Abstract
Gene transfer is a powerful, evolving technique that uses a biologic vehicle (eg, an engineered adenovirus) to introduce a specific gene of interest (ie, a recombinant gene) into a target tissue. This approach, which has considerable therapeutic potential, underlies the concept of gene therapy. Several studies have characterized the morphologic, biochemical, and functional effects of recombinant gene expression in animal and human cerebral arteries, and support the possibility of gene therapy for cerebrovascular disease. However, for successful integration into future clinical practice, key issues concerning vector safety, delivery methods, and transduction specificity need to be addressed. Alongside completion of the Human Genome Project, transfer of novel genes into the central nervous system is likely to impact greatly on our ability to favorably modify diseased human tissue. Knowledge of the fundamental concepts of cerebrovascular gene transfer is therefore useful to understanding both its molecular basis and potential clinical utility.
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References and Recommended Reading
Rosenberg SA, Aebersold P, Cornetta K, et al.: Gene transfer into humans: immunotherapy of patients with advanced melanoma using tumor infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med 1990, 323:570–578.
Brenner M: Reports of adenovector “death” are greatly exaggerated. Mol Ther 2000, 1:205.
Blau HM, Springer ML: Gene therapy — a novel form of drug delivery N Engl J Med 1995, 333:1204–1207.
Chen AFY, O’Brien T, Katusic ZS: Transfer and expression of recombinant nitric oxide synthase genes in the cardiovascular system. Trends Pharmacol Sci 1998, 19:276–286. A comprehensive review of the cardiovascular gene transfer literature.
O’Brien T: Gene transfer and vascular disease. Journal of the Irish Colleges of Physicians and Surgeons 1998, 27:33–39.
Onoue H, Tsutsui M, Smith L, et al.: Expression and function of recombinant endothelial nitric oxide synthase gene in canine basilar artery after experimental subarachnoid hemorrhage. Stroke 1998, 29:1959–1966.
Rekhter MD, Simari RD, Work CW, et al.: Gene transfer into normal and atherosclerotic human blood vessels. Circ Res 1998, 82:1243–1252.
Russell SJ: Science, medicine, and the future: gene therapy BMJ 1997, 315:1289–1292.
Dyer MR, Herrling PL: Progress and potential for gene-based medicines. Mol Ther 2000, 1:213–224. An excellent review of the fundamental principles and applications of gene therapy.
Carter BJ: Gene therapy as drug development. Mol Ther 2000, 1:211–212. An overview of the importance of applying rigorous pharmacologic standards and methods in the development and utilization of vectors and gene delivery systems.
Heistad DD, Faraci FM: Gene therapy for cerebral vascular disease. Stroke 1996, 27:1688–1693.
Richter M, Iwata A, Nyhuis J, et al.: Adeno-associated virus vector transduction of vascular smooth muscle cells in vivo. Physiol Genom 2000, 2:117–127.
Ono S, Date I, Onoda K, et al.: Decoy administration of NF-kB into the subarachnoid space for cerebral angiopathy. Human Gene Ther 1998, 9:1003–1011.
Von der Leyen HE, Gibbons GH, Morishita R, et al.: Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Natl Acad Sci U S A 1995, 92:1137–1141.
Newman KD, Dunn PF, Owens JW, et al.: Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia. J Clin Invest 1995, 96:2955–2965.
Thomas CE, Schiedner G, Kochanek S, et al.: Peripheral infection with adenovirus causes unexpected long-term brain inflammation in animals injected intracranially with firstgeneration, but not with high-capacity, adenovirus vectors: toward realistic long-term neurological gene therapy for chronic disease. Proc Natl Acad Sci U S A 2000, 97:7482–7487.
Vassalli G, Agah R, Qiao R, et al.: A mouse model of arterial gene transfer: antigen-specific immunity is a minor determinant of the early loss of adenovirus-mediated transgene expression. Circ Res (Online) 1999, 85:e25-e32.
Wen S, Schneider DB, Driscoll RM, et al.: Second-generation adenoviral vectors do not prevent rapid loss of transgene expression and vector DNA from the arterial wall. Arterioscler Thromb Vasc Biol 2000, 20:1452–1458.
Wood MJA, Charlton HM, Wood KJ, et al.: Immune responses to adenovirus vectors in the nervous system. Trends Neurosci 1996, 19:497–501.
Chen AFY, O’Brien T, Tsutsui M, et al.: Expression and function of recombinant endothelial nitric oxide synthase gene in canine basilar artery. Circ Res 1997A, 80:327–335.
Spector DJ, Samaniego LA: Construction and isolation of recombinant adenovirus with gene replacements. In Viral Gene Techniques: Methods in Molecular Genetics vol 7. Edited by Cole KW. San Diego: Academic Press; 1995:31–44.
Bergelson JM, Cunningham JA, Droguett G, et al.: Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5. Science 1997, 275:1320–1323.
Wickham TJ, Mathias P, Cheresh DA, Nemerow GR: Integrins avb3 and avb5 promote adenovirus internalization but not virus attachment. Cell 1993, 73:309–319.
Channon KM, Blazing MA, Shetty GA, et al.: Adenoviral gene transfer of nitric oxide synthase: high level expression in human vascular cells. Cardiovasc Res 1996, 32:962–972.
Hobbs AJ, Higgs A, Moncada S: Inhibition of nitric oxide synthase as a potential therapeutic target. Ann Rev Pharmacol Toxicol 1999, 39:191–220. Comprehensively reviews the role of nitric oxide synthase isoforms as potential molecular targets for pharmacologic therapy.
Khurana VG, Besser M: Pathophysiological basis of cerebral vasospasm following aneurysmal subarachnoid haemorrhage. J Clin Neurosci 1997, 4:122–131.
Moncada S, Palmer RMJ, Higgs EA: Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991, 43:109–142.
Thomas JE, Rosenwasser RH, Armondo RA, et al.: Safety of intrathecal sodium nitroprusside for the treatment and prevention of refractory cerebral vasospasm and ischemia in humans. Stroke 1999, 30:1409–1416.
Vanhoutte PM: Endothelial dysfunction and inhibition of converting enzyme. Eur Heart J 1998, 19:J7-J15.
Vanhoutte PM: How to assess endothelial function in human blood vessels. J Hypertension 1999, 17:1047–1058.
Onoue H, Tsutsui M, Smith L, O’Brien T, Katusic ZS: Adventitial expression of recombinant endothelial nitric oxide synthase gene reverses vasoconstrictor effect of endothelin-1. J Cerebr Blood Flow Metab 1999, 19:1029–1037.
Suzuki H, Kanamaru K, Tsunoda H, et al.: Heme oxygenase-1 gene induction as an intrinsic regulation against delayed cerebral vasospasm in rats. J Clin Invest 1999, 104:59–66.
Toyoda K, Faraci FM, Russo AF, et al.: Gene transfer of calcitonin gene-related peptide to cerebral arteries. Am J Physiol 2000A, 278:H586-H594.
Khurana VG, Smith LA, Weiler DA, et al.: Adenovirus-mediated gene transfer to human cerebral arteries. J Cerebr Blood Flow Metab 2000, 20:1360–1371. This recent scientific article represents the first morphologic and functional characterization of the effects of gene transfer in the human cerebral vasculature.
Kullo IJ, Mozes G, Schwartz RS, et al.: Enhanced endotheliumdependent relaxations after gene transfer of recombinant endothelial nitric oxide synthase to rabbit carotid arteries. Hypertension 1997, 30:314–320.
Ooboshi H, Chu Y, Rios CD, et al.: Altered vascular function after adenovirus-mediated overexpression of endothelial nitric oxide synthase. Am J Physiol 1997, 273:H265-H270.
Tsutsui M, Onoue H, Iida Y, et al.: Effects of recombinant eNOS gene expression on reactivity of small cerebral arteries. Am J Physiol 2000B, 278:H420-H427.
Chen AFY, Jiang SW, Crotty TB, et al.: Effects of in vivo adventitial expression of recombinant endothelial nitric oxide synthase gene in cerebral arteries. Proc Natl Acad Sci U S A 1997B, 94:12568–12573. This study represents the first functional characterization of the effects of gene transfer to animal cerebral arteries in vivo.
Christenson SD, Lake KD, Ooboshi H, et al.: Adenovirusmediated gene transfer in vivo to cerebral blood vessels and perivascular tissue in mice. Stroke 1998, 29:1411–1416.
Ooboshi H, Welsh MJ, Rios CD, et al.: Adenovirus-mediated gene transfer in vivo to cerebral blood vessels and perivascular tissue. Circ Res 1995, 77:7–13.
Stoodley M, Weihl CC, Zhang ZD, et al.: Effect of adenovirus mediated nitric oxide synthase gene transfer on vasospasm after experimental subarachnoid hemorrhage. Neurosurgery 2000, 45:1193–1203.
Toyoda K, Andresen JJ, Zabner J, et al.: Calcium phosphate precipitates augment adenovirus-mediated gene transfer to blood vessels in vitro and in vivo. Gene Ther 2000B, 7:1284–1291.
Tsutsui M, Chen AFY, O’Brien T, et al.: Adventitial expression of recombinant eNOS gene restores NO production in arteries without endothelium. Arterioscler Thromb Vasc Biol 1998, 18:1231–1241.
Tsutsui M, Onoue H, Iida Y, et al.: B1 and B2 bradykinin receptors on adventitial fibroblasts of cerebral arteries are coupled to recombinant eNOS. Amer J Physiol 2000A, 278:H367-H372.
Kim S, Lin H, Barr E, et al.: Transcriptional targeting of replication-defective adenovirus transgene expression to smooth muscle cells in vivo. J Clin Invest 1997, 100:1006–1014.
Davidson BL, Allen ED, Kozarsky KF, et al.: A model system for in vivo gene transfer into the central nervous system using an adenoviral vector. Nat Genet 1993, 3:219–223.
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Khurana, V.G., Katusic, Z.S. Gene transfer for cerebrovascular disease. Curr Cardiol Rep 3, 10–16 (2001). https://doi.org/10.1007/s11886-001-0004-2
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DOI: https://doi.org/10.1007/s11886-001-0004-2