Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

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

Gene Therapy volume 25, pages 297–311 (2018)Cite this article

Subjects

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. Institute of Medicine Committee on Advancing Pain Research, Care, Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. The National Academies Collection: Reports Funded by National Institutes of Health. (National Academies Press (US), National Academy of Sciences: Washington (DC), 2011).

  2. Levitt AE, Galor A, Chowdhury AR, Felix ER, Sarantopoulos CD, Zhuang GY, et al. Evidence that dry eye represents a chronic overlapping pain conditions. Mol Pain. 2017;13:1744806917729306.

    Article  Google Scholar 

  3. Fu ES, Erasso DM, Zhuang GZ, Upadhyay U, Ozdemir M, Wiltshire T, et al. Impact of human CA8 on thermal antinociception in relation to morphine equivalence in mice. Neuroreport. 2017;13:1215–1220.

    Article  Google Scholar 

  4. Berde CB, Athiraman U, Yahalom B, Zurakowski D, Corfas G, Bognet C. Tetrodotoxin-bupivacaine-epinephrine combinations for prolonged local anesthesia. Mar Drugs. 2011;9:2717–28.

    Article  CAS  Google Scholar 

  5. Fanelli G, Casati A, Beccaria P, Aldegheri G, Berti M, Tarantino F, et al. A double-blind comparison of ropivacaine, bupivacaine, and mepivacaine during sciatic and femoral nerve blockade. Anesth Analg. 1998;87:597–600.

    CAS  Google Scholar 

  6. Klein SM, Greengrass RA, Steele SM, D’Ercole FJ, Speer KP, Gleason DH, et al. A comparison of 0.5% bupivacaine, 0.5% ropivacaine, and 0.75% ropivacaine for interscalene brachial plexus block. Anesth Analg. 1998;87:1316–9.

    CAS  Google Scholar 

  7. Augustine GJ. How does calcium trigger neurotransmitter release? Curr Opin Neurobiol. 2001;11:320–6.

    Article  CAS  Google Scholar 

  8. Inoue T, Kato K, Kohda K, Mikoshiba K. Type 1 inositol 1,4,5-trisphosphate receptor is required for induction of long-term depression in cerebellar Purkinje neurons. J Neurosci. 1998;18:5366–73.

    Article  CAS  Google Scholar 

  9. Miyata M, Finch EA, Khiroug L, Hashimoto K, Hayasaka S, Oda SI, et al. Local calcium release in dendritic spines required for long-term synaptic depression. Neuron. 2000;28:233–44.

    Article  CAS  Google Scholar 

  10. Rizzuto R. Intracellular Ca(2+) pools in neuronal signalling. Curr Opin Neurobiol. 2001;11:306–11.

    Article  CAS  Google Scholar 

  11. Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI. Differential activation of transcription factors induced by Ca2+response amplitude and duration. Nature. 1997;386:855–8.

    Article  CAS  Google Scholar 

  12. Dolmetsch RE, Pajvani U, Fife K, Spotts JM, Greenberg ME. Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science. 2001;294:333–9.

    Article  CAS  Google Scholar 

  13. Gunter TE, Gunter KK. Uptake of calcium by mitochondria: transport and possible function. IUBMB life. 2001;52:197–204.

    Article  CAS  Google Scholar 

  14. Fang L, Wu J, Lin Q, Willis WD. Calcium-calmodulin-dependent protein kinase II contributes to spinal cord central sensitization. J Neurosci. 2002;22:4196–204.

    Article  CAS  Google Scholar 

  15. Jones TL, Lustig AC, Sorkin LS. Secondary hyperalgesia in the postoperative pain model is dependent on spinal calcium/calmodulin-dependent protein kinase II alpha activation. Anesth Analg. 2007;105:1650–6.

    Article  CAS  Google Scholar 

  16. Zeitz KP, Giese KP, Silva AJ, Basbaum AI. The contribution of autophosphorylated alpha-calcium-calmodulin kinase II to injury-induced persistent pain. Neuroscience. 2004;128:889–98.

    Article  CAS  Google Scholar 

  17. Schepelmann K, Messlinger K, Schmidt RF. The effects of phorbol ester on slowly conducting afferents of the cat’s knee joint. Exp Brain Res. 1993;92:391–8.

    Article  CAS  Google Scholar 

  18. Dray A, Rang H. The how and why of chronic pain states and the what of new analgesia therapies. Trends Neurosci. 1998;21:315–7.

    Article  CAS  Google Scholar 

  19. Rang HP, Ritchie JM. Depolarization of nonmyelinated fibers of the rat vagus nerve produced by activation of protein kinase C. J Neurosci. 1988;8:2606–17.

    Article  CAS  Google Scholar 

  20. Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth Analg. 2003;97:1108–16.

    Article  CAS  Google Scholar 

  21. Simonetti M, Hagenston AM, Vardeh D, Freitag HE, Mauceri D, Lu J, et al. Nuclear calcium signaling in spinal neurons drives a genomic program required for persistent inflammatory pain. Neuron. 2013;77:43–57.

    Article  CAS  Google Scholar 

  22. Diatchenko L, Nackley AG, Slade GD, Fillingim RB, Maixner W. Idiopathic pain disorders--pathways of vulnerability. Pain. 2006;123:226–30.

    Article  Google Scholar 

  23. Obata K, Yamanaka H, Fukuoka T, Yi D, Tokunaga A, Hashimoto N, et al. Contribution of injured and uninjured dorsal root ganglion neurons to pain behavior and the changes in gene expression following chronic constriction injury of the sciatic nerve in rats. Pain. 2003;101:65–77.

    Article  CAS  Google Scholar 

  24. Zhuang GZ, Keeler B, Grant J, Bianchi L, Fu ES, Zhang YP, et al. Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway. PLoS ONE. 2015;10:e0118273.

    Article  Google Scholar 

  25. Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol. 2000;1:11–21.

    Article  CAS  Google Scholar 

  26. Carrasco MA, Jaimovich E, Kemmerling U, Hidalgo C. Signal transduction and gene expression regulated by calcium release from internal stores in excitable cells. Biol Res. 2004;37:701–12.

    Article  Google Scholar 

  27. Verkhratsky A. Endoplasmic reticulum calcium signaling in nerve cells. Biol Res. 2004;37:693–9.

    Article  Google Scholar 

  28. Wu LJ, Zhuo M. Targeting the NMDA receptor subunit NR2B for the treatment of neuropathic pain. Neurotherapeutics . 2009;6:693–702.

    Article  CAS  Google Scholar 

  29. Furuichi T, Simon-Chazottes D, Fujino I, Yamada N, Hasegawa M, Miyawaki A, et al. Widespread expression of inositol 1,4,5-trisphosphate receptor type 1 gene (Insp3r1) in the mouse central nervous system. Recept Channels. 1993;1:11–24.

    CAS  Google Scholar 

  30. Worley PF, Baraban JM, Colvin JS, Snyder SH. Inositol trisphosphate receptor localization in brain: variable stoichiometry with protein kinase C. Nature. 1987;325:159–61.

    Article  CAS  Google Scholar 

  31. Hirasawa M, Xu X, Trask RB, Maddatu TP, Johnson BA, Naggert JK, et al. Carbonic anhydrase related protein 8 mutation results in aberrant synaptic morphology and excitatory synaptic function in the cerebellum. Mol Cell Neurosci. 2007;35:161–70.

    Article  CAS  Google Scholar 

  32. Hirota J, Ando H, Hamada K, Mikoshiba K. Carbonic anhydrase-related protein is a novel binding protein for inositol 1,4,5-trisphosphate receptor type 1. Biochem J. 2003;372(Pt 2):435–41.

    Article  CAS  Google Scholar 

  33. Ferris CD, Huganir RL, Bredt DS, Cameron AM, Snyder SH. Inositol trisphosphate receptor: phosphorylation by protein kinase C and calcium calmodulin-dependent protein kinases in reconstituted lipid vesicles. Proc Natl Acad Sci USA. 1991;88:2232–5.

    Article  CAS  Google Scholar 

  34. Haug LS, Jensen V, Hvalby O, Walaas SI, Ostvold AC. Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic nucleotide-dependent kinases in vitro and in rat cerebellar slices in situ. J Biol Chem. 1999;274:7467–73.

    Article  CAS  Google Scholar 

  35. Maes K, Missiaen L, Parys JB, Sienaert I, Bultynck G, Zizi M, et al. Adenine-nucleotide binding sites on the inositol 1,4,5-trisphosphate receptor bind caffeine, but not adenophostin A or cyclic ADP-ribose. Cell Calcium. 1999;25:143–52.

    Article  CAS  Google Scholar 

  36. Mignery GA, Johnston PA, Sudhof TC. Mechanism of Ca2+inhibition of inositol 1,4,5-trisphosphate (InsP3) binding to the cerebellar InsP3 receptor. J Biol Chem. 1992;267:7450–5.

    CAS  Google Scholar 

  37. Yamada M, Komatsu N, Okada K, Kato T, Miyazaki H, Miura Y. Thrombopoietin induces tyrosine phosphorylation and activation of mitogen-activated protein kinases in a human thrombopoietin-dependent cell line. Biochem Biophys Res Commun. 1995;217:230–7.

    Article  CAS  Google Scholar 

  38. Xu Y, Gu Y, Xu GY, Wu P, Li GW, Huang LY. Adeno-associated viral transfer of opioid receptor gene to primary sensory neurons: a strategy to increase opioid antinociception. Proc Natl Acad Sci USA. 2003;100:6204–9.

    Article  CAS  Google Scholar 

  39. Storek B, Harder NM, Banck MS, Wang C, McCarty DM, Janssen WG, et al. Intrathecal long-term gene expression by self-complementary adeno-associated virus type 1 suitable for chronic pain studies in rats. Mol Pain. 2006;2:4.

    Article  Google Scholar 

  40. Towne C, Pertin M, Beggah AT, Aebischer P, Decosterd I. Recombinant adeno-associated virus serotype 6 (rAAV2/6)-mediated gene transfer to nociceptive neurons through different routes of delivery. Mol Pain. 2009;5:52.

    Article  Google Scholar 

  41. Vulchanova L, Schuster DJ, Belur LR, Riedl MS, Podetz-Pedersen KM, Kitto KF, et al. Differential adeno-associated virus mediated gene transfer to sensory neurons following intrathecal delivery by direct lumbar puncture. Mol Pain. 2010;6:31.

    Article  Google Scholar 

  42. Xu Y, Gu Y, Wu P, Li GW, Huang LY. Efficiencies of transgene expression in nociceptive neurons through different routes of delivery of adeno-associated viral vectors. Hum Gene Ther. 2003;14:897–906.

    Article  CAS  Google Scholar 

  43. Zheng H, Qiao C, Wang CH, Li J, Li J, Yuan Z, et al. Efficient retrograde transport of adeno-associated virus type 8 to spinal cord and dorsal root ganglion after vector delivery in muscle. Hum Gene Ther. 2010;21:87–97.

    Article  CAS  Google Scholar 

  44. Mikoshiba K. The InsP3 receptor and intracellular Ca2+signaling. Curr Opin Neurobiol. 1997;7:339–45.

    Article  CAS  Google Scholar 

  45. Langford DJ, Schimdt B, Levine JD, Abrams G, Elboim C, Esserman L, et al. Preoperative breast pain predicts persistent breast pain and disability following breast cancer surgery. J Pain Symp Manag. 2014;41:981–994.

    Google Scholar 

  46. Yang FC, Tan T, Huang T, Christianson J, Samad OA, Liu Y, et al. Genetic control of the segregation of pain-related sensory neurons innervating the cutaneous versus deep tissues. Cell Rep. 2013;5:1353–64.

    Article  CAS  Google Scholar 

  47. Eskander MA, Ruparel S, Green DP, Chen PB, Por ED, Jeske NA, et al. Persistent nociception triggered by nerve growth factor (NGF) is mediated by TRPV1 and oxidative mechanisms. J Neurosci. 2015;35:8593–603.

    Article  CAS  Google Scholar 

  48. Itoh K, Ishima T, Kehler J, Hashimoto K. Potentiation of NGF-induced neurite outgrowth in PC12 cells by papaverine: role played by PLC-gamma, IP3 receptors. Brain Res. 2011;1377:32–40.

    Article  CAS  Google Scholar 

  49. Drummond ES, Dawson LF, Finch PM, Bennett GJ, Drummond PD. Increased expression of cutaneous alpha1-adrenoceptors after chronic constriction injury in rats. J Pain. 2014;15:188–96.

    Article  CAS  Google Scholar 

  50. Schlereth T, Drummond PD, Birklein F. Inflammation in CRPS: role of the sympathetic supply. Auton Neurosci. 2014;182:102–7.

    Article  CAS  Google Scholar 

  51. Jonsson EN, Xie R, Marshall SF, Arends RH. Population pharmacokinetics of tanezumab in phase 3 clinical trials for osteoarthritis pain. Br J Clin Pharmacol. 2015;81:688–699.

    Article  Google Scholar 

  52. Ekman EF, Gimbel JS, Bello AE, Smith MD, Keller DS, Annis KM, et al. Efficacy and safety of intravenous tanezumab for the symptomatic treatment of osteoarthritis: 2 randomized controlled trials versus naproxen. J Rheumatol. 2014;41:2249–59.

    Article  CAS  Google Scholar 

  53. Gimbel JS, Kivitz AJ, Bramson C, Nemeth MA, Keller DS, Brown MT, et al. Long-term safety and effectiveness of tanezumab as treatment for chronic low back pain. Pain. 2014;155:1793–801.

    Article  CAS  Google Scholar 

  54. Spierings EL, Fidelholtz J, Wolfram G, Smith MD, Brown MT, West CR. A phase III placebo- and oxycodone-controlled study of tanezumab in adults with osteoarthritis pain of the hip or knee. Pain. 2013;154:1603–12.

    Article  CAS  Google Scholar 

  55. Hochberg MC. Serious joint-related adverse events in randomized controlled trials of anti-nerve growth factor monoclonal antibodies. Osteoarthritis Cartilage. 2015;23:S18–21.

    Article  Google Scholar 

  56. Hochberg MC, Tive LA, Abramson SB, Vignon E, Vervurg KM, West CR, et al. When is osteonecrosis not osteonecrosis? adjudication of reported serious adverse joint events in the tanezumab clinical development program. Arthritis Rheumatol. 2015;68:382–391.

    Article  Google Scholar 

  57. Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 2003;26:696–705.

    Article  CAS  Google Scholar 

  58. Hagenacker T, Ledwig D, Busselberg D. Feedback mechanisms in the regulation of intracellular calcium ([Ca2+]i) in the peripheral nociceptive system: role of TRPV-1 and pain related receptors. Cell Calcium. 2008;43:215–27.

    Article  CAS  Google Scholar 

  59. Youn DH, Voitenko N, Gerber G, Park YK, Galik J, Randic M. Altered long-term synaptic plasticity and kainate-induced Ca2+transients in the substantia gelatinosa neurons in GLU(K6)-deficient mice. Brain Res Mol Brain Res. 2005;142:9–18.

    Article  CAS  Google Scholar 

  60. Bhave G, Zhu W, Wang H, Brasier DJ, Oxford GS, Gereau RW. cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation. Neuron. 2002;35:721–31.

    Article  CAS  Google Scholar 

  61. Mohapatra DP, Nau C. Regulation of Ca2+-dependent desensitization in the vanilloid receptor TRPV1 by calcineurin and cAMP-dependent protein kinase. J Biol Chem. 2005;280:13424–32.

    Article  CAS  Google Scholar 

  62. Piper AS, Yeats JC, Bevan S, Docherty RJ. A study of the voltage dependence of capsaicin-activated membrane currents in rat sensory neurones before and after acute desensitization. J Physiol. 1999;518:721–33.

    Article  CAS  Google Scholar 

  63. Rosenbaum T, Gordon-Shaag A, Munari M, Gordon SE. Ca2+/calmodulin modulates TRPV1 activation by capsaicin. J Gen Physiol. 2004;123:53–62.

    Article  CAS  Google Scholar 

  64. Cesare P, McNaughton P. A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin. Proc Natl Acad Sci USA. 1996;93:15435–9.

    Article  CAS  Google Scholar 

  65. Yamamoto S, Tanaka E, Higashi H. Mediation by intracellular calcium-dependent signals of hypoxic hyperpolarization in rat hippocampal CA1 neurons in vitro. J Neurophysiol. 1997;77:386–92.

    Article  CAS  Google Scholar 

  66. Kawano T, Zoga V, Gemes G, McCallum JB, Wu HE, Pavdic D, et al. Suppressed Ca2+/CaM/CaMKII-dependent K(ATP) channel activity in primary afferent neurons mediates hyperalgesia after axotomy. Proc Natl Acad Sci USA. 2009;106:8725–8730.

    Article  CAS  Google Scholar 

  67. Foust KD, Poirier A, Pacak CA, Mandel RJ, Flotte TR. Neonatal intraperitoneal or intravenous injections of recombinant adeno-associated virus type 8 transduce dorsal root ganglia and lower motor neurons. Hum Gene Ther. 2008;19:61–70.

    Article  CAS  Google Scholar 

  68. Storek B, Reinhardt M, Wang C, Janssen WG, Harder NM, Banck MS, et al. Sensory neuron targeting by self-complementary AAV8 via lumbar puncture for chronic pain. Proc Natl Acad Sci USA. 2008;105:1055–1060.

    Article  CAS  Google Scholar 

  69. Tse LV, Moller-Tank S, Asokan A. Strategies to circumvent humoral immunity to adeno-associated viral vectors. Expert Opin Biol Ther. 2015;15:845–55.

    Article  CAS  Google Scholar 

  70. Kohane DS, Smith SE, Louis DN, Colombo G, Ghoroghchian P, Hunfeld NG, et al. Prolonged duration local anesthesia from tetrodotoxin-enhanced local anesthetic microspheres. Pain. 2003;104:415–21.

    Article  CAS  Google Scholar 

  71. Waxman SG, Zamponi GW. Regulating excitability of peripheral afferents: emerging ion channel targets. Nat Neurosci. 2014;17:153–63.

    Article  CAS  Google Scholar 

  72. Choi DY, Toledo-Aral JJ, Segal R, Halegoua S. Sustained signaling by phospholipase C-gamma mediates nerve growth factor-triggered gene expression. Mol Cell Biol. 2001;21:2695–705.

    Article  CAS  Google Scholar 

  73. Shortland P, Kinman E, Molander C. Sprouting of A-fibre primary afferents into lamina II in two rat models of neuropathic pain. Eur J Pain. 1997;1:215–27.

    Article  CAS  Google Scholar 

  74. Kajander KC, Bennett GJ. Onset of a painful peripheral neuropathy in rat: a partial and differential deafferentation and spontaneous discharge in A beta and A delta primary afferent neurons. J Neurophysiol. 1992;68:734–44.

    Article  CAS  Google Scholar 

  75. Beck C, Uramoto H, Borén J, Akyürek LM. Tissue-specific targeting for cardiovascular gene transfer. Potential vectors and future challenges. Curr Gene Ther. 2004;4:457–67.

    Article  CAS  Google Scholar 

  76. Turkmen S, Guo G, Garshasbi M, Hoffmann K, Alshalah AJ, Mischung C, et al. CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait. PLoS Genet. 2009;5:e1000487.

    Article  Google Scholar 

  77. Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain. 1992;50:355–63.

    Article  CAS  Google Scholar 

  78. Turkmen S, Guo G, Garshasbi M, Hoffmann K, Alshalah AJ, Mischung C, et al. CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait. PLoS Genet. 2009;5:e1000487.

    Article  Google Scholar 

  79. Zhuang Z, Yang B, Theus MH, Sick JT, Bethea JR, Sick TJ, et al. EphrinBs regulate D-serine synthesis and release in astrocytes. J Neurosci. 2010;30:16015–24.

    Article  CAS  Google Scholar 

  80. Levitt RC, Zhuang GY, Kang Y, Erasso DM, Upadhyay U, Ozdemir M, et al. Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice. Mamm Genome. 2017;28:407–15.

    Article  CAS  Google Scholar 

  81. Boehmerle W, Zhang K, Sivula M, Heidrich FM, Lee Y, Jordt SE, et al. Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation. Proc Natl Acad Sci USA. 2007;104:11103–11108.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

A grant from the NIDCR R01DE022903 and funding from the Department of Anesthesiology, Perioperative Medicine, and Pain Management, University of Miami Miller School of Medicine, Miami, Florida, were used to perform this work.

Author contributions

RCL designed the overall study, setup collaborations, supervised these studies, analyzed data, primarily wrote, edited, and submitted this manuscript. GZZ performed the major portion of the experiments. GZZ assisted with experimental design, data collection, analyses, and manuscript preparation. XT, YK, UU, and DME contributed to experimental work included in this manuscript. KDS, UU, ESF, TW, ERM, LD, WM, and SBS contributed to the critical review and final editing of the manuscript.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, USA

    Gerald Z. Zhuang, Udita Upadhyay, Xiaoying Tong, Yuan Kang, Diana M. Erasso, Eugene S. Fu, Konstantinos D. Sarantopoulos & Roy C. Levitt

  2. Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA

    Konstantinos D. Sarantopoulos & Roy C. Levitt

  3. John T. MacDonald Foundation, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA

    Eden R. Martin & Roy C. Levitt

  4. John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA

    Eden R. Martin & Roy C. Levitt

  5. Department of Pharmacology and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA

    Tim Wiltshire

  6. Alan Edwards Centre for Research on Pain, Department of Anesthesiology, McGill University, Montreal, Quebec, Canada

    Luda Diatchenko

  7. Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, NC, USA

    Shad B Smith & William Maixner

Authors
  1. Gerald Z. Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Udita Upadhyay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaoying Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuan Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Diana M. Erasso
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eugene S. Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Konstantinos D. Sarantopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eden R. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tim Wiltshire
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Luda Diatchenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shad B Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. William Maixner
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Roy C. Levitt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roy C. Levitt.

Ethics declarations

Conflict of interest

WM, LD, and SBS have financial holdings receive compensation from Algynomics, Inc. The authors declare that their affiliation(s) to Algynomics, Inc., including employment, consultancy, patents, products in development, or marketed products, does not alter our adherence to Gene Therapy policies on sharing data and/or materials. Algynomics, Inc. provided support in the form of salaries for authors SBS, WM, and LD, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the “Author contributions” section. The remaining authors declare no conflicts of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhuang, G.Z., Upadhyay, U., Tong, X. et al. Human carbonic anhydrase-8 AAV8 gene therapy inhibits nerve growth factor signaling producing prolonged analgesia and anti-hyperalgesia in mice. Gene Ther 25, 297–311 (2018). https://doi.org/10.1038/s41434-018-0018-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41434-018-0018-7

This article is cited by

Search

Advanced search

Quick links