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: 10600350
• 负责人: Prashant Nagpal
• 金额: $ 30.97万
• 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: 2022-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10600350
• 关键词: Affect; Anaerobic Bacteria; Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Bacteria; Bacterial Genome; Bacteroides; 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; Lead; Literature; Messenger RNA; Microbe; Mus; Nucleic Acids; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phase; Polysaccharides; Population; Process; Production; Proteins; Quality of life; 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; base; 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.

sachi Bioworks开发了一个快速生成纳米低聚物的平台，这是一种新颖的技术