Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations

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...

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Detalles Bibliográficos
Autores: Maes, Tamara|||0000-0001-5104-6867, Mascaró, Cristina, Rotllant, David|||0000-0002-1186-4918, Lufino, Michele Matteo Pio, Estiarte, Angels|||0000-0001-8687-3395, Guibourt, Nathalie, Cavalcanti, Fernando, Griñan-Ferré, Christian, Pallàs, Mercè|||0000-0003-3095-4254, Nadal i Alemany, Roser|||0000-0001-8972-2525, Armario Garcia, Antonio|||0000-0001-9524-3635, Ferrer, Isidro|||0000-0001-9888-8754, Ortega, Alberto, Valls, Nuria, Fyfe, Matthew|||0000-0001-5258-5379, Martinell, Marc, Castro Palomino, Julio César, Buesa, Carlos|||0000-0001-6293-2514
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:252631
Acceso en línea:https://ddd.uab.cat/record/252631
https://dx.doi.org/urn:doi:10.1371/journal.pone.0233468
Access Level:acceso abierto
Descripción
Sumario: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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