Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis
Cavalcanti, Fernando (Oryzon Genomics S.A)
Gonzalez-Rey, Elena (Instituto de Parasitología y Biomedicina "López-Neyra")
Delgado, Mario (Instituto de Parasitología y Biomedicina "López-Neyra")
Falo, Clara P. (Instituto de Parasitología y Biomedicina "López-Neyra")
Mestre, Leyre (Instituto Cajal (Consejo Superior de Investigaciones Científicas))
Guaza, Carmen (Instituto Cajal (Consejo Superior de Investigaciones Científicas))
O'Valle, Francisco (Univeridad de Granada. Departamento de Patologia)
Lufino, Michele M. P. (Oryzon Genomics S.A)
Xaus, Jordi (Oryzon Genomics S.A)
Mascaró, Cristina (Oryzon Genomics S.A)
Lunardi, Serena (Oryzon Genomics S.A)
Sacilotto, Natalia (Oryzon Genomics S.A)
Dessanti, Paola (Oryzon Genomics S.A)
Rotllant, David (Oryzon Genomics S.A)
Navarro, X. (Xavier) (Universitat Autònoma de Barcelona. Institut de Neurociències)
Herrando-Grabulosa, Mireia (Universitat Autònoma de Barcelona. Institut de Neurociències)
Buesa, Carlos (Oryzon Genomics S.A)
Maes, Tamara (Oryzon Genomics S.A)

Data:	2022
Descripció:	33 pàg.
Resum:	Lysine specific demethylase 1 (LSD1; also known as KDM1A), is an epigenetic modulator that modifies the histone methylation status. KDM1A forms a part of protein complexes that regulate the expression of genes involved in the onset and progression of diseases such as cancer, central nervous system (CNS) disorders, viral infections, and others. Vafidemstat (ORY-2001) is a clinical stage inhibitor of KDM1A in development for the treatment of neurodegenerative and psychiatric diseases. However, the role of ORY-2001 targeting KDM1A in neuroinflammation remains to be explored. Here, we investigated the effect of ORY-2001 on immune-mediated and virus-induced encephalomyelitis, two experimental models of multiple sclerosis and neuronal damage. Oral administration of ORY-2001 ameliorated clinical signs, reduced lymphocyte egress and infiltration of immune cells into the spinal cord, and prevented demyelination. Interestingly, ORY-2001 was more effective and/or faster acting than a sphingosine 1-phosphate receptor antagonist in the effector phase of the disease and reduced the inflammatory gene expression signature characteristic ofEAE in the CNS of mice more potently. In addition, ORY-2001 induced gene expression changes concordant with a potential neuroprotective function in the brain and spinal cord and reduced neuronal glutamate excitotoxicity-derived damage in explants. These results pointed to ORY-2001 as a promising CNS epigenetic drug able to target neuroinflammatory and neurodegenerative diseases and provided preclinical support for the subsequent design of early-stage clinical trials.
Ajuts:	Ministerio de Economía y Competitividad RTC-2016-4955-1 Ministerio de Ciencia, Innovación y Universidades CIIP-20152001/E9683
Nota:	Altres ajuts: Oryzon Genomics, S.A; CDTI: EDOTEM (IDI-20180117)
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Epigenetics ; KDM1A ; Vafidemstat ; Multiple sclerosis ; Neuroinflammation ; SDG 3 - Good Health and Well-being
Publicat a:	Pharmaceutics, Vol. 14 Núm. 7 (2022) , p. 1420, ISSN 1999-4923

DOI: 10.3390/pharmaceutics14071420
PMID: 35890315

33 p, 8.1 MB

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