Reneurogen LLC

Kyc, an Inhibitor of Sickle Cell Disease's Vicious Cycle in Vaso-occlusive Crisis and Pain - the Work in This Proposal Will Develop a Novel Drug Candidate for Treating Vasculopathy (vp)/vasocongestion (VC), Vaso-occlusive Crisis (VOC) and Pain in People Who Have Sickle Cell Disease (SCD). SCD Is a Complex, Multifactorial Disease Process That Causes Acute, Painful Episodes of Life-threatening Voc. It Has Been Described as a Vicious Cycle, Where Hemoglobin (HB) Polymerization Leads to Impaired Red Blood Cell (RBC) Rheology, Which Increases VC and Hemolysis. Cell-free HB (CF-HB) Is Considered a Primer for Voc Because It Scavenges Nitric Oxide and Increases Endothelial Adhesion. However, It Is the RBC VC and Heterocellular Aggregates That Cause and Accelerate Microvasculature Stasis and Ischemia/reperfusion (IR) Injury and Has the Most Significant Impact on SCD Severity. N-acetyl-lysyltyrosylcysteine Amide (KYC) Is a First-in-class, Systems Chemico-pharmacology Drug (SCPD) With Multiple Mechanisms of Action That Inhibit VP and Reduce VC and Pain in SCD Mice. Kyc Inhibits Vasculopathy by Restoring Endothelial-dependent Vasodilation and Reducing VC in SCD Mice. Kyc Inhibits Hemoglobin S (HBS) Oxidation in Vitro and Reduces Blood Viscosity and the Percentage of Sickled RBC in SCD Mice Within Just One Hour of Treatment. as RBC Sickling, VC, and VP All Precede Voc and Pain, We Request Funding to Develop Kyc for Treating SCD Patients Presenting to the Emergency Department Suffering From Voc and Pain. Currently, No Widely Used Fda-approved Therapies Exist for Treating Voc and Pain in SCD Patients. This Application Will Obtain Data Showing Kyc Reduces VP, VC, Voc, Pain, and Irreversible Sickling and VP at Baseline and After Hypoxia/reoxygenation (HR) Injury. After Halting Kyc Therapy, We Will Determine the Time Required to Return to Baseline SCD Severity. Pharmacokinetic (PK), Pharmacodynamic (PD), Safety and Pathology Data Will Demonstrate That Kyc Is a Safe, Effective Drug That Reduces Voc and Pain in SCD Mice. in Aim 1, We Will Determine If Kyc Reduces VP, VC, Voc, and Biomarkers of SCD Severity Better Than Voxelotor in SS Mice. We Will Determine the Time It Takes for SCD Mice to Return to Baseline After Halting Kyc. VC in Tissue Sections Will Be Quantified, Informing Us of Kyc’s Efficacy for Reducing Multiple Organ Injuries. Microvascular Stasis, an Index of Voc, Will Be Determined Using Dorsal Skinfold Window Chambers. HBS Polymerization Will Be Determined by Oxygen Scanning Ektacytometry. Blood Viscosity, Vasodilation, VC, and Voc Will Be Determined at Baseline, After H/R Injury, and After Halting Kyc. We Will Determine the Extent to Which Kyc Reduces VC in Organs Using Established Protocols and Pain in Townes SS Mice Before and After HR Injury and After Halting Kyc. in Aim 2, We Will Determine Subcutaneous (SQ) Kyc PK-PD and Safety. Preliminary Studies Suggest Kyc Has Excellent SQ Bioavailability in Healthy Mice. We Will Also Determine in Vivo SQ Kyc Biodistribution, PK-PD, Various Standard Safety Measures, Biological Stability Properties, and Metabolism in Adult Aa and SS Mice.