This proposal describes the investigation of a new class of antithrombotic and anti-inflammatory small molecules called parmodulins for the treatment of sickle cell disease (SCD). SCD is a group of related disorders caused by mutations in the ß-globin subunit of hemoglobin that leads to polymerization of hemoglobin and the distortion of red blood cells, initiating a range of dangerous effects. In particular, SCD patients suffer from debilitating vaso-occlusive crises (VOCs), which involve the trapping of "sickled" red blood cells in small blood vessels and subsequent thrombotic and inflammatory responses that are painful and dangerous. Despite the approval of several new SCD therapies in recent years, drugs that can drastically decrease the frequency and severity of VOCs have yet to be identified. Parmodulins are allosteric modulators of protease-activated receptor 1 (PAR1), and have demonstrated the ability to inhibit the activation of both platelets and endothelial cells driven by the coagulation enzyme thrombin under inflammatory conditions (thrombo-inflammation). In a partnership between Function Therapeutics and the lab of Dr. Erica Sparkenbaugh (Univ. of North Carolina, co-investigator), certain parmodulins have already demonstrated efficacy in mouse models of SCD. Building upon these results, this Phase 1 project will identify parmodulins with improved potency and oral activity and confirm their efficacy in mouse models of SCD, including the administration of hemin to mimic the potentially deadly acute chest syndrome in SCD patients. A modest medicinal chemistry (lead optimization) program will be undertaken, followed by a sequence of established in vitro assays to identify the most promising parmodulins. This will be complemented by pharmacokinetic (PK) studies to identify bioavailable examples most suitable for oral dosing. Specific Aims: 1. Synthesize novel parmodulins with selective, nanomolar activity at PAR1, and properties consistent with chronic oral dosing. 2. Identify orally active lead parmodulins and confirm their antithrombotic and anti-inflammatory activities. 3. Confirm in vivo activity of optimal parmodulins in mouse models of SCD. In addition to confirming that orally active parmodulins for the treatment of SCD are feasible, this project will establish PK/PD relationships and early dose-responses. Successful results will justify additional safety and efficacy studies in a future preclinical development phase, which could lead to a new therapy for the prevention of VOCs in SCD, and possibly for other thrombo-inflammation-related disorders.
Public Health Relevance Statement: PROJECT NARRATIVE Sickle cell disease is a genetic disorder that causes misshapen ("sickled") red blood cells and affects millions worldwide. It causes a range of dangerous effects, including painful blockages of blood vessels (called vaso- occlusive crises) that are not well addressed by current medications. In this project, examples of a promising new class of antithrombotic and anti-inflammatory molecules called parmodulins will be prepared and tested in cell assays and mouse models of sickle cell disease and vaso-occlusive crisis.
Project Terms: Affect; Hb SS disease; HbSS disease; Hemoglobin S Disease; Hemoglobin sickle cell disease; Hemoglobin sickle cell disorder; sickle cell disease; sickle cell disorder; sickle disease; sicklemia; Sickle Cell Anemia; inhibitor; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Anti-Inflammatory Agents; beta Globin; B-globin; ß-globin; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Physiologic Availability; Blood; Blood Reticuloendothelial System; Blood Platelets; Marrow platelet; Platelets; Thrombocytes; Blood Vessels; vascular; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Complement; Complement Proteins; Dangerousness; Diabetes Mellitus; diabetes; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Endothelium; Enzymes; Enzyme Gene; Erythrocytes; Blood erythrocyte; Erythrocytic; Marrow erythrocyte; Red Blood Cells; Red Cell; blood corpuscles; Future; Grant; Hemin; Chlorohemin; Ferriheme Chloride; Ferriprotoporphyrin IX Chloride; Protohemin; Hemoglobin; Hemostatic function; Hemostasis; Hereditary Disease; Inborn Genetic Diseases; Inherited disorder; hereditary disorder; heritable disorder; inborn error; inherited diseases; inherited genetic disease; inherited genetic disorder; Human; Modern Man; Incidence; Inflammation; Interleukin-6; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; HPGF; Hepatocyte-Stimulating Factor; Hybridoma Growth Factor; IFN-beta 2; IFNB2; IL-6; IL6 Protein; MGI-2; Myeloid Differentiation-Inducing Protein; Plasmacytoma Growth Factor; interferon beta 2; Ischemia; Kidney Diseases; Nephropathy; Renal Disease; kidney disorder; renal disorder; Lead; Pb element; heavy metal Pb; heavy metal lead; Ligands; Longevity; Length of Life; life span; lifespan; Microsomes; mortality; Mus; Mice; Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Nerve Degeneration; Neuron Degeneration; neural degeneration; neurodegeneration; neurodegenerative; neurological degeneration; neuronal degeneration; North Carolina; Pain; Painful; Activated Partial Thromboplastin Time measurement; Activated Partial Thromboplastin Time; Partial Thromboplastin Time; aPTT; Patients; Drug Kinetics; Pharmacokinetics; Phenotype; Platelet aggregation; Polymers; polymer; polymeric; Pulmonary Edema; lung edema; Reperfusion Injury; Ischemia-Reperfusion Injury; Reperfusion Damage; Research; Research Personnel; Investigators; Researchers; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Solubility; Stroke; Apoplexy; Brain Vascular Accident; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; brain attack; cerebral vascular accident; cerebrovascular accident; stroked; strokes; Testing; Thrombin; Thrombase; fibrinogenase; Thrombosis; thrombotic disease; thrombotic disorder; Vascular Diseases; Vascular Disorder; blood vessel disorder; vascular dysfunction; vasculopathy; Fibrin fragment D; D-dimer; D-dimer fibrin; D-dimer fragments; fibrin fragment D-dimer; fibrin fragment D1 dimer; fibrin fragment DD; Vascular Cell Adhesion Molecule-1; CD106; CD106 Antigens; INCAM-110; Inducible Cell Adhesion Molecule 110; VCAM; VCAM-1; Vascular Cell Adhesion Molecule; Generations; Measures; G-Proteins; GTP-Regulatory Proteins; Guanine Nucleotide Coupling Protein; Guanine Nucleotide Regulatory Proteins; GTP-Binding Proteins; Mediating; Specialist; CD62P Antigens; GMP-140; LECAM-3; Platelet alpha-Granule Membrane Protein; P-Selectin; New Drug Approvals; arrestin B; ß-arrestin; beta-arrestin; Organ; improved; Chronic; Clinical; Phase; hemoglobin polymer; sickle RBC; sickle erythrocyte; sickle red blood cell; Sickle Cell; Endothelial Cells; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Collaborations; Therapeutic; polymerization; Inflammatory; programs; Investigation; Frequencies; Severities; Oral; cell type; Cytoprotection; Cell Protection; cytoprotective; meetings; meeting; cytotoxicity; Lytotoxicity; mutant; PAR-1 Receptor; Coagulation Factor II Receptor; PAR1 Receptor; Protease-Activated Receptor 1; Proteinase-Activated Receptor 1; Structure; novel; G-Protein-Coupled Receptors; G Protein-Complex Receptor; G Protein-Coupled Receptor Genes; GPCR; Disease model; disorder model; acute chest syndrome; Modeling; Property; response; drug discovery; Inflammatory Response; Coagulation Process; Clotting; Coagulation; small molecule; HMGB1 gene; Amphoterin; Amphoterin Gene; Chromosomal Protein, Nonhistone, HMG1; Chromosomal Protein, Nonhistone, HMG1 Gene; FM1 Gene Product; HMG-1; HMG-1 Gene; HMG-1 Protein; HMG1; HMG1 Gene; HMG3; HMG3 Gene; HMGB1; HMGB1 Protein; Heparin-Binding Protein p30; High Mobility Group Box Protein 1; High Mobility Group Protein 1; High Mobility Group Protein 1 Gene; High-Mobility Group (Nonhistone Chromosomal) Protein 1; High-Mobility Group (Nonhistone Chromosomal) Protein 1 Gene; High-Mobility Group Box 1; High-Mobility Group Box 1 Gene; Nonhistone Chromosomal Protein HGM1; Nonhistone Chromosomal Protein HGM1 Gene; SBP-1; SBP-1 Gene; Sulfoglucuronyl Carbohydrate Binding Protein; Sulfoglucuronyl Carbohydrate Binding Protein Gene; Signaling Protein; Signaling Factor Proto-Oncogene; Signaling Pathway Gene; Address; Dose; Structural Chemistry; in vitro Assay; in vivo; Cellular Assay; cell assay; Validation; validations; safety study; sickling; blood infection; bloodstream infection; Sepsis; Prevention therapy; innovate; innovative; innovation; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; commercialization; bio-markers; biologic marker; biomarker; Biological Markers; nano-molar; nanomolar; efficacy study; pre-clinical development; preclinical development; genetic condition; genetic disorder; Genetic Diseases; lead optimization; lead candidate; thromboinflammatory; thromboinflammation; vasoocclusive crisis; vaso-occlusive crisis; thrombotic; antagonist; antagonism; Mediator
