title: Intrathecal administration of IGF-I by AAVrh10 improves sensory and motor deficits in a mouse model of diabetic neuropathy.
abstract: Different adeno-associated virus (AAV) serotypes efficiently transduce neurons from central and peripheral nervous systems through various administration routes. Direct administration of the vectors to the cerebrospinal fluid (CSF) could be an efficient and safe strategy. Here, we show that lumbar puncture of a nonhuman AAV leads to wide and stable distribution of the vector along the spinal cord in adult mice. AAVrh10 efficiently and specifically infects neurons, both in dorsal root ganglia (60% total sensory neurons) and in the spinal cord (up to one-third of α-motor neurons). As a proof of concept, we demonstrate the efficacy of AAVrh10 in a mouse model of diabetic neuropathy, in which intrathecal delivery of the vector coding for insulin-like growth factor (IGF-I) favored the release of the therapeutic protein into the CSF through its expression by sensory and motor neurons. IGF-I-treated diabetic animals showed increased vascular endothelial growth factor expression, activation of Akt/PI3K pathway, and stimulated nerve regeneration and myelination in injured limbs. Moreover, we achieved restoration of nerve conduction velocities in both sensory and motor nerves by AAVrh10, whereas we reached only sensory nerve improvement with AAV1. Our results indicate that intrathecal injection of AAVrh10 is a promising tool to design gene therapy approaches for sensorimotor diseases.
authors.affiliation: Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona , Bellaterra, Barcelona, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Homs
authors.affiliation: Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona , Bellaterra, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Pagès
authors.affiliation: Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona , Bellaterra, Barcelona, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Ariza
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autònoma de Barcelona , Bellaterra, Barcelona, Spain ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III , Spain.
authors.forename: Caty
authors.initials: C
authors.lastname: Casas
authors.affiliation: Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona , Bellaterra, Barcelona, Spain ; Institut Català de Recerca i Estudis Avançats (ICREA) , Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Chillón
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autònoma de Barcelona , Bellaterra, Barcelona, Spain ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III , Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Navarro
authors.affiliation: Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona , Bellaterra, Barcelona, Spain.
authors.forename: Assumpció
authors.initials: A
authors.lastname: Bosch