Development of novel prodrugs targeting Glutamate Dehydrogenase (GDH) for the treatment of congenital hyperinsulinemia disorder including Hyperinsulinemia-Hyperammonemia Syndrome (HHS) and SCHAD-HI.

Avanti Biosciences Incandapos s mission is to develop best in class treatment for congenital hyperinsulinemiaCHIdisordersWe are interested in finding a cure for the rare disease HyperinsulinemiaHIHyperammonemiaHASyndromeHHS or HI HAby developing prodrugs of natural products which are potent and selective inhibitors of Glutamate DehydrogenaseGDHwhose loss in GTP regulation is the main cause of the disorderPrevious studies have been shown that GDH inhibitors can effectively restore normal levels of insulin secretion in test animalsHHS is a rare autosomal dominant disease manifested by hypoglycemic symptoms triggered by fasting or high protein mealsand by elevated serum ammoniaIt is the second most common cause of hyperinsulinemic hypoglycemia in infancyThe current treatments for HHSdiazoxideare characterized by important side effects and do not address the underlying GDH dysregulation or the resulting liverkidneyand CNS clinical complicationsInhibitors of this enzyme can also be very useful for the treatment of another congenital hyperinsulinemia disorder associated with inactivating mutations of short chainhydroxyacyl CoA dehydrogenaseSCHADThe mechanism of SCHAD HI involves loss of an inhibitory protein protein interaction between SCHAD and GDHThe SCHAD HI phenotype is like HHSfasting and leucine protein sensitive hypoglycemiabut without the associated HA or CNS disturbancesThe most promising lead compound in restoring GTP regulation of GDH is a catechin derivative found in green teanamely epigallocatechingallateEGCGwhich has been shown to be efficacious in vitroin situand in vivo in directly controlling the dysregulated GDH that causes this diseaseUnfortunatelylargeand repeated dosing of EGCG are required to achieve the desired efficacy due to low bioavailability and high metabolism of this natural productAvanti Biosciences is proposing the development of novel EGCG pro drugs with the goal to improve pharmacological and ADME properties of the active moleculeThe 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 SCHADHI Project Narrative Avanti Biosciences Incandapos s mission is to develop best in class treatment for congenital hyperinsulinemiaCHIdisordersIn particularwe are interested in finding a cure for the rare disease HyperinsulinemiaHIHyperammonemiaHASyndromeHHS or HI HAa rare autosomal dominant disease manifested by hypoglycemic symptoms and by elevated serum ammoniaIt is the second most common cause of hyperinsulinemic hypoglycemia in infancy caused by loss of GTP regulation of GDHInhibitors of this enzyme can effectively restore normal levels of insulin secretion in test animalsThese molecules can also be very useful for the treatment of another congenital hyperinsulinemia disorder associated with inactivating mutations of short chainhydroxyacyl CoA dehydrogenaseSCHADThe mechanism of SCHAD HI involves loss of an inhibitory protein protein interaction between SCHAD and GDHThe most promising lead compound in restoring GDH modulation is a polyphenol found in green teaepigallocatechingallateEGCGwhich has been shown to be efficacious in vitroin situand in vivo in directly controlling the dysregulated GDH that causes this diseaseUnfortunatelylarge and repeated dosings of EGCG are required to achieve the desired efficacy due to low bioavailability and high metabolism of this natural productAvanti Biosciencesin collaboration with the Childrenandapos s Hospital of PhiladelphiaCHOPis seeking to develop novel prodrugs of EGCG in order to improve the delivery of the active ingredient to the site of actionpancreas and brainwith the goal of identifying orally efficacious drugs for further development as therapeutics for HHS and SCHAD HI