Abstract
Neuropathy is a common, untreatable complication of type 1 and type 2 diabetes. In animal models peptide neurotrophic factors can be used to protect against the development of neuropathy, but the combination of short half-life and off-target effects of these potent pleiotropic peptides has limited translation to human therapy. Gene transfer is a promising strategy that may circumvent these limitations. In this article, we review the basic methods of gene transfer and the preclinical data in rodent models that support the use of this approach in the treatment of diabetic neuropathy. The path to clinical applications and potential pitfalls in developing gene therapy for the treatment of diabetic neuropathy are considered.
Similar content being viewed by others
References and Recommended Reading
The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group [no authors listed]. N Engl J Med 1993, 329:977–986.
Brewster WJ, Fernyhough P, Diemel LT, et al.: Diabetic neuropathy, nerve growth factor and other neurotrophic factors. Trends Neurosci 1994, 8:321–325.
Anand P, Terenghi G, Warner G, et al.: The role of endogenous nerve growth factor in human diabetic neuropathy. Nat Med 1996, 2:703–707.
Apfel SC, Arezzo JC, Brownlee M, et al.: Nerve growth factor administration protects against experimental diabetic sensory neuropathy. Brain Res 1994, 634:7–12.
Diemel LT, Brewster WJ, Fernyhough P, Tomlinson DR: Expression of neuropeptides in experimental diabetes; effects of treatment with nerve growth factor or brainderived neurotrophic factor. Brain Res 1994, 21:171–175.
Mizisin AP, Bache M, DiStefano PS, et al.: BDNF attenuates functional and structural disorders in nerves of galactose-fed rats. J Neuropathol Exp Neurol 1997, 56:1290–1301.
Huang TJ, Sayers NM, Verkhratsky A, Fernyhough P: Neurotrophin-3 prevents mitochondrial dysfunction in sensory neurons of streptozotocin-diabetic rats. Exp Neurol 2005, 194:279–283.
Mizisin AP, Calcutt NA, Tomlinson DR, et al.: Neurotrophin-3 reverses nerve conduction velocity deficits in streptozotocin-diabetic rats. J Peripher Nerv Syst 1999, 4:211–221.
Calcutt NA, Freshwater JD, Mizisin AP: Prevention of sensory disorders in diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment with ciliary neurotrophic factor. Diabetologia 2004, 47:718–724.
Mizisin AP, Vu Y, Shuff M, Calcutt NA: Ciliary neurotrophic factor improves nerve conduction and ameliorates regeneration deficits in diabetic rats. Diabetes 2004, 53:1807–1812.
Cameron NE, Cotter MA: The neurocytokine, interleukin-6, corrects nerve dysfunction in experimental diabetes. Exp Neurol 2007, 207:23–29.
Christianson JA, Riekhof JT, Wright DE: Restorative effects of neurotrophin treatment on diabetes-induced cutaneous axon loss in mice. Exp Neurol 2003, 179:188–199.
Christianson JA, Ryals JM, McCarson KE, Wright DE: Beneficial actions of neurotrophin treatment on diabetesinduced hypoalgesia in mice. J Pain 2003, 4:493–504.
Calcutt NA, Allendoerfer KL, Mizisin AP, et al.: Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy. J Clin Invest 2003, 111:507–514.
Brussee V, Cunningham FA, Zochodne DW: Direct insulin signaling of neurons reverses diabetic neuropathy. Diabetes 2004, 53:1824–1830.
Kamiya H, Zhang W, Ekberg K, et al.: C-Peptide reverses nociceptive neuropathy in type 1 diabetes. Diabetes 2006, 55:3581–3587.
Nakae M, Kamiya H, Naruse K, et al.: Effects of basic fibroblast growth factor on experimental diabetic neuropathy in rats. Diabetes 2006, 55:1470–1477.
Bianchi R, Buyukakilli B, Brines M, et al.: Erythropoietin both protects from and reverses experimental diabetic neuropathy. Proc Natl Acad Sci U S A 2004, 101:823–828.
Calcutt NA, Jolivalt CG, Fernyhough P: Growth factors as therapeutics for diabetic neuropathy. Curr Drug Targets 2008, 9:47–59.
Apfel SC, Kessler JA, Adornato BT, et al.: Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group. Neurology 1998, 51:695–702.
Apfel SC, Schwartz S, Adomato BT, et al.: Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: a randomized controlled trial. JAMA 2000, 284:2215–2221.
Apfel SC, Arezzo JC, Lipson L, Kessler JA: Nerve growth factor prevents experimental cisplatin neuropathy. Ann Neurol 1992, 31:76–80.
Poduslo JF, Curran GL: Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res Mol Brain Res 1996, 36:280–286.
Fink DJ, DeLuca NA, Goins WF, Glorioso JC: Gene transfer to neurons using herpes simplex virus-based vectors. Annu Rev Neurosci 1996, 19:265–287.
Glorioso JC, Fink DJ: Herpes vector-mediated gene transfer in treatment of diseases of the nervous system. Annu Rev Microbiol 2004, 58:253–271.
Roizman B, Sears A: Herpes simplex viruses and their replication. In Fields’ Virology, vol 2, edn 3. Edited by Fields BN, Knipe DM, Howley PM, et al.: Philadelphia: Lippincott-Raven; 1996:2231–2295.
Fink DJ, DeLuca NA, Yamada M, et al.: Design and application of HSV vectors for neuroprotection. Gene Ther 2000, 7:115–119.
Wolfe D, Goins WF, Yamada M, et al.: Engineering herpes simplex virus vectors for CNS applications. Exp Neurol 1999, 159:34–46.
Pradat PF, Finiels F, Kennel P, et al.: Partial prevention of cisplatin-induced neuropathy by electroporation-mediated nonviral gene transfer. Hum Gene Ther 2001, 12:367–375.
Schratzberger P, Schratzberger G, Silver M, et al.: Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy. Nat Med 2000, 6:405–413.
Schratzberger P, Walter DH, Rittig K, et al.: Reversal of experimental diabetic neuropathy by VEGF gene transfer. J Clin Invest 2001, 107:1083–1092.
Kato N, Nemoto K, Nakanishi K, et al.: Nonviral gene transfer of human hepatocyte growth factor improves streptozotocin-induced diabetic neuropathy in rats. Diabetes 2005, 54:846–854.
Pradat PF, Kennel P, Naimi-Sadaoui S, et al.: Viral and non-viral gene therapy partially prevents experimental cisplatin-induced neuropathy. Gene Ther 2002, 9:1333–1337.
Pradat PF, Kennel P, Naimi-Sadaoui S, et al.: Continuous delivery of neurotrophin 3 by gene therapy has a neuroprotective effect in experimental models of diabetic and acrylamide neuropathies. Hum Gene Ther 2001, 12:2237–2249.
Helgren ME, Cliffer KD, Torrento K, et al.: Neurotrophin-3 administration attenuates deficits of pyridoxine-induced large-fiber sensory neuropathy. J Neurosci 1997, 17:372–382.
Chattopadhyay M, Wolfe D, Huang S, et al.: In vivo gene therapy for pyridoxine-induced neuropathy by herpes simplex virus-mediated gene transfer of neurotrophin-3. Ann Neurol 2002, 51:19–27.
Chattopadhyay M, Goss J, Lacomis D, et al.: Protective effect of HSV-mediated gene transfer of nerve growth factor in pyridoxine neuropathy demonstrates functional activity of trkA receptors in large sensory neurons of adult animals. Eur J Neurosci 2003, 17:732–740.
Chattopadhyay M, Goss J, Wolfe D, et al.: Protective effect of herpes simplex virus-mediated neurotrophin gene transfer in cisplatin neuropathy. Brain 2004, 127:929–939.
Goss JR, Goins WF, Lacomis D, et al.: Herpes simplexmediated gene transfer of nerve growth factor protects against peripheral neuropathy in streptozotocin-induced diabetes in the mouse. Diabetes 2002, 51:2227–2232.
Chattopadhyay M, Krisky D, Wolfe D, et al.: HSV-mediated gene transfer of vascular endothelial growth factor to dorsal root ganglia prevents diabetic neuropathy. Gene Ther 2005, 12:1377–1384.
Goins WF, Sternberg LR, Croen KD, et al.: A novel latency-active promoter is contained within the herpes simplex virus type 1 UL flanking repeats. J Virol 1994, 68:2239–2252.
Goins WF, Lee KA, Cavalcoli JD, et al.: Herpes simplex virus type 1 vector-mediated expression of nerve growth factor protects dorsal root ganglion neurons from peroxide toxicity. J Virol 1999, 73:519–532.
Lokensgard JR, Berthomme H, Feldman LT: The latency-associated promoter of herpes simplex virus type 1 requires a region downstream of the transcription start site for long-term expression during latency. J Virol 1997, 71:6714–6719.
Palmer JA, Branston RH, Lilley CE, et al.: Development and optimization of herpes simplex virus vectors for multiple long-term gene delivery to the peripheral nervous system. J Virol 2000, 74:5604–5618.
Lilley CE, Groutsi F, Han Z, et al.: Multiple immediateearly gene-deficient herpes simplex virus vectors allowing efficient gene delivery to neurons in culture and widespread gene delivery to the central nervous system in vivo. J Virol 2001, 75:4343–4356.
Perez MC, Hunt SP, Coffin RS, Palmer JA: Comparative analysis of genomic HSV vectors for gene delivery to motor neurons following peripheral inoculation in vivo. Gene Ther 2004, 11:1023–1032.
Chattopadhyay M, Wolfe D, Mata M, et al.: Long-term neuroprotection achieved with latency-associated promoterdriven herpes simplex virus gene transfer to the peripheral nervous system. Mol Ther 2005, 12:307–313.
Chattopadhyay M, Mata M, Goss J, et al.: Prolonged preservation of nerve function in diabetic neuropathy in mice by herpes simplex virus-mediated gene transfer. Diabetologia 2007, 50:1550–1558.
Isner JM, Ropper A, Hirst K: VEGF gene transfer for diabetic neuropathy. Hum Gene Ther 2001, 12:1593–1594.
Sahenk Z, Nagaraja HN, McCracken BS, et al.: NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients. Neurology 2005, 65:681–689.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mata, M., Chattopadhyay, M. & Fink, D.J. Gene therapy for the treatment of diabetic neuropathy. Curr Diab Rep 8, 431–436 (2008). https://doi.org/10.1007/s11892-008-0075-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11892-008-0075-1