Novel Nanoligomer-Based Therapeutics for Inflammatory Bowel Disease

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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.