Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination

Jeffery D Haines; Olivier Herbin; Belén de la Hera; Oscar G Vidaurre; Gregory A Moy; Qingxiang Sun; Ho Yee Joyce Fung; Stefanie Albrecht; Konstantina Alexandropoulos; Dilara McCauley; Yuh Min Chook; Tanja Kuhlmann; Grahame J Kidd; Sharon Shacham; Patrizia Casaccia

doi:10.1038/nn.3953

Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination

Nat Neurosci. 2015 Apr;18(4):511-20. doi: 10.1038/nn.3953. Epub 2015 Feb 23.

Authors

Affiliations

¹ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
² Division of Clinical Immunology, Department of Medicine, The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
³ Department of Pharmacology, University of Texas Southwestern Medical Center, Texas, USA.
⁴ Institute of Neuropathology, University Hospital Münster, Münster, Germany.
⁵ Karyopharm Therapeutics, Natick, Massachusetts, USA.
⁶ Department of Neurosciences, Cleveland Clinic, Cleveland, Ohio, USA.
⁷ 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.

PMID: 25706475
PMCID: PMC4522902
DOI: 10.1038/nn.3953

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acrylamides / administration & dosage
Acrylamides / pharmacokinetics
Acrylamides / pharmacology
Active Transport, Cell Nucleus / drug effects
Animals
Axons* / drug effects
Axons* / metabolism
Axons* / pathology
Cell Nucleus / metabolism
Cells, Cultured
Disease Models, Animal
Disease Progression
Drug Evaluation, Preclinical
Encephalomyelitis, Autoimmune, Experimental / drug therapy*
Exportin 1 Protein
Female
Karyopherins / antagonists & inhibitors
Karyopherins / genetics
Karyopherins / metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neuroprotective Agents / administration & dosage
Neuroprotective Agents / pharmacokinetics
Neuroprotective Agents / pharmacology*
Proteomics
Rats
Rats, Sprague-Dawley
Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
Receptors, Cytoplasmic and Nuclear / genetics
Receptors, Cytoplasmic and Nuclear / metabolism*
Thiazoles / administration & dosage
Thiazoles / pharmacokinetics
Thiazoles / pharmacology
Treatment Outcome

Substances

Acrylamides
KPT-276
Karyopherins
Neuroprotective Agents
Receptors, Cytoplasmic and Nuclear
Thiazoles

Abstract

Publication types

MeSH terms

Substances

Grants and funding