Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations

Tamara Maes*, Cristina Mascaró, David Rotllant, Michele Matteo Pio Lufino, Angels Estiarte, Nathalie Guibourt, Fernando Cavalcanti, Christian Griñan-Ferré, Mercè Pallàs, Roser Nadal, Antonio Armario, Isidro Ferrer, Alberto Ortega, Nuria Valls, Matthew Fyfe, Marc Martinell, Julio César Castro Palomino, Carlos Buesa Arjol

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Article numbere0233468
JournalPLoS ONE
Volume15
Issue number5
DOIs
Publication statusPublished - May 2020

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