Immunometabolic NLRX1 Therapeutics for IBD

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Immunometabolic NLRX1 Therapeutics for IBD Biotherapeutics Inc (BTI) is an emerging biotech company that synergistically combines the power of advanced computational modeling with translational experimentation to accelerate the development of novel products for precision medicine and health. This SBIR application stems from data showing a vital role for nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) as a new therapeutic target for IBD. Our Product: BTI has identified the first family of small-molecule compounds that bind and activate the novel regulatory molecule, NLRX1. The goal of this project is to validate NLRX1 as a target and develop NX-13 as the lead NLRX1-based, oral first-in-class therapeutic for IBD. Background: IBD is a chronic widespread and debilitating illness that afflicts over 5 million people worldwide. Current treatments are only modestly successful with significant adverse side effects, including cancer, infection and death. Thus, there is an unmet clinical need for safer, more efficacious IBD therapeutics. NLRX1 can suppress intestinal inflammation during infections and autoimmune disorders. BTI has validated that loss of NLRX1 causes reduced mucosal healing, increased fibrosis, >5-fold up-regulation in inflammatory cytokine biomarkers, and complete restructuring of gut microbiome ecology during IBD. Additionally, our top NLRX1 ligand exerts therapeutic actions in models of IBD. This SBIR Phase I application will characterize ligand- protein interactions of NX-13 and NLRX1, define the NX-13 cellular mechanism of action and validate its safety and specificity to NLRX1. The Specific Aims are to: AIM 1. Evaluate NX-13 interactions with purified and in situ NLRX1 by CD-spectroscopy and isothermal calorimetry on purified WT and mutant NLRX1 and by cellular thermal shift assays. AIM 2. Determine the cellular mechanism of action of NX-13 in vivo in the DSS model of colitis using cre- lox cell specific (CD4+, myeloid, epithelial) knockouts of NLRX1. AIM 3. Conduct preliminary ADME-Tox and specificity assays with NX-13 in off-target binding assays, 7- d dose-range finding toxicity studies in rats and ADME-Tox assays (hERG, Ames, CYP450, P-gp). Expected Outcomes: Validation of NX-13 as a lead molecule for targeting NLRX1 through: i) engagement of NLRX1 in situ at concentrations ≤ 0.1 µM); ii) identification of cellular mechanism of action by loss of efficacy in cell specific KO mice; iii) a benign safety profile with NOAEL ≥ 1,000 mg/kg oral in rats. SBIR Phase II will validate the implication of NLRX1 in human IBD, determine PK in rats, define anti-fibrotic effects in mouse models of intestinal fibrosis and advance NX-13 to IND-enabling GLP toxicology studies. Commercial Application: Success in this project will launch a new drug development pipeline at BTI centered on NLRX1-activating therapeutics with anti-inflammatory and anti-fibrotic effects. BTI's new NLRX1-targeting oral therapeutics could disrupt a market of over $10B annually growing at 25% annual rates.