Hyperinsulinemic hypoglycemia (HH) is one of the most frequent causes of persistent hypoglycemia in infants and can result in seizures, developmental delays, learning disabilities, and even death. The most severe form of HH is inherited and referred to as congenital hyperinsulinism (CHI). CHI largely results from mutations in key genes in the insulin secretion pathway in the islets of Langerhans in the pancreas. Suspicion of CHI is confirmed by tests including the need to implement a high glucose infusion rate to maintain normal blood glucose levels. Currently, the only medical therapies used to treat CHI are used off-label. Typically, diazoxide (an insulin secretion inhibitor) is tried first, though it is often ineffective and has a side effect that causes abnormal and excessive hair growth over much of the body. The peptide sst receptor agonist octreotide is also used off-label for patients that are unresponsive to diazoxide or in conjunction with poor responders. Its pharmacological profile (sst2>sst5) leads to a host of unwanted side effects, including suppression of glucagon secretion which is detrimental to the CHI patient's utmost need, as well as inhibition of the growth hormone axis at the pituitary. Despite their poor profiles, these therapies are tried because the next line of treatment is typically a partial or full pancreatectomy. Even when successful, the result of this surgery is that the patient becomes diabetic and must actively manage glucose for the rest of their lives. Therefore, a significant unmet medical need exists for agents designed to specifically and effectively treat CHI. Here, we lay out our plan to develop orally-available, selective sst5-, sst3-, and/or dual sst5/3 agonists for the treatment of infants and children with CHI and other hyperinsulinemic disorders. Such a compound represents a major advance for infants with CHI and promises to provide specifically directed insulin control with the goal of preventing or delaying pancreatectomy without the excess of side effects that are carried along with current treatments.
Public Health Relevance Statement: Project Narrative Congenital hyperinsulinemia (CHI) is a severe endocrine disorder in infants in which the only treatment is often surgical pancreatectomy. Currently available medical therapy is poor. If successful, this project will result in a novel drug candidate for the treatment of CHI with an improved safety and efficacy profile over existing options.
Project Terms: Abbreviations; intraoral drug delivery; Oral Drug Administration; Oral Administration; adulthood; Adult Human; 21+ years old; Adult; inhibitor; inhibitor/antagonist; Bursa-Equivalent Lymphocyte; Bursa-Dependent Lymphocytes; B-cell; B-Cells; B cells; B cell; B blood cells; B-Lymphocytes; Bibliography; Blood Sugar; Blood Glucose; Pharmaceutic Chemistry; Medicinal Chemistry; Pharmaceutical Chemistry; youngster; childrens'; children; Children (0-21); Child Youth; 0-11 years old; Child; Communities; Consanguinity; P450; Cytochrome P450 Family Gene; Cytochrome P-450 Enzyme System; Cytochrome P-450; Cytochrome P450; Death; Cessation of life; psychological defense mechanism; Defense Mechanisms; diabetes; Diabetes Mellitus; Diazoxide; Disorder; Disease; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; endocrine disorder; Endocrine Diseases and Manifestations; Endocrine Diseases; Endocrine System Diseases; Genes; Micronase; Glybenclamide; Glibenclamide; Glyburide; Hyperglycemic-Glycogenolytic Factor; HG-Factor; Glukagon; Antidiabetic Hormone; Glucagon; Dextrose; D-Glucose; Glucose; Goals; Government; ontogeny; Tissue Growth; Generalized Growth; Growth; Hair; Modern Man; Human; Hyperinsulinemia; Hyperinsulinism; hypoglycemic episodes; hypoglycemic; Hypoglycemia; In Vitro; Incidence; Infant; Newborn Infant; newborn children; newborn child; Newborns; 0-4 weeks old; Insulin; Regular Insulin; Novolin R; Humulin R; Islets of Langerhans; islet progenitor; Pars endocrina pancreatis; Pancreatic Islets; Nesidioblasts; Islands of Langerhans; Endocrine Pancreas; B9 endocrine pancreas; Lead; heavy metal lead; heavy metal Pb; Pb element; Liver; hepatic organ system; hepatic body system; Molecular Models; Mutation; genome mutation; Genetic defect; Genetic Change; Genetic Alteration; Persons; Neuropeptides; Octreotide; Pancreas; Pancreatic; Pancreatectomy; Pancreas Excision; Patients; Peptides; Pharmacology; Pituitary Gland; Pituitary Nervous System; Pituitary; Hypophysis Cerebri; Hypophysis; Rattus; Rats Mammals; Rat; Common Rat Strains; Rest; Safety; Seizures; Signal Transduction; biological signal transduction; Signaling; Signal Transduction Systems; Intracellular Communication and Signaling; Cell Signaling; Cell Communication and Signaling; Solubility; Somatostatin; growth hormone release inhibiting factor; Somatotropin Release-Inhibiting Hormone; Somatotropin Release Inhibiting Factors; Somatostatin-14; SRIH-14; SRIH; Growth Hormone-Inhibiting Hormone; Growth Hormone Inhibiting Factors; Cyclic Somatostatin; Somatotropin; somatotropic hormone; Pituitary Growth Hormone; Growth Hormone 1; Growth Hormone; Testing; Toxicology; Somatotropin Release Inhibiting Hormone Receptors; SRIH Receptors; Somatostatin Receptor; Specific Child Development Disorders; Developmental Delay; Developmental Delay Disorders; Injectable; base; Label; improved; Acute; Chronic; Phase; Medical; Neurological; Neurologic; Evaluation; diabetic; Agonist; pathophysiology; Physiopathology; Dysfunction; Functional disorder; NOAEL; No-Observed-Adverse-Effect Level; Therapeutic; Metabolic; Life; programs; Inherited; Hereditary; Oral; Hormonal; Live Birth; Necrotizing Enterocolitis; D Cells; Somatostatin Secreting Cell; Somatostatin Cells; Delta Cell; Operative Surgical Procedures; surgery; Surgical Procedure; Surgical Interventions; Surgical; Operative Procedures; Infusion procedures; Infusion; receptor; Receptor Protein; molecular modeling; Molecular Modeling Protein/Amino Acid Biochemistry; Molecular Modeling Nucleic Acid Biochemistry; Pathogenesis; Learning Disabilities; Learning disability; Maximum Tolerated Dose; Maximally Tolerated Dose; Maximal Tolerated Dose; Modeling; Property; Adverse effects; treatment adverse effect; therapy adverse effect; side effect; Treatment Side Effects; Alpha Cell; a-cell; Glucagon Secreting Cell; Glucagon Cell; Pharmacologic Substance; Pharmacological Substance; Pharmaceuticals; Pharmaceutical Agent; insulin secretion; Persistent Hyperinsulinemia Hypoglycemia of Infancy; PHHI Hypoglycemia; Hypoglycemia of Infancy; Hyperinsulinemia Hypoglycemia of Infancy; Congenital hyperinsulinemia; Congenital Hyperinsulinism; Effectiveness; prevent; preventing; small molecule; Rodent Model; Preparation; developmental; Development; pathway; Pathway interactions; neonate; designing; design; islet; glucose regulation; glucose homeostasis; glucose control; blood glucose regulation; Population; innovation; innovative; innovate; novel therapeutics; novel therapy; novel drugs; novel drug treatments; next generation therapeutics; new therapy; new therapeutics; new drugs; new drug treatments; lead series; drug candidate; peptide drug; therapeutic peptide
