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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/173603
Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations
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Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation S100A9 is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies.
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MAES, Tamara, MASCARÓ, Cristina, ROTLLANT, David, PIO LUFINO, Michele matteo, ESTIARTE, Angels, GUIBOURT, Nathalie, CAVALCANTI, Fernando, GRIÑÁN FERRÉ, Christian, PALLÀS I LLIBERÍA, Mercè, NADAL, Roser, ARMARIO, Antonio, FERRER, Isidro (ferrer abizanda), ORTEGA, Alberto, VALLS, Nuria, FYFE, Matthew, MARTINELL, Marc, CASTRO PALOMINO, Julio, BUEA ARJOL, Carlos. Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations. _PLoS One_. 2020. Vol. 15, núm. 5, pàgs. e0233468. [consulta: 25 de febrer de 2026]. [Disponible a: https://hdl.handle.net/2445/173603]