title: AAV1.NT-3 gene therapy for charcot-marie-tooth neuropathy.
abstract: Charcot-Marie-Tooth (CMT) neuropathies represent a heterogeneous group of peripheral nerve disorders affecting 1 in 2,500 persons. One variant, CMT1A, is a primary Schwann cell (SC) disorder, and represents the single most common variant. In previous studies, we showed that neurotrophin-3 (NT-3) improved the trembler(J) (Tr(J)) mouse and also showed efficacy in CMT1A patients. Long-term treatment with NT-3 was not possible related to its short half-life and lack of availability. This led to considerations of NT-3 gene therapy via adenoassociated virus (AAV) delivery to muscle, acting as secretory organ for widespread distribution of this neurotrophic agent. In the Tr(J) model of demyelinating CMT, rAAV1.NT-3 therapy resulted in measurable NT-3 secretion levels in blood sufficient to provide improvement in motor function, histopathology, and electrophysiology of peripheral nerves. Furthermore, we showed that the compound muscle action potential amplitude can be used as surrogate for functional improvement and established the therapeutic dose and a preferential muscle-specific promoter to achieve sustained NT-3 levels. These studies of intramuscular (i.m.) delivery of rAAV1.NT-3 serve as a template for future CMT1A clinical trials with a potential to extend treatment to other nerve diseases with impaired nerve regeneration.
authors.affiliation: Department of Pediatrics, The Ohio State University/Nationwide Children's Hospital, Columbus, Ohio, USA; Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Department of Neurology, The Ohio State University/Nationwide Children's Hospital, Columbus, Ohio, USA; Department of Pathology, The Ohio State University/Nationwide Children's Hospital, Columbus, Ohio, USA. Electronic address: Zarife.Sahenk@nationwidechildrens.org.
authors.forename: Zarife
authors.initials: Z
authors.lastname: Sahenk
authors.affiliation: Department of Neurology, The Ohio State University/Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Gloria
authors.initials: G
authors.lastname: Galloway
authors.affiliation: Department of Pediatrics, The Ohio State University/Nationwide Children's Hospital, Columbus, Ohio, USA; Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Kelly Reed
authors.initials: KR
authors.lastname: Clark
authors.affiliation: Department of Pediatrics, The Ohio State University/Nationwide Children's Hospital, Columbus, Ohio, USA; Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Vinod
authors.initials: V
authors.lastname: Malik
authors.affiliation: Department of Pediatrics, The Ohio State University/Nationwide Children's Hospital, Columbus, Ohio, USA; Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Louise R
authors.initials: LR
authors.lastname: Rodino-Klapac
authors.affiliation: Department of Pediatrics, The Ohio State University/Nationwide Children's Hospital, Columbus, Ohio, USA; Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
authors.affiliation: Department of Pediatrics, The Ohio State University/Nationwide Children's Hospital, Columbus, Ohio, USA; Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, The Ohio State University/Nationwide Children's Hospital, Columbus, Ohio, USA; Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Cilwyn
authors.initials: C
authors.lastname: Braganza
authors.affiliation: Department of Pediatrics, The Ohio State University/Nationwide Children's Hospital, Columbus, Ohio, USA; Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Chrystal
authors.initials: C
authors.lastname: Montgomery
authors.affiliation: Department of Pediatrics, The Ohio State University/Nationwide Children's Hospital, Columbus, Ohio, USA; Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Department of Neurology, The Ohio State University/Nationwide Children's Hospital, Columbus, Ohio, USA; Department of Pathology, The Ohio State University/Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000473:pathology / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D057809:HEK293 Cells; D006801:Humans; D007273:Injections, Intramuscular; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D009416:Nerve Regeneration; D020933:Neurotrophin 3 / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D010525:Peripheral Nerves / Q000473:pathology / Q000502:physiology*
chemical_list: D020933:Neurotrophin 3