Abstract
Gene therapy shows great potential to assist numerous patients with inadequate relief of inflammatory or neuropathic pain, or intractable pain associated with advanced cancer. A brief overview is provided of the methods of gene therapy and of preclinical findings in animal models of prolonged inflammatory, neuropathic and cancer pain. Preclinical findings demonstrate no efficacy of gene therapy on basal thermal nociception and mechanical sensitivity, and almost universal effects on pathological nociception and hypersensitivity models. The status of human trials is provided with recommendations for future directions and precautions. This early stage of development of gene therapy for chronic pain will likely be followed by an increased number of human clinical trials aimed specifically at the relief of chronic, unrelenting pain.
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References
Berto, E., Bozac, A. and Marconi, P. (2005) Development and application of replication-incompetent HSV-1-based vectors. Gene Ther 12, S98–S102
Beutler, A.S., Banck, M.S., Walsh, C.E. and Milligan, E.D. (2005) Intrathecal gene transfer by adeno-associated virus for pain. Curr Opin Mol Ther 7, 431–439
Braz, J., Beaufour, C., Coutaux, A., Epstein, A.L., Cesselin, F., Hamon, M. and Pohl, M. (2001) Therapeutic efficacy in experimental polyarthritis of viral-driven enkephalin overproduction in sensory neurons. J Neurosci 21, 7881–7888
Castro, M., Hurtado-Lorenzo, A., Umana, P., Smith-Arica, J.R., Zermansky, A., Abordo-Adesida, E. and Lowenstein, P.R. (2001) Regulatable and cell-type specific transgene expression in glial cells: prospects for gene therapy for neurological disorders. Prog Brain Res 132, 655–681
Chuang, Y.C., Chou, A.K., Wu, P.C., Chiang, P.H., Yu, T.J., Yang, L.C., Yoshimura, N. and Chancellor, M.B. (2003) Gene therapy for bladder pain with gene gun particle encoding pro-opiomelanocortin cDNA. J Urol 170, 2044–2048
Chuang, Y.C., Yang, L.C., Chiang, P.H., Kang, H.Y., Ma, W.L., Wu, P.C., DeMiguel, F., Chancellor, M.B. and Yoshimura, N. (2005) Gene gun particle encoding preproenkephalin cDNA produces analgesia against capsaicin-induced bladder pain in rats. Urology 65, 804–810
Dray, A. (2004) Future pharmacologic management of neuropathic pain. J Orofac Pain 18, 381–385
Dubuisson, D. and Dennis, S.G. (1977) The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 4, 161–174
Dworkin, R.H., Backonja, M., Rowbotham, M.C., Allen, R.R., Argoff, C.R., Bennett, G.J., Bushnell, M.C., Farrar, J.T., Galer, B.S., Haythornthwaite, J.A., Hewitt, D.J., Loeser, J.D., Max, M.B., Saltarelli, M., Schmader, K.E., Stein, C., Thompson, D., Turk, D.C., Wallace, M.S., Watkins, L.R. and Weinstein, S.M. (2003) Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 60, 1524–1534
Eaton, M.J., Blits, B., Ruitenberg, M.J., Verhaagen, J. and Oudega, M. (2002) Amelioration of chronic neuropathic pain after partial nerve injury by adeno-associated viral (AAV) vector-mediated over-expression of BDNF in the rat spinal cord. Gene Ther 9, 1387–1395
Finegold, A.A., Mannes, A.J. and Iadarola, M.J. (1999) A paracrine paradigm for in vivo gene therapy in the central nervous system: treatment of chronic pain. Hum Gene Ther 10, 1251–1257
Freytag, S.O., Khil, M. Stricker, H., Peabody, J., Menon, M., DePeralta-Venturina, M., Nafziger, D., Pegg, J., Paielli, D., Brown, S., Barton, K., Lu, M., Aguilar-Cordova, E. and Kim, J.H. (2002) Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer Res 62, 4968–4976
Freytag, S.O., Stricker, H., Movsas, B. and Kim, J.H. (2007) Prostate cancer gene therapy clinical trials. Mol Ther 15, 1042–1052
Garry, M.G., Malik, S., Yu, J., Davis, M.A. and Yang, J. (2000) Knock down of spinal NMDA receptors reduces NMDA and formalin evoked behaviors in rat. Neuroreport 11, 49–55
Glorioso, J.C. and Fink, D.J. (2004) Herpes vector-mediated gene transfer in treatment of diseases of the nervous system. Annu Rev Microbiol 58, 253–271.
Glorioso, J.C., Mata, M. and Fink, D.J. (2003) Gene therapy for chronic pain. Curr Opin Mol Ther 5, 483–488
Goss, J.R. (2007) The therapeutic potential of gene transfer for the treatment of peripheral neuropathies. Expert Rev Mol Med 9, 1–20
Goss, J.R., Harley, C.F., Mata, M., O'Malley, M.E., Goins, W.F., Hu, X., Glorioso, J.C. and Fink, D.J. (2002) Herpes vector-mediated expression of proenkephalin reduces bone cancer pain. Ann Neurol 52, 662–665
Goss, J.R., Mata, M., Goins, W.F., Wu, H.H., Glorioso, J.C. and Fink, D.J. (2001) Antinociceptive effect of a genomic herpes simplex virus-based vector expressing human proenkephalin in rat dorsal root ganglion. Gene Ther 8, 551–556
Gu, Y., Xu, Y., Li, G.W. and Huang, L.Y. (2005) Remote nerve injection of mu opioid receptor adeno-associated viral vector increases antinociception of intrathecal morphine. J Pain 6, 447–454
Gudmundsson, G., Bosch, A., Davidson, B.L., Berg, D.J. and Hunninghake, G.W. (1998) Interleukin-10 modulates the severity of hypersensitivity pneumonitis in mice. Am J Respir Cell Mol Biol 19, 812–818
Hao, S., Mata, M., Fink, D.J. (2007) Viral vector-based gene transfer for treatment of chronic pain. Int Anesthesiol Clin 45, 59–71
Hao, S., Mata, M., Glorioso, J.C. and Fink, D.J. (2006) HSV-mediated expression of interleukin-4 in dorsal root ganglion neurons reduces neuropathic pain. Mol Pain 2, 6
Hao, S., Mata, M., Goins, W., Glorioso, J.C. and Fink, D.J. (2003a) Transgene-mediated enkephalin release enhances the effect of morphine and evades tolerance to produce a sustained antiallodynic effect in neuropathic pain. Pain 102, 135–142
Hao, S., Mata, M., Wolfe, D., Huang, S., Glorioso, J.C. and Fink, D.J. (2003b) HSV-mediated gene transfer of the glial cell-derived neurotrophic factor provides an antiallodynic effect on neuropathic pain. Mol Ther 8, 367–375
Hao, S., Mata, M., Wolfe, D., Huang, S., Glorioso, J.C. and Fink, D.J. (2005) Gene transfer of glutamic acid decarboxylase reduces neuropathic pain. Ann Neurol 57, 914–918
Hughes, V. (2007) Therapy on trial. Nature Med 13, 1008–1009
Kang, W., Wilson, M.A., Bender, M.A., Glorioso, J.C. and Wilson, S.P. (1998) Herpes virus-mediated preproenkephalin gene transfer to the amygdala is antinociceptive. Brain Res 792, 133–135
Kurreck, J. (2004) Antisense and RNA interference approaches to target validation in pain research. Curr Opin Drug Discov Devel 7, 179–187
Lariviere, W.R., Wilson, S.G., Laughlin, T.M., Kokayeff, A., West, E.E., Adhikari, S.M., Wan, Y. and Mogil, J.S. (2002) Heritability of nociception. III. Genetic relationships among commonly used assays of nociception and hypersensitivity. Pain 97, 75–86
Lin, C.R., Yang, L.C., Lee, T.H., Lee, C.T., Huang, H.T., Sun, W.Z. and Cheng, J.T. (2002) Electroporation-mediated pain-killer gene therapy for mononeuropathic rats. Gene Ther 9, 1247–1253
Liu, J., Wolfe, D., Hao, S., Huang, S., Glorioso, J.C., Mata, M. and Fink, D.J. (2004) Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain. Mol Ther 10, 57–66
Lu, C.Y., Chou, A.K., Wu, C.L., Yang, C.H., Chen, J.T., Wu, P.C., Lin, S.H., Muhammad, R. and Yang, L.C. (2002) Gene-gun particle with pro-opiomelanocortin cDNA produces analgesia against formalin-induced pain in rats. Gene Ther 9, 1008–1014
Mata, M. and Fink, D.J. (2007) Gene therapy for pain. Anesthesiology 106, 1079–1080
Mata, M., Glorioso, J. and Fink, D.J. (2003) Development of HSV-mediated gene transfer for the treatment of chronic pain. Exp Neurol 184 Suppl 1, S25–29
Mannes, A.J., Caudle, R.M., O'Connell, B.C. and Iadarola, M.J. (1998) Adenoviral gene transfer to spinal-cord neurons: intrathecal vs. intraparenchymal administration. Brain Res 793, 1–6
Meunier, A., Braz, J., Cesselin, F., Hamon, M. and Pohl, M. (2004) [From inflammation to pain: experimental gene therapy]. Med Sci (Paris) 20, 325–330
Meunier, A., Latremoliere, A., Mauborgne, A., Bourgoin, S., Kayser, V., Cesselin, F., Hamon, M. and Pohl, M. (2005) Attenuation of pain-related behavior in a rat model of trigeminal neuropathic pain by viral-driven enkephalin overproduction in trigeminal ganglion neurons. Mol Ther 11, 608–616
Milligan, E.D., Langer, S.J., Sloane, E.M., He, L., Wieseler-Frank, J., O'Connor, K., Martin, D., Forsayeth, J.R., Maier, S.F., Johnson, K., Chavez, R.A., Leinwand, L.A. and Watkins, L.R. (2005a) Controlling pathological pain by adenovirally driven spinal production of the anti-inflammatory cytokine, interleukin-10. Eur J Neurosci 21, 2136–2148
Milligan, E.D., Sloane, E.M., Langer, S.J., Cruz, P.E., Chacur, M., Spataro, L., Wieseler-Frank, J., Hammack, S.E., Maier, S.F., Flotte, T.R., Forsayeth, J.R., Leinwand, L.A., Chavez, R. and Watkins, L.R. (2005b) Controlling neuropathic pain by adeno-associated virus driven production of the anti-inflammatory cytokine, interleukin-10. Mol Pain 1, 9
Noureddini, S.C., Krendelshchikov, A., Simonenko, V., Hedley, S.J., Douglas, J.T., Curiel, D.T. and Korokhov, N. (2006) Generation and selection of targeted adenoviruses embodying optimized vector properties. Virus Res 116, 185–195
Pohl, M. and Braz, J. (2001) Gene therapy of pain: emerging strategies and future directions. Eur J Pharmacol 429, 39–48
Pohl, M., Meunier, A., Hamon, M. and Braz, J. (2003) Gene therapy of chronic pain. Curr Gene Ther 3, 223–238
Pradat, P.F., Finiels, F., Kennel, P., Naimi, S., Orsini, C., Delaere, P., Revah, F. and Mallet, J. (2001a) Partial prevention of cisplatin-induced neuropathy by electroporation-mediated nonviral gene transfer. Hum Gene Ther 12, 367–375
Pradat, P.F., Kennel, P., Naimi-Sadaoui, S., Finiels, F., Orsini, C., Revah, F., Delaere, P. and Mallet, J. (2001b) Continuous delivery of neurotrophin 3 by gene therapy has a neuroprotective effect in experimental models of diabetic and acrylamide neuropathies. Hum Gene Ther 12, 2237–2249
Pradat, P.F., Kennel, P., Naimi-Sadaoui, S., Finiels, F., Scherman, D., Orsini, C., Delaere, P., Mallet, J. and Revah, F. (2002) Viral and non-viral gene therapy partially prevents experimental cisplatin-induced neuropathy. Gene Ther 9, 1333–1337
Reilly, J.P., Grise, M.A., Fortuin, F.D., Vale, P.R., Schaer, G.L., Lopez, J., Van Camp, J.R., Henry, T., Richenbacher, W.E., Losordo, D.W., Schatz, R.A. and Isner, J.M. (2005) Long-term (2-year) clinical events following transthoracic intramyocardial gene transfer of VEGF-2 in no-option patients. J Interven Cardiol 18, 27–31
Shiota, M., Ikeda, Y., Kaul, Z., Itadani, J., Kaul, S.C. and Wadhwa, R. (2007) Internalizing antibody-based targeted gene delivery for human cancer cells. Hum Gene Ther 18, 1153–1160
Smith, A.E. (1999) Gene therapy – where are we? Lancet 354 Suppl 1, SI1–4
Tan, P.H., Yang, L.C., Shih, H.C., Lan, K.C. and Cheng, J.T. (2005) Gene knockdown with intrathecal siRNA of NMDA receptor NR2B subunit reduces formalin-induced nociception in the rat. Gene Ther 12, 59–66
Tsai, S.Y., Schillinger, K. and Ye, X. (2000) Adenovirus-mediated transfer of regulable gene expression. Curr Opin Mol Ther 2, 515–523
Touitou, I., Notarnicola, C., and Grandemange, S. (2004) Identifying mutations in autoinflammatory diseases: towards novel genetic tests and therapies? Am J Pharmacogenomics 4, 109–118
Weichselbaum, R.R. and Kufe, D. (1997) Gene therapy of cancer. Lancet 349 Suppl 2, SII10–12
Wilson, S.P. and Yeomans, D.C. (2002) Virally mediated delivery of enkephalin and other neuropeptide transgenes in experimental pain models. Ann NY Acad Sci 971, 515–521
Wilson, S.P., Yeomans, D.C., Bender, M.A., Lu, Y., Goins, W.F. and Glorioso, J.C. (1999) Antihyperalgesic effects of infection with a preproenkephalin-encoding herpes virus. Proc Natl Acad Sci USA 96, 3211–3216
Wirtz, S. and Neurath, M.F. (2003) Inflammatory bowel disorders: gene therapy solutions. Curr Opin Mol Ther 5, 495–502
Woolf, C.J. and Salter, M.W. (2000) Neuronal plasticity: increasing the gain in pain. Science 288, 1765–1769.
Yanez-Munoz, R.J., Balaggan, K.S., Macneil, A., Howe, S.J., Schmidt, M., Smith, A.J., Buch, P., Maclaren, R.E., Anderson, P.N., Barker, S.E., Duran, Y., Bartholomae, C., von Kalle, C., Heckenlively, J.R., Kinnon, C., Ali, R.R. and Thrasher, A.J. (2006) Effective gene therapy with nonintegrating lentiviral vectors. Nat Med 12, 348–353
Yao, M.Z., Gu, J.F., Wang, J.H., Sun, L.Y., Lang, M.F., Liu, J., Zhao, Z.Q. and Liu, X.Y. (2002b) Interleukin-2 gene therapy of chronic neuropathic pain. Neuroscience 112, 409–416
Yao, M.Z., Gu, J.F., Wang, J.H., Sun, L.Y., Liu, H. and Liu, X.Y. (2003) Adenovirus-mediated interleukin-2 gene therapy of nociception. Gene Ther 10, 1392–1399
Yao, M.Z., Wang, J.H., Gu, J.F., Sun, L.Y., Liu, H., Zhao, Z.Q. and Liu, X.Y. (2002b) Interleukin-2 gene has superior antinociceptive effects when delivered intrathecally. Neuroreport 13, 791–794
Yeomans, D.C., Jones, T., Laurito, C.E., Lu, Y. and Wilson, S.P. (2004) Reversal of ongoing thermal hyperalgesia in mice by a recombinant herpesvirus that encodes human preproenkephalin. Mol Ther 9, 24–29
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Lariviere, W.R., Cope, D.K. (2009). Gene Therapy for Chronic Pain. In: Biobehavioral Approaches to Pain. Springer, New York, NY. https://doi.org/10.1007/978-0-387-78323-9_19
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DOI: https://doi.org/10.1007/978-0-387-78323-9_19
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