Avanti Biosciences Inc's mission is to develop best-in-class treatment for congenital hyperinsulinemia (CHI) disorders. We are interested in finding a cure for the rare disease Hyperinsulinemia (HI)- Hyperammonemia (HA) Syndrome (HHS or HI/HA) by developing prodrugs of natural products which are potent and selective inhibitors of Glutamate Dehydrogenase (GDH) whose loss in GTP regulation is the main cause of the disorder. Previous studies have been shown that GDH inhibitors can effectively restore normal levels of insulin secretion in test animals. HHS is a rare autosomal dominant disease manifested by hypoglycemic symptoms triggered by fasting or high-protein meals, and by elevated serum ammonia. It is the second most common cause of hyperinsulinemic hypoglycemia in infancy. The current treatments for HHS (diazoxide) are characterized by important side-effects and do not address the underlying GDH dysregulation or the resulting liver, kidney, and CNS clinical complications. Inhibitors of this enzyme can also be very useful for the treatment of another congenital hyperinsulinemia disorder associated with inactivating mutations of short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD). The mechanism of SCHAD-HI involves loss of an inhibitory protein-protein interaction between SCHAD and GDH. The SCHAD-HI phenotype is like HHS (fasting and leucine/protein-sensitive hypoglycemia), but without the associated HA or CNS disturbances. The most promising lead compound in restoring GTP regulation of GDH is a catechin derivative found in green tea, namely epigallocatechin-3-gallate (EGCG) which has been shown to be efficacious in vitro, in situ, and in vivo in directly controlling the dysregulated GDH that causes this disease. Unfortunately, large, and repeated dosing of EGCG are required to achieve the desired efficacy due to low bioavailability and high metabolism of this natural product. Avanti Biosciences is proposing the development of novel EGCG pro-drugs with the goal to improve pharmacological and ADME properties of the active molecule. The proposal will allow us to expand our portfolio of GDH inhibitors with the goal of identifying orally efficacious candidates for further development as therapeutics for HHS and SCHAD- HI.
Project Terms: 3-Hydroxyacyl-CoA dehydrogenase; Acute; Adverse effects; Allosteric Site; Ammonia; Animal Testing; Applications Grants; aqueous; Area Under Curve; base; Beta Cell; Binding; Biological Availability; Biological Sciences; Blood Circulation; blood glucose regulation; Brain; Brain Death; Brain Injuries; Carbamates; Catechin; Cell Membrane Permeability; Characteristics; Child; Chronic; Clinical; Collaborations; Development; Diazoxide; Disease; Dose; Drug Kinetics; efficacy study; Enzyme Inhibitor Drugs; Epigallocatechin Gallate; Esters; Fasting; gamma-Aminobutyric Acid; gastrointestinal; Gastrointestinal tract structure; Genetic Diseases; Glucose; Glutamate Dehydrogenase; Glutamates; Goals; Green tea; Guanosine Triphosphate; Human; Hyperammonemia; Hyperinsulinism; Hypoglycemia; improved; In Situ; In Vitro; in vivo; infancy; inhibitor/antagonist; Insulin; insulin secretion; interest; Kidney; Lead; Leucine; Liver; liver metabolism; Measures; Metabolic; Metabolism; Mission; mouse model; Mus; Mutation; Natural Products; Neurologic; Neurotransmitters; novel; novel therapeutics; Oral; Oral Administration; Pancreas; Parents; Patients; Pediatric Hospitals; Permeability; Persistent Hyperinsulinemia Hypoglycemia of Infancy; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Philadelphia; Plasma; polyphenol; Positioning Attribute; Potassium Channel; Prodrugs; Property; protein protein interaction; Proteins; Rare Diseases; Recurrence; Regulation; Route; safety study; Serum; Site; Solubility; Symptoms; Syndrome; Testing; Therapeutic; Time; Total Pancreatectomy; Toxic effect; Transgenic Mice; Work;
