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, 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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/173603
Acceso en línea:https://hdl.handle.net/2445/173603
Access Level:acceso abierto
Palabra clave:Malaltia d'Alzheimer
Neuroplasticitat
Alzheimer's disease
Neuroplasticity
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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