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Gene Therapy in Epilepsy

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Antiepileptic Drug Discovery

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

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Abstract

The genetic modification of cell cultures and their transplantation into the brain is an effective ex vivo gene therapy. This transfer of genes via the genetic engineering of viruses or plasmids and subsequent transfection into cells that will express transgenes in the central nervous system (CNS) may allow specific treatment in epileptogenic foci while sparing healthy brain tissue, and minimize the side effects of antiepileptic drug treatment. Prime modification candidates are neuropeptide Y (NPY) and galanin, which are important modulators of neuronal excitability. These neurotransmitters exhibit an inhibitory effect on neuronal activity and provide anticonvulsant effects in animal models. Galanin also exhibits neuroprotective properties. Other modification candidates are adenosine, which acts as an endogenous anticonvulsant, and the glial cell line-derived neurotrophic factor (GDNF), which exerts neuroprotective and anticonvulsive actions. Recombinant adeno-associated viral vectors can release any of these agents because of their neuronal tropism, lack of toxicity, and stable persistence in neurons. This chapter provides an overview of gene therapy methods, and reviews several studies that used neural and non-neuronal cell transplants as a basis for expanding our understanding of diseases that affect the CNS and possible therapeutic alternatives.

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References

  1. Jorde LB, Carey JC, Bamshad MJ, White RL (1999) Genética médica. Harcourt, Madrid

    Google Scholar 

  2. Chuah MK, Collen D, Vandendriessche T (2004) Preclinical and clinical gene therapy for haemophilia. Haemophilia 10:119–125

    Article  PubMed  Google Scholar 

  3. Lazo PA (1996) Terapia génica humana: tendencias y problemas. Med Clin (Barc) 106:469–476

    CAS  Google Scholar 

  4. Ronchera-Oms CL, González JM (2013) Terapia génica. In: Gamundi Planas MC (coord) Farmacia hospitalaria, vol 2. SEFH, Madrid, pp 919–927

    Google Scholar 

  5. Rogawski MA, Löscher W (2004) The neurobiology of antiepileptic drugs. Nat Rev Neurosci 5:553–564

    Article  CAS  PubMed  Google Scholar 

  6. Pitkänen A, Sutula TP (2002) Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Lancet Neurol 1:173–181

    Article  PubMed  Google Scholar 

  7. Duncan JS, Sander JW, Sisodiya SM et al (2006) Adult epilepsy. Lancet 367:1087–1100

    Article  PubMed  Google Scholar 

  8. Foldvary N, Bingaman WE, Wyllie E (2001) Surgical treatment of epilepsy. Neurol Clin 19:491–515

    Article  CAS  PubMed  Google Scholar 

  9. Ben-Ari Y (2001) Cell death and synaptic reorganizations produced by seizures. Epilepsia 42(Suppl 3):S5–S7

    Article  Google Scholar 

  10. Gökhan S, Song Q, Mehler MF (1998) Generation and regulation of developing immortalized neural cell lines. Methods 16:345–358

    Article  PubMed  Google Scholar 

  11. Conejero-Goldberg C, Tornatore C, Abi-Saab W et al (2000) Transduction of human GAD67 cDNA into immortalized striatal cell lines using an Epstein-Barr virus-based plasmid vector increases GABA content. Exp Neurol 161:453–461

    Article  CAS  PubMed  Google Scholar 

  12. Orozco E, Gariglio P (1999) Genética y biomedicina molecular. Limusa, México D.F

    Google Scholar 

  13. Klug WS, Cummings MR (1999) Conceptos de genética. Prentice Hall, Madrid

    Google Scholar 

  14. Lindvall O, Odin P (1994) Clinical application of cell transplantation and neurotrophic factors in CNS disorders. Curr Opin Neurobiol 4:752–757

    Article  CAS  PubMed  Google Scholar 

  15. Jakobsson J, Lundberg C (2006) Lentiviral vectors for use in the central nervous system. Mol Ther 13:484–493

    Article  CAS  PubMed  Google Scholar 

  16. Mazarakis ND, Azzouz M, Rohll JB et al (2001) Rabies virus glycoprotein pseudotyping of lentiviral vectors enables retrograde axonal transport and access to the nervous system after peripheral delivery. Hum Mol Genet 10:2109–2121

    Article  CAS  PubMed  Google Scholar 

  17. Wong LF, Azzouz M, Walmsley LE et al (2004) Transduction patterns of pseudotyped lentiviral vectors in the nervous system. Mol Ther 9:101–111

    Article  CAS  PubMed  Google Scholar 

  18. Beard BC, Keyser KA, Trobridge GD et al (2007) Unique integration profiles in a canine model of long-term repopulating cells transduced with gammaretrovirus, lentivirus, or foamy virus. Hum Gene Ther 18:423–434

    Article  CAS  PubMed  Google Scholar 

  19. Derse D, Crise B, Li Y et al (2007) Human T-cell leukemia virus type 1 integration target sites in the human genome: comparison with those of other retroviruses. J Virol 81:6731–6741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang Y, Li Q, Ertl H et al (1995) Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J Virol 69:2004–2015

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Varnavski AN, Calcedo R, Bove M et al (2005) Evaluation of toxicity from high-dose systemic administration of recombinant adenovirus vector in vector-naive and pre-immunized mice. Gene Ther 12:427–436

    Article  CAS  PubMed  Google Scholar 

  22. Castle MJ, Perlson E, Holzbaur EL et al (2014) Long-distance axonal transport of AAV9 is driven by dynein and kinesin-2 and is trafficked in a highly motile Rab7-positive compartment. Mol Ther 22:554–566

    Article  CAS  PubMed  Google Scholar 

  23. Towne C, Schneider BL, Kieran D et al (2010) Efficient transduction of non-human primate motor neurons after intramuscular delivery of recombinant AAV serotype 6. Gene Ther 17:141–146

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Lovric J, Mano M, Zentilin L et al (2012) Terminal differentiation of cardiac and skeletal myocytes induces permissivity to AAV transduction by relieving inhibition imposed by DNA damage response proteins. Mol Ther 20:2087–2097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rosas LE, Grieves JL, Zaraspe K et al (2012) Patterns of scAAV vector insertion associated with oncogenic events in a mouse model for genotoxicity. Mol Ther 20:2098–2110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhao J, Lever AM (2007) Lentivirus-mediated gene expression. Methods Mol Biol 366:343–355

    Article  CAS  PubMed  Google Scholar 

  28. Hickey WF (2001) Basic principles of immunological surveillance of the normal central nervous system. Glia 36:118–124

    Article  CAS  PubMed  Google Scholar 

  29. Hacein-Bey-Abina S, Von Kalle C, Schmidt M et al (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–419

    Article  CAS  PubMed  Google Scholar 

  30. Berges BK, Wolfe JH, Fraser NW (2007) Transduction of brain by herpes simplex virus vectors. Mol Ther 15:20–29

    Article  CAS  PubMed  Google Scholar 

  31. McMenamin MM, Byrnes AP, Charlton HM et al (1998) A gamma34.5 mutant of herpes simplex 1 causes severe inflammation in the brain. Neuroscience 83:1225–1237

    Article  CAS  PubMed  Google Scholar 

  32. Yenari MA, Fink SL, Sun GH et al (1998) Gene therapy with HSP72 is neuroprotective in rat models of stroke and epilepsy. Ann Neurol 44:584–591

    Article  CAS  PubMed  Google Scholar 

  33. Laing JM, Gober MD, Golembewski EK et al (2006) Intranasal administration of the growth-compromised HSV-2 vector DeltaRR prevents kainate-induced seizures and neuronal loss in rats and mice. Mol Ther 13:870–881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ruitenberg MJ, Eggers R, Boer GJ et al (2002) Adeno-associated viral vectors as agents for gene delivery: application in disorders and trauma of the central nervous system. Methods 28:182–194

    Article  CAS  PubMed  Google Scholar 

  35. Barker RA, Widner H (2004) Immune problems in central nervous system cell therapy. NeuroRx 1:472–481

    Article  PubMed  PubMed Central  Google Scholar 

  36. Zufferey R, Nagy D, Mandel RJ et al (1997) Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat Biotechnol 15:871–875

    Article  CAS  PubMed  Google Scholar 

  37. Blesch A, Conner J, Pfeifer A et al (2005) Regulated lentiviral NGF gene transfer controls rescue of medial septal cholinergic neurons. Mol Ther 11:916–925

    Article  CAS  PubMed  Google Scholar 

  38. Ralph GS, Radcliffe PA, Day DM et al (2005) Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat Med 11:429–433

    Article  CAS  PubMed  Google Scholar 

  39. Broekman ML, Comer LA, Hyman BT et al (2006) Adeno-associated virus vectors serotyped with AAV8 capsid are more efficient than AAV-1 or -2 serotypes for widespread gene delivery to the neonatal mouse brain. Neuroscience 138:501–510

    Article  CAS  PubMed  Google Scholar 

  40. Berkovic SF, Mulley JC, Scheffer IE et al (2006) Human epilepsies: interaction of genetic and acquired factors. Trends Neurosci 29:391–397

    Article  CAS  PubMed  Google Scholar 

  41. Vezzani A (2004) Gene therapy in epilepsy. Epilepsy Curr 4:87–90

    Article  PubMed  PubMed Central  Google Scholar 

  42. Simonato M, Bennett J, Boulis NM et al (2013) Progress in gene therapy for neurological disorders. Nat Rev Neurol 9:277–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Löscher W, Ebert U, Lehmann H et al (1998) Seizure suppression in kindling epilepsy by grafts of fetal GABAergic neurons in rat substantia nigra. J Neurosci Res 51:196–209

    Article  PubMed  Google Scholar 

  44. Ruppert C, Sandrasagra A, Anton B et al (1993) Rat-1 fibroblasts engineered with GAD65 and GAD67 cDNAs in retroviral vectors produce and release GABA. J Neurochem 61:768–771

    Article  CAS  PubMed  Google Scholar 

  45. Sacchettoni SA, Benchaibi M, Sindou M et al (1998) Glutamate-modulated production of GABA in immortalized astrocytes transduced by a glutamic acid decarboxylase-expressing retrovirus. Glia 22:86–93

    Article  CAS  PubMed  Google Scholar 

  46. Gernert M, Thompson KW, Löscher W et al (2002) Genetically engineered GABA-producing cells demonstrate anticonvulsant effects and long-term transgene expression when transplanted into the central piriform cortex of rats. Exp Neurol 176:183–192

    Article  CAS  PubMed  Google Scholar 

  47. Liu W, He X, Cao Z et al (2005) Efficient therapeutic gene expression in cultured rat hippocampal neurons mediated by human foamy virus vectors: a potential for the treatment of neurological diseases. Intervirology 48:329–335

    Article  CAS  PubMed  Google Scholar 

  48. Castillo CG, Mendoza S, Freed WJ et al (2006) Intranigral transplants of immortalized GABAergic cells decrease the expression of kainic acid-induced seizures in the rat. Behav Brain Res 171:109–115

    Article  CAS  PubMed  Google Scholar 

  49. Raol YH, Lund IV, Bandyopadhyay S et al (2006) 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 26:11342–11346

    Article  CAS  PubMed  Google Scholar 

  50. During MJ, Symes CW, Lawlor PA et al (2000) An oral vaccine against NMDAR1 with efficacy in experimental stroke and epilepsy. Science 287:1453–1460

    Article  CAS  PubMed  Google Scholar 

  51. Haberman R, Criswell H, Snowdy S et al (2002) Therapeutic liabilities of in vivo viral vector tropism: adeno-associated virus vectors, NMDAR1 antisense, and focal seizure sensitivity. Mol Ther 6:495–500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Richichi C, Lin EJ, Stefanin D et al (2004) Anticonvulsant and antiepileptogenic effects mediated by adeno-associated virus vector neuropeptide Y expression in the rat hippocampus. J Neurosci 24:3051–3059

    Article  CAS  PubMed  Google Scholar 

  53. Zhang LX, Li XL, Smith MA et al (1997) Lipofectin-facilitated transfer of cholecystokinin gene corrects behavioral abnormalities of rats with audiogenic seizures. Neuroscience 77:15–22

    Article  CAS  PubMed  Google Scholar 

  54. McCown TJ (2006) Adeno-associated virus-mediated expression and constitutive secretion of galanin suppresses limbic seizure activity in vivo. Mol Ther 14:63–68

    Article  CAS  PubMed  Google Scholar 

  55. Golembewski EK, Wales SQ, Aurelian L et al (2007) The HSV-2 protein ICP10PK prevents neuronal apoptosis and loss of function in an in vivo model of neurodegeneration associated with glutamate excitotoxicity. Exp Neurol 203:381–393

    Article  CAS  PubMed  Google Scholar 

  56. Simonato M, Zucchini S (2010) Are the neurotrophic factors a suitable therapeutic target for the prevention of epileptogenesis? Epilepsia 51(Suppl 3):48–51

    Article  CAS  PubMed  Google Scholar 

  57. Simonato M, Tongiorgi E, Kokaia M (2006) Angels and demons: neurotrophic factors and epilepsy. Trends Pharmacol Sci 27:631–638

    Article  CAS  PubMed  Google Scholar 

  58. Paradiso B, Marconi P, Zucchini S et al (2009) Localized delivery of fibroblast growth factor-2 and brain-derived neurotrophic factor reduces spontaneous seizures in an epilepsy model. Proc Natl Acad Sci U S A 106:7191–7196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rowland NC, Kalia SK, Kalia LV et al (2016) Merging DBS with viral vector or stem cell implantation: “hybrid” stereotactic surgery as an evolution in the surgical treatment of Parkinson’s disease. Mol Ther Methods Clin Dev 3:15051

    Article  PubMed  PubMed Central  Google Scholar 

  60. Kasperaviciūte D, Catarino CB, Heinzen EL et al (2010) Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study. Brain 133(Pt 7):2136–2147

    Article  PubMed  PubMed Central  Google Scholar 

  61. O’Connor WM, Davidson BL, Kaplitt MG et al (1997) Adenovirus vector-mediated gene transfer into human epileptogenic brain slices: prospects for gene therapy in epilepsy. Exp Neurol 148:167–178

    Article  PubMed  Google Scholar 

  62. Simonato M (2014) Gene therapy for epilepsy. Epilepsy Behav 38:125–130

    Article  PubMed  Google Scholar 

  63. Zorzano A (2003) Terapia génica en endocrinología: una aproximación realista. Endocrinol Nutr 50:244–249

    Article  CAS  Google Scholar 

  64. Walker MC, Schorge S, Kullmann DM et al (2013) Gene therapy in status epilepticus. Epilepsia 54(Suppl 6):43–45

    Article  CAS  PubMed  Google Scholar 

  65. Tønnesen J, Sørensen AT, Deisseroth K et al (2009) Optogenetic control of epileptiform activity. Proc Natl Acad Sci U S A 106:12162–12167

    Article  PubMed  PubMed Central  Google Scholar 

  66. Young D, Fong DM, Lawlor PA et al (2014) Adenosine kinase, glutamine synthetase and EAAT2 as gene therapy targets for temporal lobe epilepsy. Gene Ther 21:1029–1040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Waldau B, Hattiangady B, Kuruba R et al (2010) Medial ganglionic eminence-derived neural stem cell grafts ease spontaneous seizures and restore GDNF expression in a rat model of chronic temporal lobe epilepsy. Stem Cells 28:1153–1164

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Noe F, Nissinen J, Pitkänen A et al (2007) Gene therapy in epilepsy: the focus on NPY. Peptides 28(2):377–383

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Council of Science and Technology, grant number 248004.

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Authors and Affiliations

  1. Unidad de Investigación Médica en Enfermedades Neurológicas. Hospital de Especialidades del Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, 06720, México City, México

    Miguel A. López-García, Iris A. Feria-Romero, Julia J. Segura-Uribe, David Escalante-Santiago & Sandra Orozco-Suárez

  2. Programa de Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Unidad-Iztapalapa, México City, México

    Miguel A. López-García

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  1. Miguel A. López-García
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  2. Iris A. Feria-Romero
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  3. Julia J. Segura-Uribe
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  4. David Escalante-Santiago
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  5. Sandra Orozco-Suárez
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Correspondence to Sandra Orozco-Suárez .

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Editors and Affiliations

  1. Laboratorio de Investigación y Desarrollo de Bioactivos (LIDeB) Faculty of Exact Sciences, National University of La Plata, La Plata, Buenos Aires, Argentina

    Alan Talevi

  2. Department of Pharmacobiology, Center for Research and Advanced Studies, Mexico City, Mexico

    Luisa Rocha

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López-García, M.A., Feria-Romero, I.A., Segura-Uribe, J.J., Escalante-Santiago, D., Orozco-Suárez, S. (2016). Gene Therapy in Epilepsy. In: Talevi, A., Rocha, L. (eds) Antiepileptic Drug Discovery. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6355-3_10

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  • DOI: https://doi.org/10.1007/978-1-4939-6355-3_10

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6353-9

  • Online ISBN: 978-1-4939-6355-3

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