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Gene Therapy for Neuroanesthesia

  • Ellen S. Hauck
  • James G. HeckerEmail author
Chapter

Abstract

Ischemic central nervous system (CNS) events during neurosurgery are potentially devastating events for patients. Currently, anesthetic management or neuroresuscitation after such injury is limited to the acute management of physiologic variables to ensure oxygenation, ventilation, and perfusion while also maintaining cerebral autoregulation. The term neuroprotection is often used interchangeably with neuroresuscitation, but is perhaps more aptly used to mean treatment prior to an ischemic CNS insult. Pathways and potential mechanisms for resuscitation after, and protection before a CNS ischemic event, have considerable overlap. However, in the near future, true neuroprotection may include delivery of prophylactic drugs, gene delivery, or other cellular manipulations prior to injury. This chapter focuses on advances in the field of gene therapy for neuroanesthesia. Potential targets for such neuroprotective therapy as well as the benefits and risks of gene delivery by viral and nonviral vectors are discussed.

Keywords

Neuroprotection Gene therapy Stress response Inflammation Viral vectors Nonviral vectors 

References

  1. 1.
    Hecker JG. Cerebral ischemia and neuroprotection. In: Ruskin KJ, Rosenbaum SH, Rampil IL, editors. Fundamentals of neuroanesthesia: a physiologic approach. 1st ed. Oxford: Oxford University Press; 2013.Google Scholar
  2. 2.
    Fukuda S, Warner DS. Cerebral protection. Br J Anaesth. 2007;99(1):10–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Urbano LA, Oddo M. Therapeutic hypothermia for traumatic brain injury. Curr Neurol Neurosci Rep. 2012;12(5):580–91.PubMedCrossRefGoogle Scholar
  4. 4.
    Kaneko T, Kibayashi K. Mild hypothermia facilitates the expression of cold-inducible RNA-binding protein and heat shock protein 70.1 in mouse brain. Brain Res. 2012;1466:128–36.PubMedCrossRefGoogle Scholar
  5. 5.
    Bandera E, Botteri M, Minelli C, Sutton A, Abrams KR, Latronico N. Cerebral blood flow threshold of ischemic penumbra and infarct core in acute ischemic stroke: a systematic review. Stroke. 2006;37(5):1334–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Huang J, Upadhyay UM, Tamargo RJ. Inflammation in stroke and focal cerebral ischemia. Surg Neurol. 2006;66(3):232–45.PubMedCrossRefGoogle Scholar
  7. 7.
    Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, et al. Tumor necrosis factor-alpha expression in ischemic neurons. Stroke. 1994;25(7):1481–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Hyakkoku K, Hamanaka J, Tsuruma K, Shimazawa M, Tanaka H, Uematsu S, et al. Toll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia. Neuroscience. 2010;171(1):258–67.PubMedCrossRefGoogle Scholar
  9. 9.
    Giuliano JS, Lahni PM, Wong HR, Wheeler DS. Pediatric sepsis - Part V: extracellular heat shock proteins: alarmins for the host immune system. Open Inflamm J. 2011;4:49–60.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Amantea D, Nappi G, Bernardi G, Bagetta G, Corasaniti MT. Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. FEBS J. 2009;276(1):13–26.PubMedCrossRefGoogle Scholar
  11. 11.
    Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol. 2006;147(Suppl 1):S232–40.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Yang MS, Min KJ, Joe E. Multiple mechanisms that prevent excessive brain inflammation. J Neurosci Res. 2007;85(11):2298–305.PubMedCrossRefGoogle Scholar
  13. 13.
    Dumas TC, Sapolsky RM. Gene therapy against neurological insults: sparing neurons versus sparing function. Trends Neurosci. 2001;24(12):695–700.PubMedCrossRefGoogle Scholar
  14. 14.
    Menon DK, Wheeler DW. Neuronal injury and neuroprotection. Anaesth Intensive Care Med. 2005;6(6):184–8.CrossRefGoogle Scholar
  15. 15.
    Kass I, Cottrell J, Lei B. Brain metabolism, the pathophysiology of brain injury, and potential beneficial agents and techniques. In: Neuroanesthesia. Philadelphia: Mosby Elsevier; 2011.Google Scholar
  16. 16.
    Loane DJ, Faden AI. Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends Pharmacol Sci. 2010;31(12):596–604.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Lange M, Hamahata A, Traber DL, Nakano Y, Traber LD, Enkhbaatar P. Heterogeneity of the effects of combined nitric oxide synthase inhibition on organ perfusion in ovine sepsis. Burns. 2013;39(8):1565–70.PubMedCrossRefGoogle Scholar
  18. 18.
    Cooke RM, Mistry R, Challiss RA, Straub VA. Nitric oxide synthesis and cGMP production is important for neurite growth and synapse remodeling after axotomy. J Neurosci. 2013;33(13):5626–37.PubMedCrossRefGoogle Scholar
  19. 19.
    Iadecola C, Anrather J. Stroke research at a crossroad: asking the brain for directions. Nat Neurosci. 2011;14(11):1363–8.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    An JJ, Lee YP, Kim SY, Lee SH, Lee MJ, Jeong MS, et al. Transduced human PEP-1-heat shock protein 27 efficiently protects against brain ischemic insult. FEBS J. 2008;275(6):1296–308.PubMedCrossRefGoogle Scholar
  21. 21.
    Hoehn B, Yenari MA, Sapolsky RM, Steinberg GK. Glutathione peroxidase overexpression inhibits cytochrome C release and proapoptotic mediators to protect neurons from experimental stroke. Stroke. 2003;34(10):2489–94.PubMedCrossRefGoogle Scholar
  22. 22.
    Gu W, Zhao H, Yenari MA, Sapolsky RM, Steinberg GK. Catalase over-expression protects striatal neurons from transient focal cerebral ischemia. Neuroreport. 2004;15(3):413–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Weller ML, Stone IM, Goss A, Rau T, Rova C, Poulsen DJ. Selective overexpression of excitatory amino acid transporter 2 (EAAT2) in astrocytes enhances neuroprotection from moderate but not severe hypoxia-ischemia. Neuroscience. 2008;155(4):1204–11.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Roy M, Hom J, Sapolsky RM. Neuroprotection with herpes simplex vectors expressing virally derived anti-apoptotic agents. Brain Res. 2001;901(1–2):12–22.PubMedCrossRefGoogle Scholar
  25. 25.
    Perdrizet GA, Lena CJ, Shapiro DS, Rewinski MJ. Preoperative stress conditioning prevents paralysis after experimental aortic surgery: increased heat shock protein content is associated with ischemic tolerance of the spinal cord. J Thorac Cardiovasc Surg. 2002;124(1):162–70.PubMedCrossRefGoogle Scholar
  26. 26.
    Gidday JM. Pharmacologic preconditioning: translating the promise. Transl Stroke Res. 2010;1(1):19–30.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Gidday JM. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci. 2006;7(6):437–48.PubMedCrossRefGoogle Scholar
  28. 28.
    McGrath LB, Locke M. Myocardial self-preservation: absence of heat shock factor activation and heat shock proteins 70 mRNA accumulation in the human heart during cardiac surgery. J Card Surg. 1995;10(4 Suppl):400–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Hecker JG, McGarvey M. Heat shock proteins as biomarkers for the rapid detection of brain and spinal cord ischemia: a review and comparison to other methods of detection in thoracic aneurysm repair. Cell Stress Chaperones. 2011;16(2):119–31.PubMedCrossRefGoogle Scholar
  30. 30.
    Armstead WM, Hecker JG. Heat shock protein modulation of KATP and KCa channel cerebrovasodilation after brain injury. Am J Physiol Heart Circ Physiol. 2005;289(3):H1184–90.PubMedCrossRefGoogle Scholar
  31. 31.
    Hecker JG, Sundram H, Zou S, Praestgaard A, Bavaria JE, Ramchandren S, et al. Heat shock proteins HSP70 and HSP27 in the cerebral spinal fluid of patients undergoing thoracic aneurysm repair correlate with the probability of postoperative paralysis. Cell Stress Chaperones. 2008;13(4):435–46.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Stenzel-Poore MP, Stevens SL, Xiong Z, Lessov NS, Harrington CA, Mori M, et al. Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states. Lancet. 2003;362(9389):1028–37.PubMedCrossRefGoogle Scholar
  33. 33.
    Hecker JG, Hall LL, Irion VR. Nonviral gene delivery to the lateral ventricles in rat brain: initial evidence for widespread distribution and expression in the central nervous system. Mol Ther. 2001;3(3):375–84.PubMedCrossRefGoogle Scholar
  34. 34.
    Li SD, Huang L. Gene therapy progress and prospects: non-viral gene therapy by systemic delivery. Gene Ther. 2006;13(18):1313–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Gao X, Kim KS, Liu D. Nonviral gene delivery: what we know and what is next. AAPS J. 2007;9(1):E92–104.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Hajj KA, Whitehead KA. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat Rev Mater. 2017;2:17056.  https://doi.org/10.1038/natrevmats.2017.56.CrossRefGoogle Scholar
  37. 37.
    Oh S, Pluhar GE, McNeil EA, Kroeger KM, Liu C, Castro MG, et al. Efficacy of nonviral gene transfer in the canine brain. J Neurosurg. 2007;107(1):136–44.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Huotari J, Helenius A. Endosome maturation. EMBO J. 2011;30(17):3481–500.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Walsh CL, Nguyen J, Tiffany MR, Szoka FC. Synthesis, characterization, and evaluation of ionizable lysine-based lipids for siRNA delivery. Bioconjug Chem. 2013;24(1):36–43.PubMedCrossRefGoogle Scholar
  40. 40.
    Nantz MH, Dicus CW, Hilliard B, Yellayi S, Zou S, Hecker JG. The benefit of hydrophobic domain asymmetry on the efficacy of transfection as measured by in vivo imaging. Mol Pharm. 2010;7(3):786–94.PubMedCrossRefGoogle Scholar
  41. 41.
    Patel S, Ashwanikumar N, Robinson E, DuRoss A, Sun C, Murphy-Benenato KE, et al. Boosting intracellular delivery of lipid nanoparticle-encapsulated mRNA. Nano Lett. 2017;17(9):5711–8.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Hauck ES, Zou S, Scarfo K, Nantz MH, Hecker JG. Whole animal in vivo imaging after transient, nonviral gene delivery to the rat central nervous system. Mol Ther. 2008;16(11):1857–64.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Hinderer C, Katz N, Buza EL, Dyer C, Goode T, Bell P, et al. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an AAV vector expressing human SMN. Hum Gene Ther. 2018;29(3):285–98.  https://doi.org/10.1089/hum.2018.015.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Flotte TR. Gene therapy: the first two decades and the current state-of-the-art. J Cell Physiol. 2007;213(2):301–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Berges BK, Wolfe JH, Fraser NW. Transduction of brain by herpes simplex virus vectors. Mol Ther. 2007;15(1):20–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Gore ME. Adverse effects of gene therapy: gene therapy can cause leukaemia: no shock, mild horror but a probe. Gene Ther. 2003;10(4):5.Google Scholar
  47. 47.
    Abdellatif AA, Pelt JL, Benton RL, Howard RM, Tsoulfas P, Ping P, et al. Gene delivery to the spinal cord: comparison between lentiviral, adenoviral, and retroviral vector delivery systems. J Neurosci Res. 2006;84(3):553–67.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Zou S, Scarfo K, Nantz MH, Hecker JG. Lipid-mediated delivery of RNA is more efficient than delivery of DNA in non-dividing cells. Int J Pharm. 2010;389(1–2):232–43.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Muttach F, Muthmann N, Rentmeister A. Synthetic mRNA capping. Beilstein J Org Chem. 2017;13:2819–32.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Holtkamp S, Kreiter S, Selmi A, Simon P, Koslowski M, Huber C, et al. Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells. Blood. 2006;108(13):4009–17.PubMedCrossRefGoogle Scholar
  51. 51.
    Karikó K, Weissman D. Naturally occurring nucleoside modifications suppress the immunostimulatory activity of RNA: implication for therapeutic RNA development. Curr Opin Drug Discov Devel. 2007;10(5):523–32.PubMedGoogle Scholar
  52. 52.
    Andries O, Mc Cafferty S, De Smedt SC, Weiss R, Sanders NN, Kitada T. N(1)-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice. J Control Release. 2015;217:337–44.PubMedCrossRefGoogle Scholar
  53. 53.
    Mashour GA. Consciousness versus responsiveness: insights from general anesthetics. Brain Cogn. 2011;77(3):325–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Tononi G. Information integration: its relevance to brain function and consciousness. Arch Ital Biol. 2010;148(3):299–322.PubMedGoogle Scholar
  55. 55.
    Tymianski M. Emerging mechanisms of disrupted cellular signaling in brain ischemia. Nat Neurosci. 2011;14(11):1369–73.PubMedCrossRefGoogle Scholar
  56. 56.
    DeGracia DJ. Towards a dynamical network view of brain ischemia and reperfusion. Part I: background and preliminaries. J Exp Stroke Transl Med. 2010;3(1):59–71.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Siegel M, Donner TH, Engel AK. Spectral fingerprints of large-scale neuronal interactions. Nat Rev Neurosci. 2012;13(2):121–34.PubMedCrossRefGoogle Scholar
  58. 58.
    Lee JK, Brady KM, Mytar JO, Kibler KK, Carter EL, Hirsch KG, et al. Cerebral blood flow and cerebrovascular autoregulation in a swine model of pediatric cardiac arrest and hypothermia. Crit Care Med. 2011;39(10):2337–45.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Brady K, Joshi B, Zweifel C, Smielewski P, Czosnyka M, Easley RB, et al. Real-time continuous monitoring of cerebral blood flow autoregulation using near-infrared spectroscopy in patients undergoing cardiopulmonary bypass. Stroke. 2010;41(9):1951–6.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Klein KU, Stadie A, Fukui K, Schramm P, Werner C, Oertel J, et al. Measurement of cortical microcirculation during intracranial aneurysm surgery by combined laser-Doppler flowmetry and photospectrometry. Neurosurgery. 2011;69(2):391–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Klein KU, Fukui K, Schramm P, Stadie A, Fischer G, Werner C, et al. Human cerebral microcirculation and oxygen saturation during propofol-induced reduction of bispectral index. Br J Anaesth. 2011;107(5):735–41.PubMedCrossRefGoogle Scholar
  62. 62.
    Navlakha S, Bar-Joseph Z. Algorithms in nature: the convergence of systems biology and computational thinking. Mol Syst Biol. 2011;7:546.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of AnesthesiologyLewis Katz School of Medicine at Temple UniversityPhiladelphiaUSA
  2. 2.Department of Anesthesiology and Pain MedicineHarborview Medical CenterSeattleUSA

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