GTMB 7 - Gene Therapy & Molecular Biology

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George et al: Gene therapy for vascular diseasesearly promoter (CMV IEP) is prone to host-mediatedsilencing in vivo (De Geest et al, 2000) leading to a shutdown in transgene expression, an effect not observed withcell-specific promoters. Further optimisation of expressioncassettes can be made through incorporation of introns andenhancers to elevate promoter activity as well as posttranscriptionalmodifications including the Woodchuckpost-transcriptional regulatory element (WPRE) which isthought to act through promoting mRNA stability (Loeb etal, 1999; Zufferey et al, 1999).Optimisation and evaluation of the gene deliveryvehicle. At present the repertoire of gene delivery vectorsavailable for human gene therapy is limited. Traditionally,non-viral vectors such as naked DNA and liposome DNAcomplexes provide low efficiency gene transfer and arerestricted to the delivery of highly potent biologicalagents, such as angiogenic gene therapy (see below).Improvements in the efficiency of non-viral vectors, suchas inclusion of targeting peptides into DNA liposomecomplexes (Hart et al, 1997; Parkes et al, 2002) have beenrealised but are still someway from the efficiency of viralvectors. Certain viruses, by virtue of evolution, infecthuman cells with high efficiency resulting in high potencygene transfer and overexpression of candidate therapeuticgenes. For gene delivery to vascular tissues the currentarmoury of viral vectors includes adenoviruses (Ad),adeno-associated viruses (AAV), lentiviruses and Semlikiforest viruses.Efficient modalities for gene delivery to the targetsite. Certain vascular diseases, such as vein grafting areoptimal for gene therapyapy since the target tissue (i.e. thevein to be grafted) is harvested and is available ex vivo forgene delivery prior to grafting within a clinically relevanttime window (approximately 30 minutes). This enablesdelivery of genes in a safe and efficient manner (Baker etal, 1997; Tamirisa et al, 2002). Due to the short timeframe, however, efficient vectors are required. Adenoviralvectors have proven particularly suited for this application(Channon et al, 1997; George et al, 2000; Tamirisa et al,2002). Conversely, gene delivery to blood vessels in vivorequires the use of devices to allow localised in vivo genedelivery. Specific catheter systems have been developedand utilised with high efficiency for post-angioplasty andin-stent restenosis in a variety of animal species and bloodvessels (French et al, 1994; Klugherz et al, 2000, 2002).Additionally, local delivery technology has been appliedfor gene therapyapy aimed at the myocardium. Differentapplications, such as atherosclerosis or hypertensionrequire alternate delivery systems and often rely onintravenous vehicle administration.Together, a combined approach to optimise the geneexpression system, the delivery vehicle and the route ofdelivery are required for successful gene therapy. Anumber of key areas within vascular diseases havesuccessfully exploited this and advanced to clinical trialswhile other areas have been severely limited due todeficiencies in one or more of the above requirements.Here, we discuss a number of these applications.There is no doubt that gene therapy may offeradvantages above traditional pharmacological therapies incertain respects. Delivery of gene can be achieved locallyin the vasculature thereby increasing the selectivity and,potentially, the safety. This would be particularlyimportant when the therapy may have an adverse effect ifcontact to non-target tissue in vivo occurred. Since manyof the strategies that have been designed to be effective invascular disease may be deleterious if exposed to nontargettissue, this advantage becomes very important. Forexample, in development of gene therapy for vein graftfailure (see later) pro-apoptotic genes are highly effectivebut clearly their expression in other tissues such as theliver, may be detrimental. Likewise, in restenosis postangioplasty(cytotoxic or cytostatic strategies) andangiogenesis gene therapy can be delivered locally and is apre-requisite for clinical translation. A second (and equallyimportant) advantage of gene therapy might be therequirement for only a single administration compared tothe requirement for multiple administrations ofconventional drugs, often daily for the lifetime of thepatient. Again, this depends largely on the application andis to date unproven. Evidence suggests that beneficialeffects of gene therapy for hypertension, vein grafting andrestenosis can be elicited in the long term from singleadministrations (see later). This provides ample preclinicalevidence to support these concepts.In the following review, we discuss gene therapy forsome vascular diseases and its progression in differentexperimental and clinical applications.II. Local gene delivery to the vesselwallIt has been known for over a decade that genedelivery to the vessel wall can result in alterations in cellbehaviour (Nabel et al, 1993 a, b, c) thereby initiating aplethora of studies that have evaluated and optimised genedelivery to the vessel wall. Although the first studiesrevealed that non-viral gene delivery could lead tophenotypic modulation of cell behaviour, it soon becameclear that adenoviral vectors provided the most efficientmeans to achieve high-level gene delivery to the vesselwall in vivo (Lemarchand et al, 1993; French et al, 1994).Pioneering studies by Lemerchand and colleagues (1993)and French et al, (1994) showed that local exposure ofhigh titre adenoviral vectors to normal and diseased bloodvessels in vivo led to high-level transduction, in sheep andrabbit models, respectively. Catheter systems were rapidlydeveloped and optimised for gene delivery postangioplastyresulting in transgene expression throughoutthe vessel wall in a geographical localisation defined bythe mode of vector delivery by the catheter utilised. Thisinitiated a host of studies and led to the use of adenoviralvectors as the most commonly used modality throughwhich to deliver genes to the vessel wall in vivo.However, this is not without limitations since adenoviralmediatedgene delivery was found to evoke aninflammatory response in the vessel wall leading totoxicity and endothelial cell activation (Newman et al,1995). Furthermore, the use of these first-generation Advectors only resulted in transient gene expression lasting7-14 days. Unlike other tissues, second generation vectors(that contained modifications of the Ad genome to reduce136
Gene Therapy and Molecular Biology Vol 7, page 137expression of Ad-related genes) did not lead to sustainedtransgene expression in the vessel wall in vivo (Engelhardtet al, 1994; Wen et al, 2000). Other vector systems haverecently been tested including improved non-viral systemssuch as peptide-targeted DNA/liposome complexes (Hartet al, 1997; Parkes et al, 2002), HVJ-modified liposomes(Morishita et al, 1995; Von Der Leyen et al, 1995; Dzau etal, 1996) and ultrasound-enhanced systems (Lawrie et al,1999; Taniyama et al, 2002). Likewise, other viral vectors(including adeno-associated viruses (Maeda et al, 1997;Richter et al, 2000), Semliki-forest viruses (Lundstrom etal, 2001) and lentiviruses (Dishart et al, 2003) have beenutilised. Modified viral systems in particular provideopportunities to modify the longevity of transgeneexpression as well as the principle cell type transduced. Asan example, adeno-associated viruses (AAV) transducesmooth muscle cells in the vessel wall, even in thepresence of an intact endothelial layer (Richter et al,2000). This is in direct comparison to Ad-mediate deliverysince endothelial transduction is high when an intactendothelium is present and represents a barrier totransduction (Lemarchand et al, 1993). This finding mayin part be due to different physical sizes of Ad and AAVand due to different vector tropisms of each, which isdictated by host expression of viral receptors and coreceptors(Wickham et al, 1993; Bergelson et al, 1997;Tomko et al, 1997; Summerford et al, 1998; Qing et al,1999; Summerford et al, 1999; Dishart et al, 2003). Hence,these systems have provided researchers with a diverserange of vectors through which to evaluate the phenotypiceffects of overexpression of candidate therapeutic genes inthe vessel wall in vivo.III. Gene therapy and vein graftfailureThe failure of vein bypass grafts in the coronary orlower extremity circulation is a common clinicaloccurrence that incurs significant morbidity and mortality.Despite the very common use of saphenous vein grafts totreat coronary and lower extremity occlusions the failurerate is extremely high, approximately 50% and 70% ofvein grafts fail within 5-10 years after surgery,respectively (Angelini 1992; Conte et al, 2001). To date,pharmacological approaches to prolong vein graft patencyhave produced very limited results. Consequently, geneticapproaches to modulate bypass grafts are actively beingstudied both in vitro and in vivo and are progressing toclinical trials. Vein grafts are uniquely amenable tointraoperative genetic modification because of the abilityto manipulate the tissue ex vivo with controlledconditions. We will describe how both geneoverexpression and gene blockade strategies have beentested, and how the latter is now in clinical trials (see alsoFigure 1 for schematic summary of gene therapystrategies).AngioplastyIntimal proliferationConstrictive remodellingRestenosisStent PlacementIntimal proliferationEarly FailureThrombosisVein Graft FailureLate FailureIntimal proliferationConstrictive remodellingGene Therapy StrategiesAnti-VSMC proliferation:-Cytostatic: cell cycleinhibitors, antisense cell cyclegenes& growth factors-Cytotoxic: tk, p53,Anti-thrombotic: uPA, tPA,NORe-endothelialization:VEGF*Anti-VSMC migration &matrix remodelling: TIMPsGene Therapy StrategiesAnti-VSMC proliferation:-Cytostatic: cell cycleinhibitors, antisense cell cyclegenes& growth factorsCytotoxic: tk, p53,Anti-thrombotic: uPA,tPA, NORe-endothelialization:VEGFGene Therapy StrategiesAnti-thrombotic: nonetestedRe-endothelialization: C-type natriuretic peptideGene Therapy StrategiesAnti-VSMC proliferation:-Cytostatic: cell cycleinhibitors, antisense cell cyclegenes, transcription factors(E2F)* & growth factorsRe-endothelialization:VEGF*Anti-VSMC migration &matrix remodelling: TIMPsFigure 1: Gene therapy strategies for the treatment of restenosis and vein graft failure. Many preclinical studies have been utilised todetermine the potential of these various strategies * indicates those that have progressed to clinical trials.137
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