针对 BGC 的纳米寡聚物。已知六种肠道细菌可产生参与抗炎或炎症过程的代谢物根据 IBD 和肠道微生物群的文献，Sachi 鉴定出了 14 种感兴趣的代谢物。编码于 6 种细菌的 BGC（表 3，研究策略）中，Sachi 将使用该平台。 a) 设计和构建纳米寡聚物来靶向这些 BGC，b) 进行体外测定以评估能力每种纳米低聚物的上调或下调相关细菌中目标代谢物的产生，以及c) 评估纳米低聚物处理的细菌裂解物对人外周血的免疫调节作用单核细胞 (PBMC) 里程碑和成功标准： 1) 设计、构建和测试至少 42 个纳米低聚物（每个代谢物三个）和 2) 从该组中选择两种产生 PBMC 细胞因子表达的最大变化（阈值：≤ 促炎性野生型表达的 50%）细胞因子或抗炎细胞因子增加 ≥ 200%）。探索性：表征代谢物的变化。目标 2. 表征免疫调节和炎症。纳米寡聚物的体内作用评估纳米寡聚物对免疫调节和免疫调节的作用。炎症标志物，并在活体动物肠道的更复杂环境中提供概念验证， Sachi 将评估 Aim 1 中前两种纳米低聚物和一种错义纳米低聚物对肠道的影响 Sachi 将对慢性结肠炎和遗传性 IBD 小鼠模型的微生物组和免疫反应进行评估。对结肠组织的组织学以及结肠和血液中细胞因子产生的影响。标准：与其他纳米低聚物相比，抑制性纳米低聚物的促炎细胞因子减少 ≥ 50% 错义纳米寡聚物和活化纳米寡聚物将产生 ≥ 200% 的抗炎细胞因子增加与错义纳米低聚物相比，探索性：描述疾病活动指数和小鼠的变化。纳米低聚物治疗小鼠的组织学结肠炎指数可为后续功效研究的设计提供信息。