| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Themed Issue papers |
1 Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa College of Medicine, Iowa City, IA,USA2 Veterans Affairs Medical Center, Iowa City, IA,USA
 |
Abstract |
|---|
 Top Abstract IntroductionReferences |
|---|
(Received 12 January 2005;
accepted after revision 1 February 2005; first published online 18 March 2005)
Corresponding author D. D. Heistad: Department of Internal Medicine, University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA. Email: donald-heistad{at}uiowa.edu
|
Introduction |
|---|
|
TopAbstractIntroductionReferences |
|---|
Approaches to modify gene expression in cerebral arteries
Modification of the expression of genes which are relevant to disease states is the basic strategy of gene therapy. For this purpose, genes or nucleotides with therapeutic potency are introduced into the target organ or cells.
Cerebral arteries supply tissue that is unusually susceptible to ischaemia, and ischaemic damage to a small region of the brain can produce neurological deficits. Thus, during the procedure for introducing genes or nucleotides into cerebral arteries, close attention must be paid to avoid interruption of blood flow even to a small region of the brain. In many studies using rodents, genes or nucleotides are introduced into the carotid artery by intraluminal administration of vectors, which usually requires interruption of blood flow for 10–30 min. In humans, however, the brain would be exposed to severe ischaemia by this procedure, especially in patients who are at risk for cerebral ischaemia.
One way to circumvent this problem is to deliver genes or nucleotides from the outside of arteries. By this ‘perivascular’ approach, cells in the adventitia and perivascular tissue are transfected with genes or nucleotides. For example, transgene expression is accomplished in the adventitia and perivascular tissue surrounding cerebral arteries on the surface of the brain after injection of an adenoviral vector into the subarachnoid space (Ooboshi et al. 1995). It does not seem possible to introduce genes or nucleotides into selected segments of cerebral arteries by this method, but widespread transfection may be advantageous for treatment of some types of cerebrovascular disorders characterized by diffuse abnormality of the intracranial arteries. For the extracranial carotid artery, to which direct access is also possible by exposure of the vessel, perivascular gene/nucleotide delivery can be achieved by injection of vectors into the periarterial sheath (Ríos et al. 1995), by use of the ‘paintbrush’ technique for adenoviral vectors (Khurana et al. 2003) or by placement of slow-releasing polymers containing ODNs or plasmid cDNAs (Indolfi et al. 1995).
Either by intraluminal or by perivascular approach, cells in different layers of the vessel wall can be transfected heterogeneously. For example, adenovirus-mediated gene transfer produces transgene expression mainly in endothelium or adventitia, while medial smooth muscle cells usually are not transfected at all (Ooboshi et al. 1995; Ríos et al. 1995; Schulick et al. 1995). In order to affect the medial layer of the vessel wall by transfecting endothelial or adventitial cells, a common strategy is to modify expression of biomolecules that are released from transfected cells, to accomplish therapeutic effects on smooth muscle cells indirectly.
Presently, accessibility to cerebral arteries is limited in terms of gene/nucleotide delivery. In addition, topical transfection is difficult in intracranial arteries. Further improvements in methods for obtaining access to cerebral arteries are required for more effective and selective targeting of gene/nucleotide delivery.
Attempts to apply gene therapy to cerebrovascular disorders
Transient therapeutic effects after gene therapy are presently one of the major problems for treatment of chronic diseases. It may not be necessary, however, to maintain long-term transgene expression for successful treatment of some cardiovascular diseases, such as restenosis after angioplasty and chronic ischaemia with poor collateral circulation, as suggested previously (Isner et al. 2001). Nevertheless, effective gene therapy may not be possible for some cerebrovascular disorders, because the time required to obtain transgene expression or downregulation of expression of a specific gene may not fit within the therapeutic time window. Several possible targets for experimental gene therapy in animal models of cerebrovascular disorders have been studied, as summarized below.
Cerebral vasospasm. Delayed cerebral vasospasm is a major complication after SAH. No effective therapy is established for prevention of sustained constriction of cerebral arteries, which may cause severe ischaemic damage to the brain (Treggiari-Venzi et al. 2001). Several unique characteristics of cerebral vasospasm after SAH provide a good rationale for application of gene therapy to the syndrome. First, there is a substantial period of time for modification of gene expression between SAH and development of vasospasm. Second, prolonged effects of gene therapy are not required, because risk of vasospasm is transient. Third, for adenovirus-mediated gene transfer, subarachnoid blood is not a physical barrier against transfection of the target vessels (Muhonen et al. 1997; Onoue et al. 1998).
Enhancement of a vasodilator mechanism by gene transfer of calcitonin gene-related peptide (CGRP), a vasodilator neuropeptide, is effective in prevention of vasospasm after SAH in rabbits and dogs (Toyoda et al. 2000; Satoh et al. 2002b). This strategy has a good rationale, because vasodilation in response to activators of ATP-sensitive K+ channels, which are also activated by CGRP, is preserved or enhanced in cerebral arteries after experimental SAH (Sobey et al. 1997). In contrast, overexpression of endothelial nitric oxide synthase in cerebral arteries failed to prevent vasospasm (Stoodley et al. 2000). This failure may be due to inactivation of nitric oxide (Sobey & Faraci, 1998) or increased degradation of cyclic guanosine monophosphate (Sobey & Quan, 1999).
Other targets for gene therapy, including modification of stress-induced cellular responses and/or cellular protection mechanisms (Ono et al. 1998, 2002; Watanabe et al. 2003; Yamaguchi et al. 2004) and downregulation of vasoconstrictor signalling (Ohkuma et al. 1999; Satoh et al. 2002a), have also been tested for prevention of vasospasm in experimental models of SAH (Table 1).
|
Presently, there is no pathway that is clearly the most appropriate for treatment of vasospasm, because the mechanisms of development, maintenance and resolution of cerebral vasospasm are not fully understood. Elucidation of the pathophysiological mechanisms of vasospasm will greatly benefit the development of effective gene therapy technique for vasospasm following SAH.
Chronic cerebral ischaemia with poor collateral circulation. For patients with chronic cerebral ischaemia, possibly with ‘hibernating’ neurones, restoration of cerebral blood flow by development of collateral circulation is critical for improvement of prognosis. In a global cerebral hypoperfusion model of rats, gene transfer of HGF and VEGF into the subarachnoid space stimulated angiogenesis in the brain, resulting in increased cerebral blood flow (Yoshimura et al. 2002). Thus, chronic and diffuse cerebral ischaemia/hypoperfusion may be treated by therapeutic angiogenesis. It is not yet clear, however, whether this strategy can be applied to treatment of focal brain ischaemia.
Safety issues for therapeutic angiogenesis in the peripheral circulation have been raised following accumulation of experience from clinical trials (Isner et al. 2001). For example, it is possible that vascular malformations may develop at the site of angiogenesis, and predispose to haemorrhagic stroke.
Restenosis of the extracranial carotid artery. In coronary arteries, restenosis after angioplasty and stenting is one of the major targets of gene therapy (Kibbe et al. 2000). Recently, the number of carotid angioplasties with Stenting has increased greatly. Restenosis of the carotid artery after the procedure is a potential target for gene therapy, although the incidence of restenosis in the carotid artery may not be as high as in the coronary and iliofemoral arteries (Chakhtoura et al. 2001).
Carotid arteries of small animals are widely used for a model of neointima formation after endothelial injury. Using this model, many studies have reported effective reduction of neointima formation by targeting various genes and with several strategies for gene therapy (Smith & Walsh, 2001). As described earlier, genes or nucleotides are generally delivered intraluminally with interruption of carotid blood flow. Recent developments in catheter- or stent-based gene/nucleotide delivery systems may provide a solution for safe and effective intraluminal approaches to the carotid artery, to avoid prolonged interruption of blood flow (Marshall et al. 2000; Takahashi et al. 2003). Most studies, however, involve small animals, and the long-term outcome of the approaches is not clear. Preclinical studies with an experimental design more relevant to the clinical setting are needed.
Other possible targets. In addition to the cerebrovascular disorders described above, cerebral aneurysms and atherosclerotic lesions of cerebral arteries are possible targets of cerebrovascular gene therapy. In order to approach these targets, establishment of techniques for topical gene therapy in cerebral arteries, such as development of endovascular devices carrying vectors, is necessary (Ribourtout & Raymond, 2004).
Safety issues in cerebrovascular gene therapy
Several initial steps towards establishment of cerebrovascular gene therapy have been relatively successful. Now, the major obstacle and urgent problem relates to safety of the techniques, especially the toxicity and pathogenicity of vectors used for the gene/nucleotide delivery (Lehrman, 1999; Marshall, 2003). Systemic toxicity of adenoviral vectors, which are one of the most promising vectors for cerebrovascular gene therapy, is unlikely when vectors are administered locally to cerebral arteries. Inflammatory and immune responses, however, are the most serious problems caused by adenoviral vectors, even after topical gene transfer to cerebral arteries. In an attempt to reduce adverse effects, intensive efforts have been made to construct a new generation of adenoviral vectors (Kay et al. 2001). Cell-based gene therapy techniques, such as transplantation of endothelial progenitor cells that are transfected with therapeutic genes ex vivo, may also be useful to circumvent the safety problems of vectors (Kong et al. 2004).
In addition to development of safe vectors, pharmacokinetics of the vectors and adverse effects caused by modification of specific genes must be clarified (Pislaru et al. 2002). Evaluation of neurological and/or psychological functions will also be important.
Conclusion
Substantial progress has been made to develop gene therapy for cerebral arterial diseases. Efforts have borne fruit by establishment of some aspects of fundamental technology. Before clinical use of cerebrovascular gene therapy, however, many basic and preclinical studies are needed to establish safe and effective techniques. In addition, elucidation of molecular mechanisms in the pathophysiology of target diseases will facilitate development of effective strategies for cerebrovascular gene therapy.
|
References |
|---|
|
TopAbstractIntroductionReferences |
|---|
Heistad
DD
&
Faraci
FM (1996). Gene therapy for cerebral vascular disease. Stroke
27, 1688–1693.
Indolfi C, Avvedimento EV, Rapacciuolo A, Di Lorenzo E, Esposito G, Stabile E et al. (1995). Inhibition of cellular ras prevents smooth muscle cell proliferation after vascular injury in vivo. Nat Med 1, 541–545. 10.1038/nm0695-541[CrossRef][Medline]
Isner
JM, Vale
PR, Symes
JF
&
Losordo
DW (2001). Assessment of risks associated with cardiovascular gene therapy in human subjects. Circ Res
89, 389–400.
Kay MA, Glorioso JC & Naldini L (2001). Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nat Med 7, 33–40. 10.1038/83324[CrossRef][Medline]
Khurana VG, Weiler DA, Witt TA, Smith LA, Kleppe LS, Parisi JE et al. (2003). A direct mechanical method for accurate and efficient adenoviral vector delivery to tissues. Gene Ther 10, 443–452. 10.1038/sj.gt.3301907[CrossRef][Medline]
Kibbe
MR, Billiar
TR
&
Tzeng
E (2000). Gene therapy for restenosis. Circ Res
86, 829–833.
Kong
D, Melo
LG, Mangi
AA, Zhang
L, Lopez-Ilasaca
M, Perrella
MA
et al. (2004). Enhanced inhibition of neointimal hyperplasia by genetically engineered endothelial progenitor cells. Circulation
109, 1769–1775.
Lehrman S (1999). Virus treatment questioned after gene therapy death. Nature 401, 517–518. 10.1038/43977[Medline]
Marshall
E (2003). Second child in French trial is found to have leukemia. Science
299, 320. 10.1126/science.299.5605.320
Marshall DJ, Palasis M, Lepore JJ & Leiden JM (2000). Biocompatibility of cardiovascular gene delivery catheters with adenovirus vectors: an important determinant of the efficiency of cardiovascular gene transfer. Mol Ther 1, 423–429. 10.1006/mthe.2000.0059[CrossRef][Medline]
Muhonen
MG, Ooboshi
H, Welsh
MJ, Davidson
BL
&
Heistad
DD (1997). Gene transfer to cerebral blood vessels after subarachnoid hemorrhage. Stroke
28, 822–829.
Ohkuma H, Parney I, Megyesi J, Ghahary A & Findlay JM (1999). Antisense preproendothelin-oligoDNA therapy for vasospasm in a canine model of subarachnoid hemorrhage. J Neurosurg 90, 1105–1114.[CrossRef][Medline]
Ono
S, Date
I, Onoda
K, Shiota
T, Ohomoto
T, Ninomiya
Y
et al. (1998). Decoy administration of NF-
B into the subarachnoid space for cerebral angiopathy. Hum Gene Ther
9, 1003–1011.[Medline]
Ono S, Komuro T & Macdonald RL (2002). Heme oxygenase-1 gene therapy for prevention of vasospasm in rats. J Neurosurg 96, 1094–1102.[Medline]
Onoue
H, Tsutsui
M, Smith
L, Stelter
A, O'Brien
T
&
Katusic
ZS (1998). Expression and function of recombinant endothelial nitric oxide synthase gene in canine basilar artery after experimental subarachnoid hemorrhage. Stroke
29, 1959–1966.
Ooboshi
H, Welsh
MJ, Ríos
CD, Davidson
BL
&
Heistad
DD (1995). Adenovirus-mediated gene transfer in vivo to cerebral blood vessels and perivascular tissue. Circ Res
77, 7–13.
Pislaru
S, Janssens
SP, Gersh
BJ
&
Simari
RD (2002). Defining gene transfer before expecting gene therapy: putting the horse before the cart. Circulation
106, 631–636.
Ribourtout
E
&
Raymond
J (2004). Gene therapy and endovascular treatment of intracranial aneurysms. Stroke
35, 786–793. 10.1161/01.STR.0000117577.94345.CC
Ríos
CD, Ooboshi
H, Piegors
D, Davidson
BL
&
Heistad
DD (1995). Adenovirus-mediated gene transfer to normal and atherosclerotic arteries: a novel approach. Arterioscler Thromb Vasc Biol
15, 2241–2245.
Satoh
M, Parent
AD
&
Zhang
JH (2002a). Inhibitory effect with antisense mitogen-activated protein kinase oligodeoxynucleotide against cerebral vasospasm in rats. Stroke
33, 775–781. 10.1161/hs0302.103734
Satoh M, Perkins E, Kimura H, Tang J, Chu Y et al. (2002b). Posttreatment with adenovirus-mediated gene transfer of calcitonin gene-related peptide to reverse cerebral vasospasm in dogs. J Neurosurg 97, 136–142.[Medline]
Schulick
AH, Dong
G, Newman
KD, Virmani
R
&
Dichek
DA (1995). Endothelium-specific in vivo gene transfer. Circ Res
77, 475–485.
Smith RC & Walsh K (2001). Local gene delivery to the vessel wall. Acta Physiol Scand 173, 93–102. 10.1046/j.1365-201X.2001.00889.x[CrossRef][Medline]
Sobey CG & Faraci FM (1998). Subarachnoid haemorrhage. What happens to the cerebral arteries? Clin Exp Pharmacol Physiol 25, 867–876.[Medline]
Sobey
CG, Heistad
DD
&
Faraci
FM (1997). Effect of subarachnoid hemorrhage on cerebral vasodilatation in response to activation of ATP-sensitive K+ channels in chronically hypertensive rats. Stroke
28, 392–397.
Sobey CG & Quan L (1999). Impaired cerebral vasodilator responses to NO and PDE V inhibition after subarachnoid hemorrhage. Am J Physiol 277, H1718–H1724.
Stoodley M, Weihl CC, Zhang Z, Lin G, Johns LM, Kowalczuk A et al. (2000). Effect of adenovirus-mediated nitric oxide synthase gene transfer on vasospasm after experimental subarachnoid hemorrhage. Neurosurgery 46, 1193–1203. 10.1097/00006123-200005000-00034
Takahashi A, Palmer-Opolski K, Smith RC & Walsh K (2003). Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent. Gene Ther 10, 1471–1478. 10.1038/sj.gt.3302010[CrossRef][Medline]
Toyoda
K, Faraci
FM, Watanabe
Y, Ueda
T, Andresen
JJ, Chu
Y
et al. (2000). Gene transfer of calcitonin gene-related peptide prevents vasoconstriction after subarachnoid hemorrhage. Circ Res
87, 818–824.
Treggiari-Venzi MM, Suter PM & Romand J (2001). Review of medical prevention of vasospasm after aneurysmal subarachnoid hemorrhage: a problem of neurointensive care. Neurosurgery 48, 249–262. 10.1097/00006123-200102000-00001
Watanabe
Y, Chu
Y, Andresen
JJ, Nakane
H, Faraci
FM
&
Heistad
DD (2003). Gene transfer of extracellular superoxide dismutase reduces cerebral vasospasm following subarachnoid hemorrhage. Stroke
34, 434–440. 10.1161/01.STR.0000051586.96022.37
Yamaguchi
M, Zhou
C, Heistad
DD, Watanabe
Y
&
Zhang
JH (2004). Gene transfer of extracellular superoxide dismutase failed to prevent cerebral vasospasm after experimental subarachnoid hemorrhage. Stroke
35, 2512–2517. 10.1161/01.STR.0000145198.07723.8e
Yoshimura
S, Morishita
R, Hayashi
K, Kokuzawa
J, Aoki
M, Matsumoto
K
et al. (2002). Gene transfer of hepatocyte growth factor to subarachnoid space in cerebral hypoperfusion model. Hypertension
39, 1028–1034. 10.1161/01.HYP.0000017553.67732.E1
|
Acknowledgements |
|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
