title: Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy.
abstract: Inherited demyelinating peripheral neuropathies are progressive incurable diseases without effective treatment. To develop a gene therapy approach targeting myelinating Schwann cells that can be translatable, we delivered a lentiviral vector using a single lumbar intrathecal injection and a myelin-specific promoter. The human gene of interest, GJB1, which is mutated in X-linked Charcot-Marie-Tooth Disease (CMT1X), was delivered intrathecally into adult Gjb1-null mice, a genetically authentic model of CMT1X that develops a demyelinating peripheral neuropathy. We obtained widespread, stable, and cell-specific expression of connexin32 in up to 50% of Schwann cells in multiple lumbar spinal roots and peripheral nerves. Behavioral and electrophysiological analysis revealed significantly improved motor performance, quadriceps muscle contractility, and sciatic nerve conduction velocities. Furthermore, treated mice exhibited reduced numbers of demyelinated and remyelinated fibers and fewer inflammatory cells in lumbar motor roots, as well as in the femoral motor and sciatic nerves. This study demonstrates that a single intrathecal lentiviral gene delivery can lead to Schwann cell-specific expression in spinal roots extending to multiple peripheral nerves. This clinically relevant approach improves the phenotype of an inherited neuropathy mouse model and provides proof of principle for treating inherited demyelinating neuropathies.
authors.affiliation: Neuroscience Laboratory, Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus;
authors.forename: Alexia
authors.initials: A
authors.lastname: Kagiava
authors.affiliation: Neuroscience Laboratory, Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus;
authors.forename: Irene
authors.initials: I
authors.lastname: Sargiannidou
authors.affiliation: Laboratory of Animal Physiology, Department of Zoology, School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
authors.forename: George
authors.initials: G
authors.lastname: Theophilidis
authors.affiliation: Neuroscience Laboratory, Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus;
authors.forename: Christos
authors.initials: C
authors.lastname: Karaiskos
authors.affiliation: Department of Molecular Virology, Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus;
authors.forename: Jan
authors.initials: J
authors.lastname: Richter
authors.affiliation: Department of Molecular Virology, Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus;
authors.forename: Stavros
authors.initials: S
authors.lastname: Bashiardes
authors.affiliation: Neuroscience Laboratory, Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus;
authors.forename: Natasa
authors.initials: N
authors.lastname: Schiza
authors.affiliation: Department of Molecular Pathology and Electron Microscopy, Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus;
authors.forename: Marianna
authors.initials: M
authors.lastname: Nearchou
authors.affiliation: Department of Molecular Virology, Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus;
authors.forename: Christina
authors.initials: C
authors.lastname: Christodoulou
authors.affiliation: Department of Neurology, The University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Steven S
authors.initials: SS
authors.lastname: Scherer
authors.affiliation: Neuroscience Laboratory, Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus; Neurology Clinics, Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus kleopa@cing.ac.cy.
authors.forename: Kleopas A
authors.initials: KA
authors.lastname: Kleopa
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D003711:Demyelinating Diseases / Q000235:genetics*; D015316:Genetic Therapy; D006801:Humans; D009186:Myelin Sheath / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism
keywords: Charcot–Marie–Tooth disease; connexin32; demyelinating neuropathy; gene therapy; peripheral nerve