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

Authors: 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  Cang, Yong  Su, Shin-San Michael  Jin, Shengfang 
Citation: Wang F, etal., J Inherit Metab Dis. 2016 Nov;39(6):807-820. doi: 10.1007/s10545-016-9960-y. Epub 2016 Jul 28.
Pubmed: (View Article at PubMed) PMID:27469509
DOI: Full-text: 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.


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RGD Object Information
RGD ID: 13506812
Created: 2018-02-20
Species: All species
Last Modified: 2018-02-20
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.