5e1cebd651ad0e56ae2285e79e8d5380 pharmaceutics_14_01420_v3.pdf 1dcc0509d11846228f53546551cd619022825aeb pharmaceutics_14_01420_v3.pdf fc433e1314c3c292ab5e1952ce1f3dd3e963315f796265c2689573c405e92d66 pharmaceutics_14_01420_v3.pdf Title: Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis Subject: 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. Keywords: epigenetics; KDM1A; vafidemstat; multiple sclerosis; neuroinflammation 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 and Tamara Maes Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Jul 21 08:20:43 2022 CEST ModDate: Thu Jul 21 08:29:45 2022 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 33 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 8476075 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- SOZKOC+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 CCUGLD+VnURWPalladioL Type 1 Custom yes yes no 15 0 RQFMPA+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 LMITSE+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 BNXXSX+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 IAFAOG+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 47 0 LEVXPH+EURM10 Type 1 Builtin yes yes no 75 0 FGLHJM+CMSY10 Type 1 Builtin yes yes no 82 0 MPUDFL+PazoMath Type 1 Builtin yes yes no 104 0 DUJUUF+PazoMath-Italic Type 1 Builtin yes yes no 108 0 NUUXUW+VnURWPalladioL-Italic Type 1 Custom yes yes no 217 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-03-25 02:30:38 CET RepresentationInformation: pharmaceutics_14_01420_v3.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-02-23 05:57:00 CET Size: 8476075 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 569 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Reagents and Resources Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Animals and Ethic Statement Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Induction and Treatment of Experimental Autoimmune Encephalomyelitis (EAE) Model Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Induction and Treatment of Theiler’s Murine Encephalomyelitis Virus (TMEV) Model Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Evaluation of Motor Function in TMEV Model Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Tissue Collection and Cell Isolation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Histopathological Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Flow Cytometry Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Determination of Autoreactive Response Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Determination of Autoantibodies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Spinal Cord Organotypic Cultures and Excitotoxicity Assays Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Analysis of Gene Expression Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Biochemical Assays Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Cellular Assays Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Children: Item: Title: Treatment with ORY-2001 Protects from Chronic EAE Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: ORY-2001 Reduces Inflammatory Infiltration and Demyelination in EAE Mice Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Treatment with ORY-2001 Improves Motor Function and Reduces the Clinical Score in the TMEV Model of Multiple Sclerosis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: ORY-2001 Protects Motoneurons from Chronic Excitotoxic Stress Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Comparison of the Effects Exerted by ORY-2001 and Current Oral Drugs for the Treatment of MS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Gene Expression Regulation by ORY-2001, ORY-LSD1 and FTY720 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Item: Title: ORY-2001 and FTY720 Act through Different Mechanisms of Action Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Item: Title: Patents Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@11758f2a Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@e720b71 Info: Title: Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis 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 and Tamara Maes Subject: 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. 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