Decreased spinal cord opioid receptor mRNA expression and antinociception in a Theiler's murine encephalomyelitis virus model of multiple sclerosis

Abstract Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR. Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalomyelitis virus. The compound reduced lymphocyte egress and infiltration of immune cells in the spinal cord and prevented demyelination. 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 induction of the inflammatory gene expression signature in the central nervous system more potently. Gene expression changes and axonal protection in animals, and protection against glutamate excitoxicity in spinal cord explants support that ORY-2001 has neuroprotective qualities. Conclusions ORY-2001 exerts therapeutic activity in two mouse models of multiple sclerosis. The anti-inflammatory properties of ORY-2001 are being tested in a Phase IIa clinical trial in patients with relapse remitting and secondary progressive multiple sclerosis, and in severely ill COVID-19 patients at risk for acute respiratory distress syndrome.

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Efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the KDM1A/RCOR1/HDAC epigenetic axis in multiple sclerosis

10.21203/rs.3.rs-114482/v1 ◽

2020 ◽

Author(s):

Fernando Cavalcanti ◽

Elena Gonzalez-Rey ◽

Mario Delgado ◽

Leyre Mestre ◽

Carmen Guaza ◽

...

Keyword(s):

Gene Expression ◽

Multiple Sclerosis ◽

Spinal Cord ◽

Experimental Autoimmune Encephalomyelitis ◽

Gene Expression Signature ◽

Autoimmune Encephalomyelitis ◽

Theiler's Murine Encephalomyelitis Virus ◽

Theiler’S Murine Encephalomyelitis Virus ◽

Encephalomyelitis Virus ◽

Experimental Autoimmune

Abstract Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR.Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalomyelitis virus. The compound reduced lymphocyte egress and infiltration of immune cells in the spinal cord and prevented demyelination. 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 induction of the inflammatory gene expression signature in the central nervous system more potently. Gene expression changes and axonal protection in animals, and protection against glutamate excitoxicity in spinal cord explants support that ORY-2001 has neuroprotective qualities.Conclusions ORY-2001 exerts therapeutic activity in two mouse models of multiple sclerosis. The anti-inflammatory properties of ORY-2001 are being tested in a Phase IIa clinical trial in patients with relapse remitting and secondary progressive multiple sclerosis, and in severely ill COVID-19 patients at risk for acute respiratory distress syndrome.

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Efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the KDM1A/RCOR1/HDAC epigenetic axis in multiple sclerosis

10.21203/rs.3.rs-114482/v5 ◽

2021 ◽

Author(s):

Fernando Cavalcanti ◽

Elena Gonzalez-Rey ◽

Mario Delgado ◽

Leyre Mestre ◽

Carmen Guaza ◽

...

Keyword(s):

Gene Expression ◽

Multiple Sclerosis ◽

Spinal Cord ◽

Experimental Autoimmune Encephalomyelitis ◽

Gene Expression Signature ◽

Autoimmune Encephalomyelitis ◽

Theiler's Murine Encephalomyelitis Virus ◽

Theiler’S Murine Encephalomyelitis Virus ◽

Encephalomyelitis Virus ◽

Experimental Autoimmune

Abstract Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR. Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalomyelitis virus. The compound reduced lymphocyte egress and infiltration of immune cells in the spinal cord and prevented demyelination. 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 induction of the inflammatory gene expression signature in the central nervous system more potently. Gene expression changes and axonal protection in animals, and protection against glutamate excitoxicity in spinal cord explants support that ORY-2001 has neuroprotective qualities. Conclusions ORY-2001 exerts therapeutic activity in two mouse models of multiple sclerosis. The anti-inflammatory properties of ORY-2001 are being tested in a Phase IIa clinical trial in patients with relapse remitting and secondary progressive multiple sclerosis, and in severely ill COVID-19 patients at risk for acute respiratory distress syndrome.

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Efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the KDM1A/RCOR1/HDAC epigenetic axis in multiple sclerosis

10.21203/rs.3.rs-114482/v2 ◽

2020 ◽

Author(s):

Fernando Cavalcanti ◽

Elena Gonzalez-Rey ◽

Mario Delgado ◽

Leyre Mestre ◽

Carmen Guaza ◽

...

Keyword(s):

Gene Expression ◽

Multiple Sclerosis ◽

Spinal Cord ◽

Experimental Autoimmune Encephalomyelitis ◽

Gene Expression Signature ◽

Autoimmune Encephalomyelitis ◽

Theiler's Murine Encephalomyelitis Virus ◽

Theiler’S Murine Encephalomyelitis Virus ◽

Encephalomyelitis Virus ◽

Experimental Autoimmune

Abstract Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR.Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalomyelitis virus. The compound reduced lymphocyte egress and infiltration of immune cells in the spinal cord and prevented demyelination. 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 induction of the inflammatory gene expression signature in the central nervous system more potently. Gene expression changes and axonal protection in animals, and protection against glutamate excitoxicity in spinal cord explants support that ORY-2001 has neuroprotective qualities.Conclusions ORY-2001 exerts therapeutic activity in two mouse models of multiple sclerosis. The anti-inflammatory properties of ORY-2001 are being tested in a Phase IIa clinical trial in patients with relapse remitting and secondary progressive multiple sclerosis, and in severely ill COVID-19 patients at risk for acute respiratory distress syndrome.

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Comparison of Reported Spinal Cord Lesions in Progressive Multiple Sclerosis with Theiler’s Murine Encephalomyelitis Virus Induced Demyelinating Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20040989 ◽

2019 ◽

Vol 20 (4) ◽

pp. 989 ◽

Cited By ~ 4

Author(s):

Eva Leitzen ◽

Wen Jin ◽

Vanessa Herder ◽

Andreas Beineke ◽

Suliman Elmarabet ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Axonal Degeneration ◽

Demyelinating Disease ◽

Progressive Multiple Sclerosis ◽

Axonal Damage ◽

Theiler's Murine Encephalomyelitis Virus ◽

Consistent Finding ◽

Theiler’S Murine Encephalomyelitis Virus ◽

Encephalomyelitis Virus

Background: Spinal cord (SC) lesions in Theiler’s murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) resemble important features of brain lesions in progressive multiple sclerosis (MS) including inflammation, demyelination, and axonal damage. The aim of the present study was a comparison of SC lesions in MS and TMEV-IDD focusing on spatial and temporal distribution of demyelination, inflammation, SC atrophy (SCA), and axonal degeneration/loss in major descending motor pathways. Methods: TMEV and mock-infected mice were investigated clinically once a week. SC tissue was collected at 42, 98, 147, and 196 days post infection, and investigated using hematoxylin and eosin (HE) staining, immunohistochemistry targeting myelin basic protein (demyelination), Mac3 (microglia/macrophages), phosphorylated neurofilaments (axonal damage) and transmission electron microscopy. Results: Demyelination prevailed in SC white matter in TMEV-IDD, contrasting a predominant gray matter involvement in MS. TMEV-infected mice revealed a significant loss of axons similar to MS. Ultrastructural analysis in TMEV-IDD revealed denuded axons, degenerative myelin changes, axonal degeneration, as well as remyelination. SCA is a consistent finding in the SC of MS patients and was also detected at a late time point in TMEV-IDD. Conclusion: This comparative study further indicates the suitability of TMEV-IDD as animal model also for the investigation of progressive SC lesions in MS.

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Efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the KDM1A/RCOR1/HDAC epigenetic axis in multiple sclerosis

10.21203/rs.3.rs-114482/v4 ◽

2021 ◽

Author(s):

Fernando Cavalcanti ◽

Elena Gonzalez-Rey ◽

Mario Delgado ◽

Leyre Mestre ◽

Carmen Guaza ◽

...

Keyword(s):

Gene Expression ◽

Multiple Sclerosis ◽

Spinal Cord ◽

Experimental Autoimmune Encephalomyelitis ◽

Gene Expression Signature ◽

Autoimmune Encephalomyelitis ◽

Theiler's Murine Encephalomyelitis Virus ◽

Theiler’S Murine Encephalomyelitis Virus ◽

Encephalomyelitis Virus ◽

Experimental Autoimmune

Abstract Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR. Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalomyelitis virus. The compound reduced lymphocyte egress and infiltration of immune cells in the spinal cord and prevented demyelination. 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 induction of the inflammatory gene expression signature in the central nervous system more potently. Gene expression changes and axonal protection in animals, and protection against glutamate excitoxicity in spinal cord explants support that ORY-2001 has neuroprotective qualities. Conclusions ORY-2001 exerts therapeutic activity in two mouse models of multiple sclerosis. The anti-inflammatory properties of ORY-2001 are being tested in a Phase IIa clinical trial in patients with relapse remitting and secondary progressive multiple sclerosis, and in severely ill COVID-19 patients at risk for acute respiratory distress syndrome.

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