A small molecule inhibitor of mutant IDH2 rescues cardiomyopathy in a D-2-hydroxyglutaric aciduria type II mouse model

作者：Wang Fang; Travins Jeremy; Lin Zhizhong; Si Yaguang; Chen Yue; Powe Josh; Murray Stuart; Zhu Dongwei; Artin Erin; Gross Stefan; Santiago Stephanie; Steadman Mya; Kernytsky Andrew; Straley Kimberly; Lu Chenming; Pop Ana; Struys Eduard A; Jansen Erwin E W; Salomons Gajja S; David Muriel D; Quivoron Cyril; Penard Lacronique Virginie; Regan Karen S; Liu Wei; Dang Lenny; Yang Hua; Silverman Lee; Agresta Samuel; Dorsch Marion; Biller Scott; Yen Katharine

来源：Journal of Inherited Metabolic Disease, 2016, 39(6): 807-820.

DOI：10.1007/s10545-016-9960-y

D-2-hydroxyglutaric aciduria (D2HGA) type II is a rare neurometabolic disorder caused by germline gain-of-function mutations in isocitrate dehydrogenase 2 (IDH2), resulting in accumulation of D-2-hydroxyglutarate (D2HG). Patients exhibit a wide spectrum of symptoms including cardiomyopathy, epilepsy, developmental delay and limited life span. Currently, there are no effective therapeutic interventions. We generated a D2HGA type II mouse model by introducing the Idh2R140Q mutation at the native chromosomal locus. Idh2R140Q mice displayed significantly elevated 2HG levels and recapitulated multiple defects seen in patients. AGI-026, a potent, selective inhibitor of the human IDH2R140Q-mutant enzyme, suppressed 2HG production, rescued cardiomyopathy, and provided a survival benefit in Idh2R140Q mice; treatment withdrawal resulted in deterioration of cardiac function. We observed differential expression of multiple genes and metabolites that are associated with cardiomyopathy, which were largely reversed by AGI-026. These findings demonstrate the potential therapeutic benefit of an IDH2R140Q inhibitor in patients with D2HGA type II.

• 出版日期2016-11