title: Behavioral assessment of neuropathic pain, fatigue, and anxiety in experimental autoimmune encephalomyelitis (EAE) and attenuation by interleukin-10 gene therapy.
abstract: Relapsing-remitting multiple sclerosis is commonly associated with motor impairments, neuropathic pain, fatigue, mood disorders, and decreased life expectancy. However, preclinical pharmacological studies predominantly rely on clinical scoring of motor deficit as the sole behavioral endpoint. Thus, the translational potential of these studies is limited. Here, we have assessed the therapeutic potential of a novel anti-inflammatory interleukin-10 (IL-10) non-viral gene therapy formulation (XT-101-R) in a rat relapsing remitting experimental autoimmune encephalomyelitis (EAE) model. EAE induced motor deficits and neuropathic pain as reflected by induction of low-threshold mechanical allodynia, suppressed voluntary wheel running, decreased social exploration, and was associated with markedly enhanced mortality. We also noted that voluntary wheel running was depressed prior to the onset of motor deficit, and may therefore serve as a predictor of clinical symptoms onset. XT-101-R was intrathecally dosed only once at the onset of motor deficits, and attenuated each of the EAE-induced symptoms and improved survival, relative to vehicle control. This is the first pharmacological assessment of such a broad range of EAE symptoms, and provides support for IL-10 gene therapy as a clinical strategy for the treatment of multiple sclerosis.
authors.affiliation: Department of Psychology and The Center for Neuroscience, University of Colorado, Boulder, CO, USA. Electronic address: peter.grace@colorado.edu.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Grace
authors.affiliation: Department of Psychology and The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Loram
authors.affiliation: Department of Psychology and The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Christianson
authors.affiliation: Department of Psychology and The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Strand
authors.affiliation: Department of Psychology and The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
authors.forename: Johanna G
authors.initials: JG
authors.lastname: Flyer-Adams
authors.affiliation: Department of Chemical & Biological Engineering Pharmacology, University of Colorado, Boulder, CO, USA.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Penzkover
authors.affiliation: Xalud Therapeutics, San Francisco, CA, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Forsayeth
authors.affiliation: Department of Anatomy and Neurosciences, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: van Dam
authors.affiliation: Department of Chemical & Biological Engineering Pharmacology, University of Colorado, Boulder, CO, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Mahoney
authors.affiliation: Department of Psychology and The Center for Neuroscience, University of Colorado, Boulder, CO, USA.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
authors.affiliation: Xalud Therapeutics, San Francisco, CA, USA.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Chavez
authors.affiliation: Department of Psychology and The Center for Neuroscience, University of Colorado, Boulder, CO, USA; Xalud Therapeutics, San Francisco, CA, USA.
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
mesh_terms: D000818:Animals; D001007:Anxiety / Q000523:psychology* / Q000628:therapy*; D001522:Behavior, Animal / Q000187:drug effects*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000523:psychology* / Q000628:therapy*; D005106:Exploratory Behavior; D005221:Fatigue / Q000523:psychology* / Q000628:therapy*; D015316:Genetic Therapy; D006930:Hyperalgesia / Q000523:psychology / Q000628:therapy; D007278:Injections, Spinal; D016753:Interleukin-10 / Q000235:genetics*; D007398:Interpersonal Relations; D008017:Life Expectancy; D008297:Male; D009043:Motor Activity; D009437:Neuralgia / Q000523:psychology* / Q000628:therapy*; D051381:Rats
chemical_list: D016753:Interleukin-10
keywords: Dark agouti; Myelin oligodendrocyte glycoprotein; Neuroinflammation