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

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Maes T, Mascaro C, Rotllant D, Lufino MMP, Estiarte A, Guibourt N, Cavalcanti F, Grinan-Ferre C, Pallas M, Nadal R, Armario A, Ferrer I, Ortega A, Valls N, Fyfe M, Martinell M, Castro Palomino JC, Buesa Arjol C

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

PLoS One. 2020 May 29;15(5):e0233468. doi: 10.1371/journal.pone.0233468. eCollection 2020.

PubMed ID

32469975 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Vafidemstat	Amine oxidase [flavin-containing] B	Protein	Humans	Unknown	Inhibitor	Details
Vafidemstat	Lysine-specific histone demethylase 1A	Protein	Humans	Unknown	Inhibitor Binder Modulator	Details