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http://hdl.handle.net/2445/173603
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DC Field | Value | Language |
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dc.contributor.author | Maes, Tamara | - |
dc.contributor.author | Mascaró, Cristina | - |
dc.contributor.author | Rotllant, David | - |
dc.contributor.author | Pio Lufino, Michele Matteo | - |
dc.contributor.author | Estiarte, Angels | - |
dc.contributor.author | Guibourt, Nathalie | - |
dc.contributor.author | Cavalcanti, Fernando | - |
dc.contributor.author | Griñán Ferré, Christian | - |
dc.contributor.author | Pallàs i Llibería, Mercè, 1964- | - |
dc.contributor.author | Nadal, Roser | - |
dc.contributor.author | Armario, Antonio | - |
dc.contributor.author | Ferrer, Isidro (Ferrer Abizanda) | - |
dc.contributor.author | Ortega, Alberto | - |
dc.contributor.author | Valls, Nuria | - |
dc.contributor.author | Fyfe, Matthew | - |
dc.contributor.author | Martinell, Marc | - |
dc.contributor.author | Castro Palomino, Julio | - |
dc.contributor.author | Buea Arjol, Carlos | - |
dc.date.accessioned | 2021-02-03T10:40:55Z | - |
dc.date.available | 2021-02-03T10:40:55Z | - |
dc.date.issued | 2020-05-29 | - |
dc.identifier.uri | http://hdl.handle.net/2445/173603 | - |
dc.description.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. | - |
dc.format.extent | 26 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Public Library of Science (PLoS) | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.1371/journal.pone.0233468 | - |
dc.relation.ispartof | PLoS One, 2020, vol. 15, num. 5, p. e0233468 | - |
dc.relation.uri | https://doi.org/10.1371/journal.pone.0233468 | - |
dc.rights | cc by (c) Maes et al., 2020 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | - |
dc.source | Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica) | - |
dc.subject.classification | Malaltia d'Alzheimer | - |
dc.subject.classification | Neuroplasticitat | - |
dc.subject.other | Alzheimer's disease | - |
dc.subject.other | Neuroplasticity | - |
dc.title | Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 707624 | - |
dc.date.updated | 2021-01-25T08:12:43Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 32469975 | - |
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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