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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 <jats:italic>Idh2R140Q<\/jats:italic> mutation at the native chromosomal locus. Idh2R140Q mice displayed significantly elevated 2HG levels and recapitulated multiple defects seen in patients. AGI\u2010026, a potent, selective inhibitor of the human IDH2R140Q\u2010mutant 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\u2010026. These findings demonstrate the potential therapeutic benefit of an IDH2R140Q inhibitor in patients with D2HGA type II.<\/jats:p>","DOI":"10.1007\/s10545-016-9960-y","type":"journal-article","created":{"date-parts":[[2016,7,28]],"date-time":"2016-07-28T07:45:41Z","timestamp":1469691941000},"page":"807-820","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A small molecule inhibitor of mutant IDH2 rescues cardiomyopathy in a D\u20102\u2010hydroxyglutaric aciduria type II mouse model"],"prefix":"10.1002","volume":"39","author":[{"given":"Fang","family":"Wang","sequence":"first","affiliation":[{"name":"Agios Pharmaceuticals Inc. 88 Sidney Street Cambridge MA 02139\u20104169 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Travins","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals Inc. 88 Sidney Street Cambridge MA 02139\u20104169 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhizhong","family":"Lin","sequence":"additional","affiliation":[{"name":"Oncology Business Unit WuXi AppTec Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaguang","family":"Si","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals Inc. 88 Sidney Street Cambridge MA 02139\u20104169 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Chen","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals Inc. 88 Sidney Street Cambridge MA 02139\u20104169 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josh","family":"Powe","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals Inc. 88 Sidney Street Cambridge MA 02139\u20104169 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Murray","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals Inc. 88 Sidney Street Cambridge MA 02139\u20104169 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongwei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals Inc. 88 Sidney Street Cambridge MA 02139\u20104169 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Artin","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals Inc. 88 Sidney Street Cambridge MA 02139\u20104169 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Gross","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals Inc. 88 Sidney Street Cambridge MA 02139\u20104169 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Santiago","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals Inc. 88 Sidney Street Cambridge MA 02139\u20104169 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mya","family":"Steadman","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals Inc. 88 Sidney Street Cambridge MA 02139\u20104169 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Kernytsky","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals Inc. 88 Sidney Street Cambridge MA 02139\u20104169 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Straley","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals Inc. 88 Sidney Street Cambridge MA 02139\u20104169 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenming","family":"Lu","sequence":"additional","affiliation":[{"name":"Oncology Business Unit WuXi AppTec Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Pop","sequence":"additional","affiliation":[{"name":"Metabolic Unit, Department of Clinical Chemistry VU University Medical Center\/ Neuroscience Campus Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard A.","family":"Struys","sequence":"additional","affiliation":[{"name":"Metabolic Unit, Department of Clinical Chemistry VU University Medical Center\/ Neuroscience Campus Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwin E. 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