Fitxers

MaesT.pdf (3.85 MB)

Tipus de document

Article

Versió

Versió publicada

Data de publicació

2020-05-29

Llicència de publicació

cc by (c) Maes et al., 2020
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/173603

Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations

Títol de la revista

Autors

Director/Tutor

ISSN de la revista

Títol del volum

Recurs relacionat

https://doi.org/10.1371/journal.pone.0233468

Resum

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.

Matèries

Malaltia d'Alzheimer, Neuroplasticitat

Matèries (anglès)

Alzheimer's disease, Neuroplasticity

Citació

Col·leccions

Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Institut de Neurociències (UBNeuro))

Citació

MAES, Tamara, et al. Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations. PLoS One. 2020. Vol. 15, num. 5, pags. e0233468. [consulted: 24 of May of 2026]. Available at: https://hdl.handle.net/2445/173603

Exportar metadades

JSON - METS

Compartir registre