GTMB 7 - Gene Therapy & Molecular Biology

Gascón-Irún et al: Gene therapy antiproliferative strategies against cardiovascular diseaseMitogenic and antimitogenic stimuli affect the rates ofsynthesis and degradation of CKIs, as well as theirredistribution among different CDK/cyclin pairs (Philipp-Staheli et al, 2001). For example, p27 Kip1 promotes theassembly of CDK4/cyclin D complexes by binding tothem, thus facilitating CDK2/cyclin E activation throughG1/S phase.VSMC proliferation in the balloon-injured rat carotidartery is associated with a temporally and spatiallycoordinated expression of CDKs and cyclins (Wei et al,1997; Braun-Dullaeus et al, 2001). Importantly,augmented expression of these factors is associated withan increase in their kinase activity (Abe et al, 1994; Wei etal, 1997), demonstrating the assembly of functionalCDK/cyclin holoenzymes in the injured arterial wall.Expression of CDK2 and cyclin E was also detected inhuman VSMCs within atherosclerotic and restenotic tissue(Kearney et al, 1997; Wei et al, 1997; Ihling et al, 1999),suggesting that induction of positive cell-cycle controlgenes is a hallmark of vascular proliferative disease inhuman patients.In the following sections, we will discuss the use ofgene therapy strategies targeting cellular proliferation inpreclinical (Table 1) and clinical studies (Table 2) relatedto cardiovascular disease.Table 1: Attenuation of neointimal thickening by antiproliferative gene therapy approaches in animal models of vascularproliferative disease.Strategy Target gene Animal model Ref.Antisense (ODN)CDK2 Balloon angioplasty (rat) Abe et al, 1994; Morishita et al, 1994aCDC2 Balloon angioplasty (rat) Abe et al, 1994; Morishita et al, 1994bCyclin B1 Balloon angioplasty (rat) Morishita et al, 1994bCDC2/PCNA Graft arteriosclerosis (rabbit, rat) Mann et al, 1995; Miniati et al, 2000CDC2/PCNA Balloon angioplasty (rat) Morishita et al, 1993CDK2 Graft arteriosclerosis (mouse) Suzuki et al, 1997c-myb * Balloon angioplasty (pig, rat) Simons et al, 1992; Gunn et al, 1997c-myc * Balloon angioplasty (rat, pig, rabbit) Bennett et al, 1994a; Shi et al, 1994b;Kipshidze et al, 2001, 2002c-myc * Graft arteriosclerosis (pig) Mannion et al, 1998PDGFβ receptor Balloon angioplasty (rat) Cohen-Sacks et al, 2002Antisense (retrovirus) Cyclin G1 Balloon angioplasty (rat) Zhu et al, 1997Ribozyme‘Decoy’ ODNOveexpression ofgrowth suppressorsOverexpression ofdominant-negativePCNA Stent (pig) Frimerman et al, 1999TGF-β1 Balloon angioplasty (rat) Yamamoto et al, 2000PDGF-A Balloon angioplasty (rat) Kotani et al, 200312-lipoxygenase Balloon angioplasty (rat) Gu et al, 2001E2F Balloon angioplasty (rat, pig) Morishita et al, 1995; Ahn et al, 2002a;Nakamura et al, 2002E2FAP-1Graft arteriosclerosis (rabbit, mouse,monkey)Balloon angioplasty (rat, rabbit,minipig)Mann et al, 1997; Kawauchi et al, 2000;Ehsan et al, 2001Ahn et al, 2002b; Buchwald et al, 2002; Kumeet al, 2002p21 Cip1 Balloon angioplasty (rat, mouse, pig) Chang et al, 1995a; Yang et al, 1996; Ueno etal, 1997a; Condorelli et al, 2001;p21 Cip1 Graft arteriosclerosis (rabbit) Bai et al, 1998p27 Kip1 Balloon angioplasty (rat, pig) Chen et al, 1997; Tanner et al, 2000pRb Balloon angioplasty (rat, pig) Chang et al, 1995b; Smith et al, 1997bRB2/p130 Balloon angioplasty (rat) Claudio et al, 1999p53 Balloon angioplasty (rabbit, rat) Yonemitsu et al, 1998; Scheinman et al, 1999;Matsushita et al, 2000GAX Balloon angioplasty (rat, rabbit) Maillard et al, 1997; Smith et al, 1997a;Perlman et al, 1999GATA-6 Balloon angioplasty (rat) Mano et al, 1999RAS Balloon angioplasty (rat) Indolfi et al, 1995; Ueno et al, 1997bERK Balloon angioplasty (rat) Izumi et al, 2001mutants JNK Balloon angioplasty (rat) Izumi et al, 2001* These inhibitory effects might be caused by a nonantisense mechanism (Burgess et al, 1995; Chavany et al, 1995; Guvakova et al,1995; Villa et al, 1995; Wang et al, 1996).78