A small molecule inhibitor of mutant IDH2 rescues cardiomyopathy in a D-2-hydroxyglutaric aciduria type II mouse model.
J Inherit Metab Dis
; 39(6): 807-820, 2016 11.
Article
in En
| MEDLINE
| ID: mdl-27469509
ABSTRACT
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.
Full text:
1
Database:
MEDLINE
Main subject:
Brain Diseases, Metabolic, Inborn
/
Small Molecule Libraries
/
Isocitrate Dehydrogenase
/
Mutation
/
Cardiomyopathies
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
J Inherit Metab Dis
Year:
2016
Type:
Article
Affiliation country:
United States