title: AAV1.NT-3 gene therapy attenuates spontaneous autoimmune peripheral polyneuropathy.
abstract: The spontaneous autoimmune peripheral polyneuropathy (SAPP) model in B7-2 knockout non-obese diabetic mice shares clinical and histological features with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Secondary axonal loss is prominent in the progressive phase of this neuropathy. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulates neurite outgrowth and myelination. The anti-inflammatory and immunomodulatory effects of NT-3 raised considerations of potential efficacy in the SAPP model that could be applicable to CIDP. For this study, scAAV1.tMCK.NT-3 was delivered to the gastrocnemius muscle of 25-week-old SAPP mice. Measurable NT-3 levels were found in the serum at 7-week postgene delivery. The outcome measures included functional, electrophysiological and histological assessments. At week 32, NT-3-treated mice showed increased hind limb grip strength that correlated with improved compound muscle action potential amplitude. Myelinated fiber density was 1.9 times higher in the NT-3-treated group compared with controls and the number of demyelinated axons was significantly lower. The remyelinated nerve fiber population was significantly increased. These improved histopathological parameters from scAAV1.tMCK.NT-3 treatment occurred in the setting of reduced sciatic nerve inflammation. Collectively, these findings suggest a translational application to CIDP.
authors.affiliation: Department of Pediatrics, The Ohio State University, Columbus, OH, USA.|Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Yalvac
authors.affiliation: Department of Physical Medicine and Rehabilitation, The Ohio State University, Columbus, OH, USA.|Department of Neurology, The Ohio State University, Columbus, OH, USA.|Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
authors.forename: W D
authors.initials: WD
authors.lastname: Arnold
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Braganza
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, The Ohio State University, Columbus, OH, USA.|Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.|Department of Neurology, The Ohio State University, Columbus, OH, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Mendell
authors.affiliation: Department of Pediatrics, The Ohio State University, Columbus, OH, USA.|Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.|Department of Neurology, The Ohio State University, Columbus, OH, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Sahenk
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000628:therapy*; D003713:Dendritic Cells / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D008297:Male; D051379:Mice; D020933:Neurotrophin 3 / Q000097:blood / Q000235:genetics*; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating / Q000235:genetics / Q000628:therapy*; D012583:Schwann Cells
chemical_list: D020933:Neurotrophin 3