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Title: Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations
Author: 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 César
Buea Arjol, Carlos
Keywords: Malaltia d'Alzheimer
Alzheimer's disease
Issue Date: 29-May-2020
Publisher: Public Library of Science (PLoS)
Abstract: 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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It is part of: PLoS One, 2020, vol. 15, num. 5, p. e0233468
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Appears in Collections:Articles publicats en revistes (Institut de Neurociències (UBNeuro))
Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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