title: Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination.
abstract: Axonal damage has been associated with aberrant protein trafficking. We examined a newly characterized class of compounds that target nucleo-cytoplasmic shuttling by binding to the catalytic groove of the nuclear export protein XPO1 (also known as CRM1, chromosome region maintenance protein 1). Oral administration of reversible CRM1 inhibitors in preclinical murine models of demyelination significantly attenuated disease progression, even when started after the onset of paralysis. Clinical efficacy was associated with decreased proliferation of immune cells, characterized by nuclear accumulation of cell cycle inhibitors, and preservation of cytoskeletal integrity even in demyelinated axons. Neuroprotection was not limited to models of demyelination, but was also observed in another mouse model of axonal damage (that is, kainic acid injection) and detected in cultured neurons after knockdown of Xpo1, the gene encoding CRM1. A proteomic screen for target molecules revealed that CRM1 inhibitors in neurons prevented nuclear export of molecules associated with axonal damage while retaining transcription factors modulating neuroprotection.
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Haines
authors.affiliation: Division of Clinical Immunology, Department of Medicine, The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Herbin
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Belén
authors.initials: B
authors.lastname: de la Hera
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Oscar G
authors.initials: OG
authors.lastname: Vidaurre
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Moy
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Texas, USA.
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Texas, USA.
authors.forename: Ho Yee Joyce
authors.initials: HY
authors.lastname: Fung
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Albrecht
authors.affiliation: Division of Clinical Immunology, Department of Medicine, The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Alexandropoulos
authors.affiliation: Karyopharm Therapeutics, Natick, Massachusetts, USA.
authors.forename: Dilara
authors.initials: D
authors.lastname: McCauley
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Texas, USA.
authors.forename: Yuh Min
authors.initials: YM
authors.lastname: Chook
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
authors.affiliation: Department of Neurosciences, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Grahame J
authors.initials: GJ
authors.lastname: Kidd
authors.affiliation: Karyopharm Therapeutics, Natick, Massachusetts, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: 1] Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casaccia
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D016896:Treatment Outcome; D000097606:Exportin 1 Protein
chemical_list: D000178:Acrylamides; D028884:Karyopherins; D018696:Neuroprotective Agents; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D000097606:Exportin 1 Protein; C586831:KPT-276