Maes, TamaraMascaró, CristinaRotllant, DavidPio Lufino, Michele MatteoEstiarte, AngelsGuibourt, NathalieCavalcanti, FernandoGriñán Ferré, ChristianPallàs i Llibería, Mercè, 1964-Nadal, RoserArmario, AntonioFerrer, Isidro (Ferrer Abizanda)Ortega, AlbertoValls, NuriaFyfe, MatthewMartinell, MarcCastro Palomino, JulioBuea Arjol, Carlos2021-02-032021-02-032020-05-29https://hdl.handle.net/2445/173603Transcription 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.26 p.application/pdfengcc by (c) Maes et al., 2020http://creativecommons.org/licenses/by/3.0/es/Malaltia d'AlzheimerNeuroplasticitatAlzheimer's diseaseNeuroplasticityinfo:eu-repo/semantics/article7076242021-01-25info:eu-repo/semantics/openAccess32469975