Human carbonic anhydrase-8 AAV8 gene therapy inhibits nerve growth factor signaling producing prolonged analgesia and anti-hyperalgesia in mice.

Published

Journal Article

Carbonic anhydrase-8 (Car8; murine gene symbol) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates neuronal intracellular calcium release. We previously reported that wild-type Car8 overexpression corrects the baseline allodynia and hyperalgesia associated with calcium dysregulation in the waddle (wdl) mouse due to a 19 bp deletion in exon 8 of the Car8 gene. In this report, we provide preliminary evidence that overexpression of the human wild-type ortholog of Car8 (CA8WT), but not the reported CA8 S100P loss-of-function mutation (CA8MT), inhibits nerve growth factor (NGF)-induced phosphorylation of ITPR1, TrkA (NGF high-affinity receptor), and ITPR1-mediated cytoplasmic free calcium release in vitro. In addition, we show that gene transfer using AAV8-V5-CA8WT viral particles via sciatic nerve injection demonstrates retrograde transport to dorsal root ganglia (DRG) producing prolonged V5-CA8WT expression, pITPR1 and pTrkA inhibition, and profound analgesia and anti-hyperalgesia in male C57BL/6J mice. AAV8-V5-CA8WT-mediated overexpression prevented and treated allodynia and hyperalgesia associated with chronic neuropathic pain produced by the spinal nerve ligation (SNL) model. These AAV8-V5-CA8 data provide a proof-of-concept for precision medicine through targeted gene therapy of NGF-responsive somatosensory neurons as a long-acting local analgesic able to prevent and treat chronic neuropathic pain through regulating TrkA signaling, ITPR1 activation, and intracellular free calcium release by ITPR1.

Full Text

Duke Authors

Cited Authors

  • Zhuang, GZ; Upadhyay, U; Tong, X; Kang, Y; Erasso, DM; Fu, ES; Sarantopoulos, KD; Martin, ER; Wiltshire, T; Diatchenko, L; Smith, SB; Maixner, W; Levitt, RC

Published Date

  • July 2018

Published In

Volume / Issue

  • 25 / 4

Start / End Page

  • 297 - 311

PubMed ID

  • 29789638

Pubmed Central ID

  • 29789638

Electronic International Standard Serial Number (EISSN)

  • 1476-5462

International Standard Serial Number (ISSN)

  • 0969-7128

Digital Object Identifier (DOI)

  • 10.1038/s41434-018-0018-7

Language

  • eng