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Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations.

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.

SUBMITTER: Maes T

PROVIDER: S-EPMC7259601 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations.

Maes Tamara T Mascaró Cristina C Rotllant David D Lufino Michele Matteo Pio MMP Estiarte Angels A Guibourt Nathalie N Cavalcanti Fernando F Griñan-Ferré Christian C Pallàs Mercè M Nadal Roser R Armario Antonio A Ferrer Isidro I Ortega Alberto A Valls Nuria N Fyfe Matthew M Martinell Marc M Castro Palomino Julio César JC Buesa Arjol Carlos C

PloS one 20200529 5

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 ...[more]

PMID: 32469975

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Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations.

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Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations.

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