Signablok, Inc.

Novel Medical Countermeasure to Mitigate Potentially Lethal Acute Radiation Syndrome - Project Summary/abstract Despite Significant Advances, Gaps Remain in Developing Treatments That Address Persistent Inflammation That Ensue After Acute Radiation Exposure. the Long-term Objective of the Proposed Project Is to Develop a Well-tolerable and Effective First-in-class Medical Countermeasure (MCM) Designed for Mitigation and Treatment of Potentially Lethal Acute Radiation Syndrome (ARS) and Administered at Least 24 H Post-radiation to Significantly Extend Survival of Irradiated Patients and Radiation Casualties. Radiation Injury Is Accompanied by Macrophage-driven Uncontrolled Inflammation. Ionizing Radiation Increases Expression of Triggering Receptor Expressed on Myeloid CELLS-1 (TREM-1) in Macrophages. in Animals, TREM-1 Has Been Shown to Contribute to Worse Survival After Total Body Irradiation (tbi). This Implicates TREM-1 as a Promising Emerging Target to Develop a Novel MCM for Radiation Injury. Current TREM-1 Blockers Are All Ligand-dependent and Attempt to Block Binding of TREM-1 to Its Multiple Known and Unknown Ligands, Bearing Thus High Risk of Drug Failure in Clinical Efficacy Testing. First Clinical TREM-1 Blocker LR12 Recently Failed to Reach Significance for the Primary Endpoint in Phase Iib Sepsis Trial. to Minimize the Risk of Failure in the Clinic, We Developed Ligand-independent TREM-1 Inhibitory Peptide Sequence GF9 That Can Be Used as a Part of Trifunctional Peptide GA31 Formulated Into Macrophage- Specific Lipopeptide Complexes (LPC) to Improve Its Half-life and Targeting. Macrophage-targeted Delivery Also Addresses the Potential for Different TREM-1-EXPRESSING Cell Types (e.g., Neutrophils VS Macrophages) Playing Different Roles in the Pathogenesis of Inflammatory Diseases. TREM-1 Blockade by GA31-LPC Inhibits Uncontrolled Inflammatory Response and Ameliorates the Disease in Animal Models of Sepsis, Acute Respiratory Distress Syndrome, Sulfur Mustard-induced Lung Injury, Cancer, Arthritis, Retinopathy, and Other Inflammation-associated Diseases. GA31-LPC Is Safe and Well-tolerable by Healthy and Diseased Animals. the Major Goal of the Proposed Research Is to Test the Hypothesis That Therapeutic Blockade of TREM-1 by Using GA31-LPC Will Significantly Extend Survival of Mice Exposed to LD70/30 Radiation Dose When Administered at 24 H or Later Post-radiation. Specific Aims of This Project Are to: 1) Generate, Characterize and Test GA31-LPC in Vitro; and 2) Determine the in Vivo Feasibility of Using GA31-LPC as a Therapeutic MCM to Significantly Extend Survival of Mice Exposed to LD70/30 Radiation Dose. We Will Generate GA31-LPC, Characterize Its Composition, Size and Stability, and Test in Vitro in Cell- Based Assays. We Will Next Test GA31-LPC in Mice Exposed to LD70/30 Radiation Dose for Its Ability to Improve 30 Day Animal Survival When Systemically Administered 24 or 48 H Post-tbi. If Successful, This Project Will Generate Preliminary Data Supporting the Development of a New Mechanism-based, Well- Tolerable and Effective MCM for Mitigation and Treatment of Potentially Lethal Ars.