A series of glucagon analogues will be designed, produced at milligram levels, tested for solution stability and both in vitro and in vivo activity with the goal of providing a long term treatment for hyperinsulinism.
Public Health Relevance Statement: NARRATIVE In severe persistent HI, repeated hypoglycemic episodes can ultimately lead to permanent seizure disorders, learning disabilities, cerebral palsy, blindness and even death. Clinical studies have demonstrated the effectiveness of both short-term and long-term treatment with glucagon for severe forms of HI and continuous subcutaneous administration of glucagon has been recommended both because of the potential improvement in patient outcome and high costs of surgical intervention followed by long-term annual care costs. However, the instability of glucagon in solution creates both administration problems and potential complications due to infusion tube blockage. These instability problems have limited the use of glucagon for severe persistent HI. To overcome this problem, we propose to develop a series of solution stable glucagon analogs and test them both in-vitro and in-vivo. These analogs when formulated in a conventional sterile diluent will maintain not only the standard 95% potency requirement throughout a 2 year storage period at 4ºC but more importantly will offer an extended "in use" stability period of at least 6 months at 40ºC. Such analogs will be capable to be implemented in pump system for the long-term management of severe persistent HI without concern for complications due to glucagon instability and pump clogging issues.
Project Terms: Biologic Assays; Bioassay; Assay; Biological Assay; Parturition; Birth; Cerebral Palsy; youngster; childrens'; children; Children (0-21); Child Youth; 0-11 years old; Child; High Speed Liquid Chromatography; High Performance Liquid Chromatography; HPLC; High Pressure Liquid Chromatography; Clinical Study; Clinical Research; Clinical Trials; Death; Cessation of life; diabetes; Diabetes Mellitus; Disorder; Disease; epileptogenic; epileptiform; epilepsia; Seizure Disorder; Epileptics; Epileptic Seizures; Epilepsy; Family; Fluorescence; Future; Hyperglycemic-Glycogenolytic Factor; HG-Factor; Glukagon; Antidiabetic Hormone; Glucagon; Dextrose; D-Glucose; Glucose; Q. Levoglutamide; Q Levoglutamide; L-Glutamine; Gln; Glutamine; Goals; Modern Man; Human; Hyperinsulinemia; Hyperinsulinism; hypoglycemic episodes; hypoglycemic; Hypoglycemia; In Vitro; Incidence; Newborn Infant; newborn children; newborn child; Newborns; 0-4 weeks old; Kinetics; Lead; heavy metal lead; heavy metal Pb; Pb element; Length of Stay; hospital stay; hospital length of stay; hospital days; Number of Days in Hospital; Libraries; Life Style; Lifestyle; Mutation; genome mutation; Genetic defect; Genetic Change; Genetic Alteration; Pancreatectomy; Pancreas Excision; Legal patent; Patents; Patients; Production; Technology; Testing; Thermodynamics; Thermodynamic; United States; Glucagon Receptor; Restlessness; Psychomotor Restlessness; Psychomotor Hyperactivity; Psychomotor Excitement; Psychomotor Agitation; Agitation; Caring; Tube; base; Pump; improved; Clinical; Diffuse; Phase; Medical; Series; Chemicals; Failure; analog; Life; milligram; Side; subcutaneous; System; Blindness; visual loss; vision loss; Amino Acid Substitution; Operative Surgical Procedures; surgery; Surgical Procedure; Surgical Interventions; Surgical; Operative Procedures; Infusion procedures; Infusion; amino group; chemical stability; Sterility; sterile; Learning Disabilities; Learning disability; Regulation; Property; insulin secretion; Persistent Hyperinsulinemia Hypoglycemia of Infancy; PHHI Hypoglycemia; Hypoglycemia of Infancy; Hyperinsulinemia Hypoglycemia of Infancy; Congenital hyperinsulinemia; Congenital Hyperinsulinism; Effectiveness; prevent; preventing; deamidation; Defect; DNA Sequence Alteration; genomic alteration; Sequence Alteration; Genetic mutation; DNA mutation; DNA Alteration; Glucose Plasma Concentration; in vivo; Patient-Centered Outcomes; Patient outcome; Patient-Focused Outcomes; Monitor; Process; cost; designing; design; Outcome; Resistance; resistant; mouse model; murine model; effective therapy; effective treatment; large scale production; stability testing; phase 2 study; phase II study; Formulation
