TY - JOUR
T1 - Behavioral assessment of neuropathic pain, fatigue, and anxiety in experimental autoimmune encephalomyelitis (EAE) and attenuation by interleukin-10 gene therapy
AU - Grace, Peter M.
AU - Loram, Lisa C.
AU - Christianson, John P.
AU - Strand, Keith A.
AU - Flyer-Adams, Johanna G.
AU - Penzkover, Kathryn R.
AU - Forsayeth, John R.
AU - van Dam, Anne Marie
AU - Mahoney, Melissa J.
AU - Maier, Steven F.
AU - Chavez, Raymond A.
AU - Watkins, Linda R.
N1 - Funding Information:
This work was generously supported by a National Multiple Sclerosis Society Grant (L.R.W., P.M.G.), and an NIH SBIR Grant R43NS81878 (R.A.C.). P.M.G. is an Australian National Health and Medical Research Council C.J. Martin Fellow (ID 1054091; 2013-). J.R.F., R.A.C. and L.R.W. are co-founders of Xalud Therapeutics, a start up company working toward bringing XT-101 to human clinical trials. R.A.C. is the Vice President of Research and Development of Xalud; J.R.F. and L.R.W. serve on the Scientific Advisory Board of Xalud.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
KW - Dark agouti
KW - Myelin oligodendrocyte glycoprotein
KW - Neuroinflammation
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U2 - 10.1016/j.bbi.2016.05.012
DO - 10.1016/j.bbi.2016.05.012
M3 - Article
C2 - 27189037
AN - SCOPUS:84969512975
SN - 0889-1591
VL - 59
SP - 49
EP - 54
JO - Brain, behavior, and immunity
JF - Brain, behavior, and immunity
ER -