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. 2009 Apr;6(2):300–306. doi: 10.1016/j.nurt.2009.01.012

Neuropeptide Y overexpression using recombinant adenoassociated viral vectors

Francesco Noé 1, Angelisa Frasca 1, Claudia Balducci 1, Mirjana Carli 1, Gunther Sperk 2, Francesco Ferraguti 2, Asla Pitkänen 3,4, Ross Bland 5,6, Helen Fitzsimons 5,6, Matthew During 6, Annamaria Vezzani 1,✉
PMCID: PMC5084207  PMID: 19332323

Summary

Gene therapy may represent a promising alternative treatment of epileptic patients who are resistant to conventional anti-epileptic drugs. Among the various approaches for the application of gene therapy in the treatment of CNS disorders, recombinant adeno-associated viral (AAV) vectors have been most widely used. Preclinical studies using a selection of “therapeutic” genes injected into the rodent brain to correct the compromised balance between inhibitory and excitatory transmission in epilepsy, showed significant reduction of seizures and inhibition of epileptogenesis. In particular, transduction of neuropeptide genes, such as galanin and neuropeptide Y (NPY) in specific brain areas in experimental models of seizures resulted in significant anticonvulsant effects. Recent findings showed a long-lasting NPY over-expression in the rat hippocampus by local application of recombinant AAV vectors associated with reduced generalization of seizures, delayed kindling epileptogenesis, and strong reduction of chronic spontaneous seizures. These results establish a proof-of-principle evidence of the efficacy of gene therapy as anticonvulsant treatment. Additional investigations are required to address safety concerns and possible side effects in more detail.

Key Words: Adeno-associated viral vectors, anticonvulsant, gene therapy in epilepsy, neuropeptides, temporal lobe epilepsy

References

  • 1.Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci. 2004;5:553–564. doi: 10.1038/nrn1430. [DOI] [PubMed] [Google Scholar]
  • 2.Foldvary N, Bingaman WE, Wyllie E. Surgical treatment of epilepsy. Neurol Clin. 2001;19:491–515. doi: 10.1016/S0733-8619(05)70028-1. [DOI] [PubMed] [Google Scholar]
  • 3.Duncan JS, Sander JW, Sisodiya SM, Walker MC. Adult epilepsy. Lancet. 2006;367:1087–1100. doi: 10.1016/S0140-6736(06)68477-8. [DOI] [PubMed] [Google Scholar]
  • 4.Perucca E. Pharmacoresistance in epilepsy: how should it be defined? CNS Drugs. 1998;10:171–179. doi: 10.2165/00023210-199810030-00002. [DOI] [Google Scholar]
  • 5.Kaplitt MG, During MJ. Gene therapy in the central nervous system. From bench to bedside. 1st ed. San Diego, CA: Elsevier Inc.; 2006. [Google Scholar]
  • 6.Haberman R, Criswell H, Snowdy S, et al. Therapeutic liabilities of in vivo viral vector tropism: adeno-associated virus vectors, NMDAR1 antisense, and focal seizure sensitivity. Mol Ther. 2002;6:495–500. doi: 10.1006/mthe.2002.0701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Raol YH, Lund IV, Bandyopadhyay S, et al. Enhancing GABA(A) receptor alpha 1 subunit levels in hippocampal dentate gyrus inhibits epilepsy development in an animal model of temporal lobe epilepsy. J Neurosci. 2006;26:11342–11346. doi: 10.1523/JNEUROSCI.3329-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Mazarati AM. Galanin and galanin receptors in epilepsy. Neuropeptides. 2004;38:331–343. doi: 10.1016/j.npep.2004.07.006. [DOI] [PubMed] [Google Scholar]
  • 9.Noé F, Nissinen J, Pitkanen A, et al. Gene therapy in epilepsy: the focus on NPY. Peptides. 2007;28:377–383. doi: 10.1016/j.peptides.2006.07.025. [DOI] [PubMed] [Google Scholar]
  • 10.Lin EJ, Richichi C, Young D, Baer K, Vezzani A, During MJ. Recombinant AAV-mediated expression of galanin in rat hippocampus suppresses seizure development. Eur J Neurosci. 2003;18:2087–2092. doi: 10.1046/j.1460-9568.2003.02926.x. [DOI] [PubMed] [Google Scholar]
  • 11.Foti S, Haberman RP, Samulski RJ, McCown TJ. Adeno-associated virus-mediated expression and constitutive secretion of NPY or NPY13-36 suppresses seizure activity in vivo. Gene Ther. 2007;14:1534–1536. doi: 10.1038/sj.gt.3303013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.de Lanerolle NC, Kim JH, Robbins RJ, Spencer DD. Hippocampal intemeuron loss and plasticity in human temporal lobe epilepsy. Brain Res. 1989;495:387–395. doi: 10.1016/0006-8993(89)90234-5. [DOI] [PubMed] [Google Scholar]
  • 13.Vezzani A, Sperk G, Colmers WF. Neuropeptide Y: emerging evidence for a functional role in seizure modulation. Trends Neurosci. 1999;22:25–30. doi: 10.1016/S0166-2236(98)01284-3. [DOI] [PubMed] [Google Scholar]
  • 14.Furtinger S, Pirker S, Czech T, Baumgartner C, Ransmayr G, Sperk G. Plasticity of Y1 and Y2 receptors and neuropeptide Y fibers in patients with temporal lobe epilepsy. J Neurosci. 2001;21:5804–5812. doi: 10.1523/JNEUROSCI.21-15-05804.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Patrylo PR, van den Pol AN, Spencer DD, Williamson A. NPY inhibits glutamatergic excitation in the epileptic human dentate gyrus. J Neurophysiol. 1999;82:478–483. doi: 10.1152/jn.1999.82.1.478. [DOI] [PubMed] [Google Scholar]
  • 16.Baraban SC, Hollopeter G, Erickson JC, Schwartzkroin PA, Palmiter RD. Knock-out mice reveal a critical antiepileptic role for neuropeptide Y. J Neurosci. 1997;17:8927–8936. doi: 10.1523/JNEUROSCI.17-23-08927.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.El Bahh B, Balosso S, Hamilton T, et al. The anti-epileptic actions of neuropeptide Y in the hippocampus are mediated by Y2 and not Y5 receptors. Eur J Neurosci. 2005;22:1417–1430. doi: 10.1111/j.1460-9568.2005.04338.x. [DOI] [PubMed] [Google Scholar]
  • 18.Colmers WF, Lukowiak K, Pittman QJ. Neuropeptide Y action in the rat hippocampal slice: site and mechanism of presynaptic inhibition. J Neurosci. 1988;8:3827–3837. doi: 10.1523/JNEUROSCI.08-10-03827.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Greber S, Schwarzer C, Sperk G. Neuropeptide Y inhibits potassium-stimulated glutamate release through Y2 receptors in rat hippocampal slices in vitro. Br J Pharmacol. 1994;113:737–740. doi: 10.1111/j.1476-5381.1994.tb17055.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Richichi C, Lin EJ, Stefanin D, et al. Anticonvulsant and antiepileptogenic effects mediated by adeno-associated virus vector neuropeptide Y expression in the rat hippocampus. J Neurosci. 2004;24:3051–3059. doi: 10.1523/JNEUROSCI.4056-03.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Noé F, Pool AH, Nissinen J, et al. Neuropeptide Y gene therapy decreases chronic spontaneous seizures in a rat model of temporal lobe epilepsy. Brain. 2008;131:1506–1515. doi: 10.1093/brain/awn079. [DOI] [PubMed] [Google Scholar]
  • 22.Pheng LH, Dumont Y, Founder A, Chabot JG, Beaudet A, Quirion R. Agonist- and antagonist-induced sequestration/intemalization of neuropeptide Y Y1 receptors in HEK293 cells. Br J Pharmacol. 2003;139:695–704. doi: 10.1038/sj.bjp.0705306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Sorensen AT, Nikitidou L, Ledri M, et al. Hippocampal NPY gene transfer attenuates seizures without affecting epilepsy-induced impairment of LTP. Exp Neurol. 2009;215:328–333. doi: 10.1016/j.expneurol.2008.10.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Holmes GL, Ben-Ari Y. Seizing hold of seizures (News and Views) Nat Med. 2003;9:994–996. doi: 10.1038/nm0803-994. [DOI] [PubMed] [Google Scholar]
  • 25.van Vliet EA, van Schaik R, Edelbroek PM, et al. Inhibition of the multidrug transporter P-glycoprotein improves seizure control in phenytoin-treated chronic epileptic rats. Epilepsia. 2006;47:672–680. doi: 10.1111/j.1528-1167.2006.00496.x. [DOI] [PubMed] [Google Scholar]
  • 26.Danger JM, Tonon MC, Jenks BG, et al. Neuropeptide Y: localization in the central nervous system and neuroendocrine functions. Fundam Clin Pharmacol. 1990;4:307–340. doi: 10.1111/j.1472-8206.1990.tb00497.x. [DOI] [PubMed] [Google Scholar]
  • 27.Hokfelt T, Broberger C, Zhang X, et al. Neuropeptide Y: some viewpoints on a multifaceted peptide in the normal and diseased nervous system. Brain Res Brain Res Rev. 1998;26:154–166. doi: 10.1016/S0165-0173(97)00052-0. [DOI] [PubMed] [Google Scholar]

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