GTMB 7 - Gene Therapy & Molecular Biology

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George et al: Gene therapy for vascular diseasesIV. Gene therapy and restenosisTreatment of symptomatic coronary arteryatherosclerotic plaques by angioplasty leads to vascularresponses including intimal thickening and constrictiveremodelling causing restenosis in approximately 30% ofinitially successfully treated patients. Although stentsprevent constrictive vascular remodelling, they inducevascular injury eventually leading to intimal thickeningand thereby restenosis. Gene therapy has been perceivedas attractive to treat restenosis as it can be deliveredlocally and appears to be able to treat excessive vascularcell proliferation.To date, a number of small (rat, mice) or large sizeanimal modes (rabbit, pig) have been used to evaluate thepotential of many gene therapy approaches for restenosis.The gene therapy strategies for treatment of restenosis aresummarized below and also in Figure 1. However, despitethe successful use of gene therapy to treat animalrestenosis by various approaches, application of genetherapy to prevent restenosis in man has only been carriedout using a re-endothelialization strategy with VEGF.Before further clinical trials are initiated a betterunderstanding of vascular biology, gene expression, vectordesign, and catheter-tissue interactions is required. It mustalso be mentioned that the efficacy of sirolimus(rapamycin) for the treatment of in-stent restenosis(Serruys et al, 2002; Sousa et al, 2003) has reduced theimpetus for designing gene therapy for in-stent restenosis.A. Biological processes involved inrestenosis and molecular targets in restenosisThe two major components that lead to restenosis areintimal thickening and negative (constrictive) remodelling.Intimal thickening following experimental injury involvesa combination of many processes, including VSMC andadventitial cell migration, proliferation, and matrixdeposition. Negative remodelling, which only occurs afterangioplasty and not after stent placement may also arisefrom many processes, including VSMC apoptosis, medialand adventitial fibrosis and matrix remodelling. However,restenosis, both in the absence and in the presence ofstents, is primarily due to VSMC accumulation. Sincemural thrombi may aggravate restenosis by contributingdirectly to cell proliferation, anti-thrombotic strategieshave received attention. Finally, strategies that acceleratere-endothelialization of the injury artery have beeninvestigated.B. Inhibition of VSMC proliferationCytotoxic strategies have been tested based on theexpression of enzymes capable of converting nucleosideanalogues into toxic metabolites that impair DNAreplication and consequently cause death of transducedcells entering S phase. Adenoviral delivery of thymidinekinase (tk), a gene from herpes simplex virus (HSV),followed by ganciclovir treatment led to death of tkexpressingcells and reduced intimal thickening afterinjury of rat and rabbit arteries (Guzman et al, 1994;Simari et al, 1996). Similarly, expression of cytosinedeaminase in the presence of 5-fluorocytosine caused a45% reduction of stenosis (Harrell et al, 1997).Endogenous inducers of cell death have also been utilized.Delivery of the tumour suppressor p53 to injured ratcarotid arteries reduced intimal thickening (Yonemitsu etal, 1998), as did gene transfer of FasL (Luo et al, 1999).Some caution has been applied to the use of cytotoxicgene therapy for restenosis, since VSMC viability isessential for the integrity of the lesion, particularly thefibrous cap, and thereby the stability of atheroscleroticplaques. In addition, promotion of apoptosis in injuredvessels may increase intimal thickening, sinceoverexpression of fortilin, a recently characterised,negative regulator of apoptosis reduced intimal thickeningin injured rat arteries (Tulis et al, 2003).It has been well documented that cytostatic geneticstrategies using antisense oligonucleotides (ODN), decoyODN and gene transfer of cell cycle inhibitory genes (Li etal, 1999) limit VSMC proliferation and inhibit intimalthickening following experimental injury. Despiteencouraging results using antisense ODN to immediateearly genes such as c-myb (Simons et al, 1992) and c-myc(Shi et al, 1994) and promoters of cell cycle such as cyclinB and CDK-2 (Morishita et al, 1994), where intimalthickening was inhibited between 40 and 84% to in rat andin some cases also porcine injured arteries some years ago,this strategy appears to have made little progress recently.This is despite the observation that co-transfection ofcombinations of these antisense resulted in furtherinhibition (Morishita et al, 1994). Transfer ofretinoblastoma protein (Rb) to restrict the cell cycle, intorat and porcine injured arteries prevented intimalthickening (Chang et al, 1995). Similarly, overexpressionof the CDK inhibitors p21 and p27 resulted in reduction ofintimal thickening both in rat and porcine injured arteries(Chang et al, 1995; Yang et al, 1996; Chen et al, 1997).Furthermore, overexpression of a mutated form of p21 wasable to reduce restenosis in hypercholesterolemic mice byenhancing vascular apoptosis and reducing VSMCproliferation (Condorelli et al, 2001). A further strategythat has been examined is the inhibition of signallingmolecules. H-ras, a key protein in signal transduction,mediates mitogenic signals, therefore blocking this earlysignal transduction. Application of an adenoviral dominantnegative H-ras and Gβγ-binding peptide affecteddownstream signalling events and reduced intimalthickening by 70-80% (Ueno et al, 1997; Iaccarino et al,1999). Targeting of transcription factors by gene therapy isalso a strategy of interest. Inhibition of NFκB and E2F,cytoplasmic transcription factor using antisense ODNs inballoon-injured rat carotid arteries reduced intimalthickening by approximately 70% (Autieri et al, 1995;Morishita et al, 1995). Overexpression of the growth arresthomeobox gene (GAX) reduced intimal thickening by 50-70% in rat and rabbit injury models (Maillard et al, 1997;Smith et al, 1997). Although the use of transcriptionfactors as targets for gene therapyapy in restenosisappeared promising, it should be noted that thesetranscription factors are also involved in severalmechanisms regulating vascular wall homeostasis.140
Gene Therapy and Molecular Biology Vol 7, page 141Control of VSMC proliferation has also beenattempted by inhibition of growth factor expression andoverexpression of inhibitory growth factors and cytokines.Delivery of basic fibroblast growth factor (bFGF) (Hannaet al, 1997) as well as platelet-derived growth factor-β(PDGF-β) (Deguchi et al, 1999) antisense ODN and TGFβribozyme ODN (Yamamoto et al, 2000) inhibitedintimal thickening by 60-90% in injured rat carotidarteries. Similarly, adenoviral delivery of the extracellularregion of the PDGF-β receptor and of endovascularPDGF-β receptor antisense ODN reduced intimalthickening in injured rat arteries (Sirois et al, 1997;Noiseux et al, 2000). Activin, a TGF-β-like factor thatinduces a contractile phenotype in VSMCs, reducedintimal thickening by more that 70% in injured mousefemoral arteries (Engelse et al, 2002). The inhibitorycytokine interferon-g delivery by Ad-mediated genetherapy reduced intimal thickening in a porcine model ofarterial injury (Stephan et al, 1997).C. Cell migration and matrix remodellingConstrictive (negative) remodelling plays a veryimportant in human restenosis particularly in the absenceof a stent (Mintz et al, 1996), therefore gene therapystrategies aimed at reducing intimal thickening alone areunlikely to be successful in humans following angioplasty.Post injury intimal thickening is also reliant on VSMCmigration, which requires remodelling of the extracellularmatrix that surrounds the VSMC. Adenoviral gene transferof tissue inhibitor of metalloproteinase-1 (TIMP-1) andTIMP-2 reduced intimal thickening (Cheng et al, 1998;Furman et al, 2002). A combination of anti-proliferativeand anti-migratory approaches may therefore be useful.D. Anti-thrombotic strategyA number of studies have focused on seeding stentswith genetically modified endothelial cells with increasedfibrinolytic of anticoagulant activity (Dichek et al, 1989,1996; Dunn et al, 1996). Although seeding stented vesselswith endothelial cells overexpressing tPA and uPAproduced anti-thrombotic activity (Dichek et al, 1996),overexpression of tPA was associated with increaseddetachment of seeded cells (Dunn et al, 1996).Another strategy to prevent thrombosis as well asintimal thickening is to inhibit platelet activation oraggregation or to increase nitric oxide (NO). NO isvasoprotective by inhibiting platelet and leukocyteadhesion, inhibiting VSMC proliferation and migrationand promoting endothelial cell survival and proliferation(Li et al, 1999); therefore, nitric oxide synthase (NOS) thatincreases NO production was proposed as a suitablecandidate to treat restenosis. Delivery of endothelial(e)NOS by non-viral methods (von der Leyen et al, 1995)and adenoviruses (Chen et al, 1998; Janssen et al, 1998;Varenne et al, 1998) reduced intimal thickening by 37-70% in rat and pig injured arteries. Interestingly,adenoviral delivery of inducible (i)NOS by adenovirusesto rat injured arteries almost completely (95%) inhibitedintimal thickening, whilst reduced it by only 50% inporcine injured arteries (Shears et al, 1998), illustratingthat the degree of response differs greatly betweendifferent animal models. Furthermore, administration ofthe iNOS Ad could not mediate regression of establishedintimal thickening.D. Re-endothelializationAs regeneration of the endothelium is associatedwith reduction in thrombotic and proliferative processes inthe vessel wall it has been seen as a potential strategy ofgene therapy for restenosis. Local intravascular andextravascular expression of vascular endothelial growthfactor (VEGF), a potent endothelium specific angiogenicfactor, using plasmid DNA accelerated reendothelializationand decreased intimal thickening afterarterial injury in rabbit models (Asahara et al, 1996;Laitinen et al, 2000), and reduced in-stent restenosis by50% (Van Belle et al, 1997).The feasibility of this approach was tested in a smallclinical trial, in which VEGF plasmid/liposome genetransfer after angioplasty was seen to be safe and welltolerated (Laitinen et al, 2000). A recently published largerclinical trial was designed to test the feasibility,tolerability and efficacy of VEGF gene therapy to preventrestenosis after stenting (Hedman et al, 2003). The overallrestenosis rate in this study was surprisingly low (6%),virtually precluding the detection of a difference amongtreatments. Nevertheless, the results establish feasibilityand provide safety data on the used of naked DNA and Adto express VEGF. This strategy is perceived attractive as itis trying to mimic nature’s inhibitory strategy to limitintimal thickening, but we await clinical evidence of itssuccess. The use of VEGF is also attractive as it should beendothelial cell specific; however, there are safetyconcerns in respect to tumour growth as VEGF isinvolved in induction and progression (Huang et al, 2003).V. Gene therapy for hypertensionGene therapy for essential hypertension represents isan enormous challenge due to the complex polygenic traitthat underlies human essential hypertension. Gene therapyis however attractive since it offers the opportunity to treatthe disease with a single administration rather than dailydrug regimens. Essential hypertension is associated withendothelial dysfunction and contributes significantly tocardiovascular risk. Gene therapy would, therefore, targetspecific systems with the explicit aim of lowering bloodpressure and reducing end organ damage. Unlike otherdisease targets discussed above, gene therapy forhypertension requires the use of strategies to provide longtermeffects on blood pressure. These have includedantisense/ribozyme strategies to block systems thatregulate blood pressure as well as vasodilator strategiesusing overexpression of pro-vasodilator genes.Preclinical studies on gene therapy for hypertensionhave taken two main approaches (Phillips, 2002). First,extensive studies on gene transfer to increase vasodilatorproteins (kallikrein, atrial natriuretic peptide,adrenomedullin, and endothelin nitric oxide synthase)141
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