GTMB 7 - Gene Therapy & Molecular Biology

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Gascón-Irún et al: Gene therapy antiproliferative strategies against cardiovascular diseaseet al, 1995), and lack of proliferation markers in vascular expression and G1 cell cycle arrest (Perlman et al, 1998).The GATA transcription factors play a critical role in ERKs disclosed persistent hyperexpression and activationthe establishment of hematopoietic cell lineages and in atherosclerotic lesions of cholesterol-fed rabbits,during the development of the cardiovascular system suggesting that these factors play critical roles in initiating(Simon, 1995). GATA-6 is rapidly downregulated upon and perpetuating cell proliferation during the developmentmitogen stimulation of quiescent VSMCs (Suzuki et al, of atherosclerosis (Hu et al, 2000; Metzler et al, 2000).1996), and overexpression of GATA-6 induced p21 Cip1 Likewise, angioplasty in porcine and rat arteries led to thecells coexpressing p53 and p21 Cip1 within advanced human Importantly, p21 Cip1 -null mouse embryonic fibroblastsatherosclerotic lesions suggests that transcriptional were refractory to the GATA-6-induced growth inhibitionactivation of the p21 Cip1 gene by p53 may be a protective (Perlman et al, 1998). The level of GATA-6 mRNA,mechanism against excessive vascular cell growth (Ihling protein, and DNA-binding activity is transientlyet al, 1997).downregulated at early time points after balloonp53 appears to play an important role in the angioplasty in the rat carotid artery, and reversal ofpathogenesis of restenosis, as suggested by both animal GATA-6 downregulation by adenovirus-mediated GATAandhuman studies. Transfection of antisense p53 ODN 6 gene transfer to the vessel wall inhibited intimalinto rat intact carotid artery decreased p53 protein hyperplasia in this animal model (Mano et al, 1999).expression and resulted in a significant increase inneointimal lesion growth at 2 and 4 weeks after balloonangioplasty(Matsushita et al, 2000). Evidence suggests5. GAXthat human cytomegalovirus (HCMV) infection Gax is a homeobox gene highly expressed in culturescontributes to the development of atherosclerosis and of quiescent VSMCS, which is rapidly downregulated inrestenosis, and part of this effect may be due to increased vitro upon growth factor stimulation of VSMCs, and afterVSMC proliferation and migration by inactivation of p53 balloon angioplasty in vivo (Gorski et al, 1993; Weir et al,(Speir et al, 1994; Zhou et al, 1996; 1999; Tanaka et al, 1995). Overexpression of GAX inhibited VSMC1999). It is also noteworthy that human VSMCs from proliferation in vitro and attenuated neointimal thickeningrestenosis or in-stent stenosis sites demonstrate normal or in balloon-injured rat carotid arteries in a p21 Cip1 -enhanced responses to p53 when compared to VSMCs dependent manner (Smith et al, 1997a; Perlman et al,from normal vessels (Scott et al, 2002). Moreover, p53 1999). Percutaneous delivery of the Gax gene alsogene transfer effectively inhibited neointimal hyperplasia inhibited vessel stenosis in a rabbit model of balloonafter experimental angioplasty (Yonemitsu et al, 1998; angioplasty (Maillard et al, 1997).Scheinman et al, 1999; Matsushita et al, 2000), and inhuman saphenous vein (George et al, 2001).E. Overexpression of transdominantnegative mutants of positive cell cycle3. pRbregulators.The complex interplay between pRb and 1. Rastranscription factors of the E2F family plays a critical rolein the control of cell growth (Stevaux and Dyson, 2002).Ras-dependent signaling plays an important role inmitogen-stimulated cell growth (Pronk and Bos, 1994).E2F-dependent transactivation of genes required for cell Ras is implicated in the activation of the G1cycle progression is prevented in quiescent cells due to the CDK/cyclin/E2F pathway (Winston et al, 1996;Aktas et al,accumulation of hypophosphorylated pRb. 1997; Kerkhoff and Rapp, 1997; Leone et al, 1997; LloydHyperphorylation of pRb by mitogenic stimuli leads toE2F activation and cell growth. Transfer of antisense pRbODN into human VSMCs resulted in the induction of theproapoptotic factors bax and p53, and this was associatedwith increased number of apoptotic cells and a higher rateet al, 1997; Peeper et al, 1997; Zou et al, 1997) and iscritical for the normal induction of cyclin A promoteractivity and DNA synthesis in mitogen-stimulated VSMCs(Sylvester et al, 1998). Consistent with these findings,local delivery of transdominant negative mutants of Rasof DNA synthesis (Aoki et al, 1999). Inhibition of VSMC attenuated neointimal thickening after experimentalproliferation in vitro and attenuation of neointimaformation after balloon angioplasty can be achieved byballoon angioplasty (Indolfi et al, 1995; Ueno et al,1997b).adenovirus-mediated transfer of several forms of pRb,including full-length constitutively active(nonphosphorylatable) and phosphorylation-competent 2. Mitogen-activatedpRb, and truncated versions of pRb (Chang et al, 1995b; (MAPKs)protein kinasesSmith et al, 1997b). Similarly, adenoviral transfer of the The MAPK pathway is critical in the transducction ofpRb related protein RB2/p130 inhibited VSMC proliferative signals in many mammalian tissues, includingproliferation in vitro and prevented neointimal hyperplasia the cardiovascular system (Zou et al, 1998; Bogoyevitch,after experimental angioplasty (Claudio et al, 1999). 2000). Several families of MAPKs have been described,including the stress-activated protein kinases/c-jun NH 2 -terminal protein kinases (SAPKs/JNKs), extracellular4. GATA-6signal-regulated kinases (ERKs), and p38. JNKs and82
Gene Therapy and Molecular Biology Vol 7, page 83rapid activation of ERKs and JNKs (Lai et al, 1996; Lilleet al, 1997; Pyles et al, 1997; Koyama et al, 1998).Consistent with this notion, gene transfer of dominantnegativemutants of ERK or JNK prevented neointimalformation in balloon-injured rat artery (Izumi et al, 2001).III. Clinical studiesThe antiproliferative approaches used so far for thetreatment of cardiovascular disease have focused onrestenosis and graft atherosclerosis, during whichneointimal hyperplasia is rapid and localized. Thesedisorders remain the major limitation of revascularizationby percutaneous transluminal angioplasty (PTCA) andartery bypass surgery.A. E2F ‘decoy’Encouraging results of the E2F ‘decoy’ strategy inanimal models of balloon angioplasty and graftatherosclerosis (see above) led to the initiation of the firstProject of Ex-vivo Vein graft Engineering via Transfection(PREVENT I) (Mann et al, 1999). In this single-centre,randomized, controlled gene therapy trial, 41 patientsundergoing bypass for the treatment of peripheral arterialocclusions were randomly assigned untreated (n=16), E2F-‘decoy’-ODN-treated (n=17), or scrambled-ODN-treated(n=8) human infrainguinal vein grafts. Ex vivo delivery ofODNs was achieved intraoperatively via pressuremediatedtransfection. This procedure was associated witha 70-74% decrease in the level of PCNA and c-mycmRNA expressed by the VSMCs in the vein, and astatistically significant reduction in primary graft failurecompared to control groups. Following to this pilot trial, arandomized, double-blinded, placebo controlled Phase IIbtrial (PREVENT II) was carried out in patients undergoingcoronary artery bypass surgery. The results of quantitativecoronary angiography and intravascular ultrasound (IVUS)showed larger patency and inhibition of neointimalthickening in treated patients at 12 months afterintervention (Dzau et al, 2002).B. c-myc antisense ODNPharmacokinetics and clinical safety of ascendingdoses of c-myc antisense ODN (LR-3280) administeredafter PTCA was assessed by Roque et al. (2001a). Seventyeight patients were randomized to receive either standardcare (n = 26) or standard care and escalating doses (1 to 24mg) of LR-3280 (n = 52), administered into target vesselthrough a guiding catheter. The peak plasmaconcentrations of LR-3280 occurred at 1 minute anddecreasing rapidly after approximately 1 hour, with littleLR-3280 detected in the urine between 0-6 hours and 12-24 hours. The intracoronary administration of LR-3280was well tolerated at doses up to 24 mg and produced noadverse effects in dilated coronary arteries, thus providingthe basis for the evaluation of local delivery of c-mycantisense ODN for the prevention of humanvasculoproliferative disease.Kutryk et al. (2002) recently reported the results ofthe Investigation by the Thoraxcenter of Antisense DNAusing Local delivery and IVUS after Coronary Stenting(ITALICS) trial. This randomized, placebo controlledstudy was designed to determine the efficacy of antisenseODN against c-myc in inhibiting in-stent restenosis.Eighty-five patients were randomly assigned to receiveeither c-myc antisense ODN or saline vehicle byintracoronary local delivery after coronary stentimplantation. Follow-up included the percent neointimalvolume obstruction measured by IVUS, clinical outcomeand quantitative coronary angiography. There was noreduction in either the neointimal volume obstruction orthe angiographic restenosis rate after treatment with 10 mgof phosphorothioate-modified ODN directed against c-myc as demonstrated by the analysis of 77 patients.IV. ConclusionsExcessive cell proliferation within the arterial wall isthought to contribute to neointimal thickening during thepathogenesis of atherosclerosis, in-stent restenosis, andvessel bypass graft failure. Animal models ofatherosclerosis have demonstrated an inverse correlationbetween neointimal cell proliferation and atheroma size,suggesting that excessive cell growth prevails at the onsetof atherogenesis. Cell proliferation may also predominateat the early stages of human atheroma development. Thus,given that patients frequently exhibit advancedatherosclerotic plaques when first diagnosed, the potentialbenefit of antiproliferative strategies for the treatment ofhuman atherosclerosis is uncertain. The antiproliferativeapproaches used so far in the setting of vascularobstructive disease have focused on restenosis and graftatherosclerosis, during which neointimal hyperplasia isspatially localized and develops over a short period of time(typically 2-12 months). Gene therapy is emerging as anattractive strategy in the treatment of vascular proliferativedisease due to minimally invasive and easily monitoredgene delivery in vascular interventions. Antiproliferativegene therapy strategies that have proven efficient ininhibiting neointimal thickening in animal models ofvascular obstructive disease include the use of antisenseandribozyme-mediated inactivation of positive cell cycleregulators, overexpression of negative regulators of cellgrowth, and ‘decoy’ strategies to inactivate transcriptionfactors that promote cell cycle progression. Althoughsome of these strategies have shown encouraging results inhumans, further studies are required to override the currentpractical barriers and limitations placed on most clinicaltrials before gene therapy strategies exhibit wideapplication in clinic. These should include the clarificationof safety issues, development of better gene deliveryvectors, and improvement of transgene expression. Asidefrom these technical improvements, significant effort inbasic research is warranted to identify more effective andsafer treatment genes.83
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