Mastocytosis is a term used to describe a set of rare diseases that are characterized by increased mast cell development and the enhanced presence of mast cells in various tissues and organs. Once activated, mast cells promote inflammation through their robust production of histamines, leukotrienes, prostaglandins and many other effector molecules that promote itching, burning, smooth muscle contraction and life-threatening anaphylaxis, all of which are common symptoms of mastocytosis. Although patients suffering from mastocytosis are prescribed antihistamines and mast cell stabilizers, treatment options are limited, and more severe forms of the disease are extremely difficult to treat and remain life-threatening. Further, an incomplete understanding of the factors that regulate mast cell development has dramatically limited the ability to design novel therapeutics that selectively target mast cells. NemaGen's published and preliminary studies have revealed that the enzyme carbonic anhydrase (Car)1 is exclusively expressed by mast cell progenitors. Further, we have demonstrated that small molecule-mediated inhibition of Car1 is sufficient to prevent murine and human mast cell development. In addition, our data demonstrate that in vivo treatment with known carbonic anhydrase inhibitors is sufficient to prevent mast cell development and inflammation in a murine model of mastocytosis. Collectively, these studies suggest that Car1 represents a novel therapeutic target for the treatment of mastocytosis and mast cell-mediated inflammation. Although existing carbonic anhydrase inhibitors are available, our studies have shown that their effective doses far exceed those required for translational applications. To address this, we have generated a strong team and effective workflow that allows us to synthesize and test new Car enzyme inhibitors. Further, our data demonstrate that we can generate significantly more effective inhibitors than currently available options. These exciting findings form the foundation of this SBIR proposal and two specific aims: (i) Design, synthesize and optimize novel carbonic anhydrase inhibitors. (ii) Evaluate the effects of Car enzyme inhibitors on enzymatic function and mast cell development both in vitro and in vivo. Collectively, these pre-clinical studies will allow us to generate new Car enzyme inhibitors for the treatment of mastocytosis and other mast cell-related disorders.
Public Health Relevance Statement: PROJECT NARRATIVE Mastocytosis is a term used to describe a rare set of diseases that are characterized by dangerously high mast cell levels in various tissues and organs. Despite the debilitating and often life-threatening symptoms of mastocytosis, drug therapies remain limited. This proposal seeks to develop and commercialize novel therapeutic compounds to diminish mast cell populations for the effective treatment of mastocytosis.
Project Terms: Abdominal Pain; Anaphylaxis; Anaphylactic Reaction; Anaphylactic Shock; Anemia; inhibitor; Antihistamines; Biological Assay; Assay; Bioassay; Biologic Assays; carbonate dehydratase; Carbonate hydro-lyase; Carbonic Anhydrases; Carbonic Anhydrase Inhibitors; Carbonate Dehydratase Inhibitors; Carboxyanhydrase Inhibitors; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cells; Cell Body; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Dangerousness; Disease; Disorder; Pharmacotherapy; Drug Therapy; drug treatment; Enzymes; Enzyme Gene; Foundations; Patient Care; Patient Care Delivery; Headache; Cephalalgia; Cephalgia; Cephalodynia; Cranial Pain; Head Pain; head ache; Histamine Release; Histamine Liberation; Human; Modern Man; In Vitro; Inflammation; Lead; Pb element; heavy metal Pb; heavy metal lead; Leukotrienes; Lung; Lung Respiratory System; pulmonary; mast cell; Marrow Mast Cell; Tissue Basophils; mastocyte; mastocytosis; Mast-Cell Disease; mast cell hyperplasia; Methods; Study models; Motivation; Mus; Mice; Mice Mammals; Murine; Muscle Contraction; Muscle Cell Contraction; Muscular Contraction; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Patients; Physicians; Production; Prostanoids; Prostaglandins; Itching; Pruritic Disorder; Pruritis; itch sensation; Pruritus; Publishing; Societies; Progenitor Cells; stem cells; Survey Instrument; Surveys; Testing; Tissues; Body Tissues; Urticaria; Hives; Proto-Oncogene Protein c-kit; C-KIT Gene; CD117; CD117 Antigens; Mast Cell Growth Factor Receptor; SCF Receptor; SCF Receptor Gene; SCFR; Stem Cell Factor Receptor; Stem Cell Factor Receptor Gene; c kit; c-kit Protein; c-kit Receptor; kit Proto-Oncogene Protein; p145(c-kit); p145c-kit; falls; Mediating; base; Organ; improved; Surface; Chronic; Phase; Stimulus; inflammatory mediator; Inflammation Mediators; enzyme activity; Letters; Life; programs; System; physical property; Receptor Protein; receptor; nature therapy; Orphan Disease; Rare Disorder; orphan disorder; Rare Diseases; novel; Modeling; response; computational chemistry; Enzyme Inhibitor Drugs; Enzyme Antagonist; Enzyme Inhibitor; Enzyme Inhibitor Agent; Skin; Involuntary Muscle; Smooth Muscle; Mast Cell Stabilizer; preventing; prevent; small molecule; Address; Dose; Symptoms; protein structures; proteins structure; protein structure; CD117 Mutation; C-KIT Mutation; Data; Histamine Production; in vivo; in vivo Model; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Characteristics; Development; developmental; preclinical study; pre-clinical study; design; designing; pathogen; Population; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; mouse model; murine model; new therapeutic target; new drug target; new druggable target; new pharmacotherapy target; new therapy target; novel drug target; novel druggable target; novel pharmacotherapy target; novel therapeutic target; novel therapy target; patient population; treatment strategy; effective therapy; effective treatment; process optimization; drug candidate; targeted treatment; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; nanomolar; nano-molar; common symptom; care providers; primary care provider; side effect; protein data bank; protein databank; translational applications
