Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis
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 (...
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MDPI AG
2022-07-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/7/1420 |
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| author | Fernando Cavalcanti Elena Gonzalez-Rey Mario Delgado Clara P. Falo Leyre Mestre Carmen Guaza Francisco O’Valle Michele M. P. Lufino Jordi Xaus Cristina Mascaró Serena Lunardi Natalia Sacilotto Paola Dessanti David Rotllant Xavier Navarro Mireia Herrando-Grabulosa Carlos Buesa Tamara Maes |
| author_facet | Fernando Cavalcanti Elena Gonzalez-Rey Mario Delgado Clara P. Falo Leyre Mestre Carmen Guaza Francisco O’Valle Michele M. P. Lufino Jordi Xaus Cristina Mascaró Serena Lunardi Natalia Sacilotto Paola Dessanti David Rotllant Xavier Navarro Mireia Herrando-Grabulosa Carlos Buesa Tamara Maes |
| author_sort | Fernando Cavalcanti |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T13:11:03Z |
| format | Article |
| id | doaj.art-df089ff6678843aa91f71f1d603fc7ce |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T13:11:03Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-df089ff6678843aa91f71f1d603fc7ce2023-11-30T21:41:53ZengMDPI AGPharmaceutics1999-49232022-07-01147142010.3390/pharmaceutics14071420Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple SclerosisFernando Cavalcanti0Elena Gonzalez-Rey1Mario Delgado2Clara P. Falo3Leyre Mestre4Carmen Guaza5Francisco O’Valle6Michele M. P. Lufino7Jordi Xaus8Cristina Mascaró9Serena Lunardi10Natalia Sacilotto11Paola Dessanti12David Rotllant13Xavier Navarro14Mireia Herrando-Grabulosa15Carlos Buesa16Tamara Maes17Oryzon Genomics S.A., Carrer Sant Ferran 74, 08940 Cornellà de Llobregat, SpainInstitute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, PTS-Granada, 18016 Granada, SpainInstitute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, PTS-Granada, 18016 Granada, SpainInstitute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, PTS-Granada, 18016 Granada, SpainDepartment of Functional and Systems Neurobiology, Cajal Institute (CSIC), 28034 Madrid, SpainDepartment of Functional and Systems Neurobiology, Cajal Institute (CSIC), 28034 Madrid, SpainDepartment of Pathology, School of Medicine, IBIMER and IBS-Granada, Granada University, 18071 Granada, SpainOryzon Genomics S.A., Carrer Sant Ferran 74, 08940 Cornellà de Llobregat, SpainOryzon Genomics S.A., Carrer Sant Ferran 74, 08940 Cornellà de Llobregat, SpainOryzon Genomics S.A., Carrer Sant Ferran 74, 08940 Cornellà de Llobregat, SpainOryzon Genomics S.A., Carrer Sant Ferran 74, 08940 Cornellà de Llobregat, SpainOryzon Genomics S.A., Carrer Sant Ferran 74, 08940 Cornellà de Llobregat, SpainOryzon Genomics S.A., Carrer Sant Ferran 74, 08940 Cornellà de Llobregat, SpainOryzon Genomics S.A., Carrer Sant Ferran 74, 08940 Cornellà de Llobregat, SpainDepartament de Biologia Cellular, Fisiologia i Immunologia, Institut de Neurociències, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 08193 Barcelona, SpainDepartament de Biologia Cellular, Fisiologia i Immunologia, Institut de Neurociències, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 08193 Barcelona, SpainOryzon Genomics S.A., Carrer Sant Ferran 74, 08940 Cornellà de Llobregat, SpainOryzon Genomics S.A., Carrer Sant Ferran 74, 08940 Cornellà de Llobregat, SpainLysine 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.https://www.mdpi.com/1999-4923/14/7/1420epigeneticsKDM1Avafidemstatmultiple sclerosisneuroinflammation |
| spellingShingle | Fernando Cavalcanti Elena Gonzalez-Rey Mario Delgado Clara P. Falo Leyre Mestre Carmen Guaza Francisco O’Valle Michele M. P. Lufino Jordi Xaus Cristina Mascaró Serena Lunardi Natalia Sacilotto Paola Dessanti David Rotllant Xavier Navarro Mireia Herrando-Grabulosa Carlos Buesa Tamara Maes Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis Pharmaceutics epigenetics KDM1A vafidemstat multiple sclerosis neuroinflammation |
| title | Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis |
| title_full | Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis |
| title_fullStr | Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis |
| title_full_unstemmed | Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis |
| title_short | Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis |
| title_sort | efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the kdm1a rcor1 hdac epigenetic axis in multiple sclerosis |
| topic | epigenetics KDM1A vafidemstat multiple sclerosis neuroinflammation |
| url | https://www.mdpi.com/1999-4923/14/7/1420 |
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