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

• 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
• 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

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开发了一个平台来快速产生纳米构体，这是一种小说 纳米粒子结合的家族，修饰的核酸寡聚物，上调或下调的表达 通过与靶向DNA或mRNA结合选择蛋白质。在初步工作中，萨奇证明了能够 有选择地靶向并改变了> 30人肠产生的免疫调节蛋白的表达 厌氧菌，这表明可以开发纳米脂质体作为炎症肠的潜在疗法 疾病（IBD）或肠道菌群中炎症过程促进的其他疾病。在这个阶段第一 SBIR，SACHI提议将此平台应用于快速设计和构建纳米构体以靶向生物合成基因 肠道微生物菌株中产生免疫调节代谢产物的簇（BGC），然后测试这些 体外和体内的纳米素体，以建立概念证明，以支持进一步发展 IBD的标准化或个性化治疗。目标1。设计和构建纳米构体以瞄准BGC 已知六种肠道细菌会产生参与抗炎或炎症过程的代谢产物 在肠道中。根据有关IBD和肠道菌群的文献，Sachi确定了14个感兴趣的代谢物 在6种细菌的BGC中编码（表3，研究策略）。在此目标中，Sachi将使用平台 a）设计和构建纳米构体以瞄准这些BGC中的每一个，b）进行体外评估以评估能力 每种纳米聚物以上调或下调相关细菌中靶代谢产物的产生，c） 评估来自纳米聚细菌对人外周血的裂解物的免疫调节作用 单核细胞（PBMC）。里程碑和成功标准：1）设计，构建和测试至少42 纳米聚体（每种代谢物三个）和2）从该组中选择两个纳米聚体 PBMC细胞因子表达的最大变化（阈值：≤50％的促炎的野生型表达 细胞因子或抗炎细胞因子增加≥200％）。探索性：代表代谢物的变化特征 响应纳米聚体治疗的产生。 AIM 2。特征是免疫调节和炎症的 体内纳米素体的作用。评估纳米聚体对免疫调节和 炎症的标记，并在活动物肠道更复杂的环境中提供概念证明， SACHI将评估AIM 1的前两个纳米聚物的效果和肠道上的一个错义纳米聚物的效果 慢性结肠炎和遗传IBD小鼠模型中的微生物组和免疫反应。 Sachi将评估 对结肠组织中组织学和结肠和血液中细胞因子产生的影响。里程碑和成功 标准：与 错义纳米聚物和激活纳米脂质体将使抗炎细胞因子增加≥200％ 与错义纳米聚物相比。探索性：表征疾病活动指数和小鼠的变化 纳米聚物治疗的小鼠中的组织学结肠指数，以告知随后的有效研究的设计。