Sepsis and consequent acute kidney injury (AKI) are major public health concerns, with high mortality and morbidity, and increasing incidence. Despite efforts to develop new interventions, current therapeutic options are limited in scope and effectiveness. Eliaz Therapeutics (ET), based on substantial literature support and successful initial proof of concept in a porcine cutaneous inflammatory injury model, direct our approach to depletion of the endogenous galectin-3 (Gal-3) protein from septic patients blood using a novel high affinity immunoadsorption apheresis column. Gal-3 is a known key driver of organ inflammation and fibrosis in numerous acute and chronic disorders, with substantial amelioration shown in experimental inhibition and Gal-3 -/- models. Gal-3, while essential for initial immune pathogen recognition and immune activation in infections, becomes a driver of excessive and dysregulated cytokine responses in sepsis development and subsequent organ damage. Gal-3 -/- models showed reduced pathology and improved survival. We hypothesize that selectively depleting Gal-3 by apheresis will exert synergistic therapeutic effects on both sepsis and sepsis-related AKI. Our intervention has potential to address the urgent need for mortality and morbidity reduction, advance sepsis/AKI treatment options and expand applications in apheresis medicine. ET will test proof of concept of our device using a relevant rat model of sepsis - cecal ligation and puncture. We will assess apheresis treatment XGal-3 column feasibility, procedural safety and tolerability, and ability to suppress sepsis-induced inflammation and kidney injury, indicated by increased survival, altered inflammatory and kidney injury/renal function markers and histological indication of reduced kidney fibrosis and macrophage infiltration. Aim 1: To establish the time course of blood levels of Gal-3 and pertinent biomarkers in the circulation of septic rats. Cecal ligation and puncture (CLP) will induce sepsis via the robust inflammatory response. Data will be used to determine correlation with Gal-3 induction to select timing for Gal-3 depletion for AIM 3 study. Aim 2: To assess the safety and tolerability of the selective Gal-3-adsorption apheresis procedure in healthy rats. Clinical observation of physiology, blood chemistry, kidney and liver function, will provide procedure tolerance and guidance on treatment duration for AIM 3 study. Aim 3: To determine whether Gal-3 adsorption apheresis in a CLP rat sepsis model effectively reduces systemic levels of Gal-3, protects against acute, model-induced kidney injury, reduces systemic inflammation, and improves overall survival during sepsis. Survival, Gal-3 levels and selected biomarkers of sepsis, inflammation, fibrosis, renal injury/function will be compared in active treatment vs sham groups. Successful results of Phase I studies will allow us to proceed to further preclinical studies and planned application for Phase II funding, with the goal of FDA-IDE application submission, and commercialization of the XGal-3 immunoaffinity adsorption apheresis column.
Public Health Relevance Statement: Eliaz Therapeutics Phase I SBIR Project Narrative This project aims to test the safety and feasibility of treating sepsis and sepsis induced acute kidney injury with a new medical device that removes galectin-3 from a patients blood with therapeutic apheresis treatment. The novel concept is based on substantial literature support for the pivotal role of the galectin-3 protein in driving the excessive inflammation and dysregulated response to infection that makes sepsis/AKI a life threatening condition with high mortality rates, increasing incidence, and lack of effective treatments.
Project Terms: active method; Acute; Acute Disease; Acute Renal Failure with Renal Papillary Necrosis; Address; Adsorption; Adverse effects; Affinity; Anti-inflammatory; Antigen-Antibody Complex; Automobile Driving; base; Binding; Biological Markers; Blood; Blood Chemical Analysis; Blood Circulation; Blood Component Removal; Cardiovascular Diseases; cecal ligation puncture; Cell surface; Chronic Disease; Chronic Kidney Failure; Clinical; Collaborations; commercialization; Communication; Complementary therapies; Complex; cost; cost effective; Critical Illness; Cutaneous; cytokine; Data; Development; Devices; Drug Interactions; Drug Kinetics; Early Intervention; effective therapy; Effectiveness; efficacy testing; extracellular; Family suidae; Fibrosis; Funding; Future; Galectin 3; Glycolipids; Glycoproteins; Goals; healing; Health; Histologic; Homeostasis; Host Defense; Immune; immune activation; Immune response; Immune System Diseases; Immunosuppression; improved; Incidence; Induration; Infection; Infection Control; Infiltration; Inflammation; Inflammatory; Inflammatory Response; inhibitor/antagonist; Injury; innate immune function; Innate Immune System; innovation; Intensive Care Units; Intercellular Fluid; Intercept; International; Intervention; Kidney; Kidney Diseases; Knowledge; Leadership; Life; Ligands; Literature; Liver diseases; liver function; Lung diseases; macrophage; Mediating; Mediator of activation protein; Medical Device; Medicine; microorganism; Modeling; Morbidity - disease rate; mortality; novel; Organ; pathogen; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; phase 1 study; Physiology; placebo group; Plasma; preclinical study; procalcitonin; Procedures; Production; prognostic value; Proteins; Public Health; Rattus; Renal function; Research; response; Risk; Role; Safety; safety and feasibility; safety testing; Savings; Sepsis; septic; septic patients; Signal Transduction; Skin; Small Business Innovation Research Grant; Survivors; System; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Toll-like receptors; Toxic effect; treatment duration
