PMID- 24322332 OWN - NLM STAT- MEDLINE DCOM- 20141126 LR - 20211021 IS - 1525-0024 (Electronic) IS - 1525-0016 (Print) IS - 1525-0016 (Linking) VI - 22 IP - 2 DP - 2014 Feb TI - Intrathecal AAV serotype 9-mediated delivery of shRNA against TRPV1 attenuates thermal hyperalgesia in a mouse model of peripheral nerve injury. PG - 409-419 LID - S1525-0016(16)31162-5 [pii] LID - 10.1038/mt.2013.247 [doi] AB - 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. FAU - Hirai, Takashi AU - Hirai T AD - Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Enomoto, Mitsuhiro AU - Enomoto M AD - Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: enomorth@tmd.ac.jp. FAU - Kaburagi, Hidetoshi AU - Kaburagi H AD - Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Sotome, Shinichi AU - Sotome S AD - Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Yoshida-Tanaka, Kie AU - Yoshida-Tanaka K AD - Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Ukegawa, Madoka AU - Ukegawa M AD - Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Kuwahara, Hiroya AU - Kuwahara H AD - Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Yamamoto, Mariko AU - Yamamoto M AD - Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Tajiri, Mio AU - Tajiri M AD - Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Miyata, Haruka AU - Miyata H AD - Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Hirai, Yukihiko AU - Hirai Y AD - Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan. FAU - Tominaga, Makoto AU - Tominaga M AD - Division of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki, Japan. FAU - Shinomiya, Kenichi AU - Shinomiya K AD - Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Mizusawa, Hidehiro AU - Mizusawa H AD - Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Okawa, Atsushi AU - Okawa A AD - Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Yokota, Takanori AU - Yokota T AD - Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: yokonuro@tmd.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20131028 PL - United States TA - Mol Ther JT - Molecular therapy : the journal of the American Society of Gene Therapy JID - 100890581 RN - 0 (RNA, Messenger) RN - 0 (RNA, Small Interfering) RN - 0 (TRPV Cation Channels) RN - 0 (TRPV1 protein, mouse) SB - IM MH - Animals MH - Base Sequence MH - Dependovirus/*genetics/immunology MH - Disease Models, Animal MH - Female MH - Ganglia, Spinal/metabolism MH - Gene Expression MH - Gene Order MH - Gene Silencing MH - Gene Transfer Techniques MH - Genetic Therapy MH - Genetic Vectors/administration & dosage/*genetics/immunology MH - Hyperalgesia/*genetics/therapy MH - Injections, Spinal MH - Mice MH - Peripheral Nerve Injuries/genetics/therapy MH - RNA Interference MH - RNA, Messenger/genetics/metabolism MH - RNA, Small Interfering/chemistry/*genetics/metabolism MH - Spinal Cord/metabolism MH - TRPV Cation Channels/chemistry/*genetics/metabolism PMC - PMC3916042 EDAT- 2013/12/11 06:00 MHDA- 2014/12/15 06:00 PMCR- 2015/02/01 CRDT- 2013/12/11 06:00 PHST- 2013/03/04 00:00 [received] PHST- 2013/10/17 00:00 [accepted] PHST- 2013/12/11 06:00 [entrez] PHST- 2013/12/11 06:00 [pubmed] PHST- 2014/12/15 06:00 [medline] PHST- 2015/02/01 00:00 [pmc-release] AID - S1525-0016(16)31162-5 [pii] AID - 10.1038/mt.2013.247 [doi] PST - ppublish SO - Mol Ther. 2014 Feb;22(2):409-419. doi: 10.1038/mt.2013.247. Epub 2013 Oct 28.