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Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations Maes, Tamara Mascaró, Cristina Rotllant, David Pio Lufino, Michele Matteo Estiarte, Angels Guibourt, Nathalie Cavalcanti, Fernando Griñán Ferré, Christian Pallàs i Llibería, Mercè, 1964- Nadal, Roser Armario, Antonio Ferrer, Isidro (Ferrer Abizanda) Ortega, Alberto Valls, Nuria Fyfe, Matthew Martinell, Marc Castro Palomino, Julio Buea Arjol, Carlos Malaltia d'Alzheimer Neuroplasticitat Alzheimer's disease Neuroplasticity 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. 2021-02-03T10:40:55Z 2021-02-03T10:40:55Z 2020-05-29 2021-01-25T08:12:43Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1371/journal.pone.0233468 PLoS One, 2020, vol. 15, num. 5, p. e0233468 https://doi.org/10.1371/journal.pone.0233468 cc by (c) Maes et al., 2020 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Public Library of Science (PLoS) Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)