2026-04-17T05:16:17Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1736032025-12-05T14:10:06Zcom_2072_1057col_2072_478815col_2072_478916col_2072_478906col_2072_478917

00925njm 22002777a 4500 dc Maes, Tamara author Mascaró, Cristina author Rotllant, David author Pio Lufino, Michele Matteo author Estiarte, Angels author Guibourt, Nathalie author Cavalcanti, Fernando author Griñán Ferré, Christian author Pallàs i Llibería, Mercè, 1964- author Nadal, Roser author Armario, Antonio author Ferrer, Isidro (Ferrer Abizanda) author Ortega, Alberto author Valls, Nuria author Fyfe, Matthew author Martinell, Marc author Castro Palomino, Julio author Buea Arjol, Carlos author 2021-02-03T10:40:55Z 2021-02-03T10:40:55Z 2020-05-29 2021-01-25T08:12:43Z 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. Malaltia d'Alzheimer Neuroplasticitat Alzheimer's disease Neuroplasticity Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations