title: Intrathecal shRNA-AAV9 inhibits target protein expression in the spinal cord and dorsal root ganglia of adult mice.
abstract: Gene therapy for neurological diseases requires efficient gene delivery to target tissues in the central and peripheral nervous systems. Although adeno-associated virus is one of the most promising vectors for clinical use against neurological diseases, it is difficult to get it across the blood-brain barrier. A clinically practical approach to using a vector based on adeno-associated virus to decrease the expression of a specific gene in both the central and the peripheral nervous system has yet to be established. Here, we analyzed whether upper lumbar intrathecal administration of a therapeutic vector incorporating adeno-associated virus and short-hairpin RNA against superoxide dismutase-1 bypassed the blood-brain barrier to target the spinal cord and dorsal root ganglia. The therapeutic vector effectively suppressed mRNA and protein expression of endogenous superoxide dismutase-1 in the lumbar spinal cord and dorsal root ganglia. Moreover, neither neurological side effects nor toxicity due to the incorporated short-hairpin RNA occurred after the injection. We propose that this approach could be developed into novel therapies for motor neuron diseases and chronic pain conditions, such as complex regional pain syndrome, through silencing of the genes responsible for pathologies in the spinal cord and dorsal root ganglia.
authors.affiliation: Department of Orthopedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hirai
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Enomoto
authors.forename: Akira
authors.initials: A
authors.lastname: Machida
authors.forename: Mariko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kuwahara
authors.forename: Mio
authors.initials: M
authors.lastname: Tajiri
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Hirai
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sotome
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shinomiya
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okawa
authors.forename: Takanori
authors.initials: T
authors.lastname: Yokota
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006358:Hot Temperature; D007278:Injections, Spinal; D051379:Mice; D008813:Mice, Inbred ICR; D010812:Physical Stimulation; D034741:RNA, Small Interfering / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D045442:Rotarod Performance Test; D013116:Spinal Cord / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014110:Touch / Q000502:physiology
chemical_list: D017931:DNA Primers; D034741:RNA, Small Interfering; D013482:Superoxide Dismutase