Intrathecal AAV serotype 9-mediated delivery of shRNA against TRPV1 attenuates thermal hyperalgesia in a mouse model of peripheral nerve injury

Mol Ther. 2014 Feb;22(2):409-419. doi: 10.1038/mt.2013.247. Epub 2013 Oct 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Dependovirus / genetics*
  • Dependovirus / immunology
  • Disease Models, Animal
  • Female
  • Ganglia, Spinal / metabolism
  • Gene Expression
  • Gene Order
  • Gene Silencing
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics*
  • Genetic Vectors / immunology
  • Hyperalgesia / genetics*
  • Hyperalgesia / therapy
  • Injections, Spinal
  • Mice
  • Peripheral Nerve Injuries / genetics
  • Peripheral Nerve Injuries / therapy
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / chemistry
  • RNA, Small Interfering / genetics*
  • RNA, Small Interfering / metabolism
  • Spinal Cord / metabolism
  • TRPV Cation Channels / chemistry
  • TRPV Cation Channels / genetics*
  • TRPV Cation Channels / metabolism

Substances

  • RNA, Messenger
  • RNA, Small Interfering
  • TRPV Cation Channels
  • TRPV1 protein, mouse