title: Intrathecal AAV serotype 9-mediated delivery of shRNA against TRPV1 attenuates thermal hyperalgesia in a mouse model of peripheral nerve injury.
abstract: Gene therapy for neuropathic pain requires efficient gene delivery to both central and peripheral nervous systems. We previously showed that an adenoassociated virus serotype 9 (AAV9) vector expressing short-hairpin RNA (shRNA) could suppress target molecule expression in the dorsal root ganglia (DRG) and spinal cord upon intrathecal injection. To evaluate the therapeutic potential of this approach, we constructed an AAV9 vector encoding shRNA against vanilloid receptor 1 (TRPV1), which is an important target gene for acute pain, but its role in chronic neuropathic pain remains unclear. We intrathecally injected it into the subarachnoid space at the upper lumbar spine of mice 3 weeks after spared nerve injury (SNI). Delivered shTRPV1 effectively suppressed mRNA and protein expression of TRPV1 in the DRG and spinal cord, and it attenuated nerve injury-induced thermal allodynia 10-28 days after treatment. Our study provides important evidence for the contribution of TRPV1 to thermal hypersensitivity in neuropathic pain and thus establishes intrathecal AAV9-mediated gene delivery as an investigative and potentially therapeutic platform for the nervous system.
authors: Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Takashi
authors: T
authors: Hirai
authors: Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: enomorth@tmd.ac.jp.
authors: Mitsuhiro
authors: M
authors: Enomoto
authors: Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Hidetoshi
authors: H
authors: Kaburagi
authors: Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Shinichi
authors: S
authors: Sotome
authors: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Kie
authors: K
authors: Yoshida-Tanaka
authors: Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Madoka
authors: M
authors: Ukegawa
authors: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Hiroya
authors: H
authors: Kuwahara
authors: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Mariko
authors: M
authors: Yamamoto
authors: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Mio
authors: M
authors: Tajiri
authors: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Haruka
authors: H
authors: Miyata
authors: Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.
authors: Yukihiko
authors: Y
authors: Hirai
authors: Division of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki, Japan.
authors: Makoto
authors: M
authors: Tominaga
authors: Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Kenichi
authors: K
authors: Shinomiya
authors: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Hidehiro
authors: H
authors: Mizusawa
authors: Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Atsushi
authors: A
authors: Okawa
authors: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: yokonuro@tmd.ac.jp.
authors: Takanori
authors: T
authors: Yokota
mesh_terms: D000818:Animals; D001483:Base Sequence; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D015870:Gene Expression; D023061:Gene Order; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D006930:Hyperalgesia / Q000235:genetics* / Q000628:therapy; D007278:Injections, Spinal; D051379:Mice; D059348:Peripheral Nerve Injuries / Q000235:genetics / Q000628:therapy; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D050916:TRPV Cation Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse