GTMB 7 - Gene Therapy & Molecular Biology

More documents

Recommendations

Info

George et al: Gene therapy for vascular diseaseshave been carried out in different rat models (Lin et al,1995; Chao et al, 1996, 1997; Lin et al, 1997; Chao et al,1998 a, b; Yayama et al, 1998; Alexander et al, 1999;Dobrzynski et al, 1999; Lin et al, 1999; Alexander et al,2000; Dobrzynski et al, 2000; Wolf et al, 2000; Zhang etal, 2000; Wang et al, 2001; Emanueli et al, 2002). Usingthese approaches, blood pressure can be lowered for 3-12weeks with the expression of these genes. Second, anantisense approach, which began by targetingangiotensinogen and the angiotensin type 1 (AT1)receptor, has now been tested independently by severaldifferent groups in multiple models of hypertension(Katovich et al, 1999; Tang et al, 1999; Wang et al, 2000;Kimura et al, 2001). Other genes targeted include the β1-adrenoreceptor, TRH, angiotensin gene activatingelements, carboxypeptidase Y, c-fos, and CYP4A1(Gardon et al, 2000; Phillips, 2001; Tomita et al, 2002).There have been two methods of delivery antisense, shortODNs, and full-length DNA in viral vectors. All thestudies show a decrease in blood pressure lasting severaldays to weeks or months. ODNs are safe and particularnon-toxic. The decreased hypertension after systemicadeno-associated virus delivery antisense to AT1 receptorsin adult rodents for up to 6 months, may constitute a goodincentive for testing the antisense ODNs first and later theAAV (Kimura et al, 2001; Phillips 2001).Hypertension is also the presenting feature of someof these disorders, such as congenital adrenal diseases, andadrenal and pituitary tumors. Preclinical data indicate thatgene transfer to both the adrenal gland and the pituitary isnot only feasible but also quite efficient (Alesci et al,2002).A. Inhibition of vasoconstrictor genesThis has been achieved using antisenseoligonucleotides to block the renin-angiotensin system.For example, Wielbo et al (1996) used DNA/liposomescomplexes containing angiotensinogen antisense andlowered mean arterial pressure, angiotensinogen andangiotensin II levels in adult spontaneously hypertensiverats following systemic administration. These highlyeffective results are somewhat surprising when it isrealised that the in vivo uptake of DNA/liposomecomplexes into the vasculature and organs is very poorwhen delivery intravenously. Not surprisingly viral vectorsystems have also been engineered to deliver antisense.Using a retroviral system to deliver antisense against theangiotensin type-1 receptor to young (5 day old)hypertensive and normotensive animals, blood pressurewas significantly lowered selectively in the hypertensiveanimals (Lu et al, 1996). Interestingly, the effect of theantisense was sustained for 90 days while losartan had theexpected transient effect of less than 24 hours. This doeshighlight the clinical relevance of such technology toprovide sustained benefit compared to traditionalpharmacological regimens. However, in the light of recentclinical experience using retroviral vectors withdevelopment of leukaemia on phase I trial (Cavazzana etal, 2000), the use of retroviral vectors is unlikely to bedeveloped in this disease. Other studies have alsohighlighted the benefit of viral delivery of antisense(Wang C et al, 1995; Martens et al, 1998; Reaves et al,1999; Tang et al, 1999; Wang H et al, 1999).B. Vasodilator overexpressionThere are a number of candidate genes foroverexpression that may provide therapeutic benefit ofdifferent aspects of hypertension. These include kallikrein,adrenomedullin, nitric oxide synthase and superoxidedismutase. Kallikrein cleaves kininogen producing kininpeptide, which in turn stimulates the release of thevasodilators prostacyclin, endothelium-derivedhyperpolarising factor and nitric oxide. Based on thisprinciple, infusion of naked DNA expressing kallikreinreduced blood pressure for 6 weeks (Wang et al, 1995).Comparative studies showed that naked DNA plasmidsand adenoviral vectors both proved effective (Chao et al,1997). Kallikrein delivery using viruses has also beenestablished as an anti-hypertensive strategy in differentmodels demonstrating the potential benefit of this strategyand the potency of the transgene (Dobrzynski et al, 1999;Wolf et al, 2000).Adrenomedullin also causes vasodilation.Adenoviral-mediated overexpression of adrenomedullin inhypertensive rats led to a blood pressure drop of 41 mmHg 9 days after tail vein injection (Dobrzynski et al,2000). This lasted nearly 20 days. Again, proof of thisstrategy was realised when other studies gained similarfindings in different labs and models of hypertension(Zhang et al, 2000; Wang et al, 2001).Targeting endothelial dysfunction is highly attractivefor gene therapyapy. Endothelial dysfunction ischaracterised by reduced nitric oxide (NO)-mediatedvasodilation and a reduction in available NO. The loss ofNO leads to deleterious effects on platelet aggregation andadhesion, smooth muscle proliferation, inflammation andincreased oxidative stress in the vessel wall. Improving thebioavailability of NO, therefore, is a highly logicalstrategy to improve a number of key processes that areintegral to vessel wall homeostasis in order to reduceblood pressure. This can be achieved by increasing NOproduction itself through nitric oxide synthase (NOS) genedelivery or by preventing NO degradation by superoxidedismutase (SOD) gene transfer. A number of studies haveaddressed these issues. An early study established such aconcept by systemic delivery of naked DNA encoding theendothelial form of NOS (eNOS) with a significantreduction in blood pressure that lasted for at least 12weeks (Lin et al, 1997). Again, such effects with nakedDNA are astonishing since little uptake was achieved invivo and the majority was sequestered to the liver. It isimportant to note that targeting gene delivery to theendothelium is extremely difficult using currentlyavailable vector systems when the delivery mode isintravenously. The liver sequesters the vast majority of allcommonly used vector systems with relatively little uptakeby the endothelium itself. This has restricted studies tolocal applications of gene delivery to selected bloodvessels in vivo. Adenoviral delivery of eNOS or SOD3,142
Gene Therapy and Molecular Biology Vol 7, page 143but not SOD-1 or –2 are able to improve endothelialfunction in carotid arteries in the spontaneouslyhypertensive stroke-prone (SHRSP) rats (Alexander et al,1999, 2000; Fennell et al, 2002).VI. Therapeutic angiogenesisTherapeutic angiogenesis represents a novel strategyfor the treatment of vascular insufficiency. It is based onsupplementation with angiogenic growth factors toenhance native angiogenesis in critical myocardial orperipheral ischaemia. Angiogenic growth factors havebeen delivered both as protein and by way of gene transferand have demonstrated positive results (Yla-Herttuala etal, 2003). The recent insights in the molecular basis ofangiogenesis have resulted in great interest in the genetherapy field. However, because of the rapid evolution andenthusiasm in the field, angiogenic molecules have beentested without a complete understanding of theirmechanism of action. Among the angiogenic growthfactors used in pre-clinical studies, VEGF165 andVEGF121, FGF1, FGF2 and hepatocyte growth factor(HGF) have all shown significant improvement of nativeangiogenic response to ischemia, resulting in acceleratedrate of perfusion, (see reviews by Hammond et al, 2001)(Emanueli et al, 2001; Manninen et al, 2002). Besidesgrowth factors a number of other substances have beeninvestigated, such as human tissue kallikrein (Emanueli etal, 2001), angiopoietin (Shyu et al, 1998), leptin(Bouloumie et al, 1998) and thrombopoietin (Brizi et al,1999).Although difficulties have been encountered in thefield of gene therapy, great progress has been made in thefield of pro-angiogenic gene therapy. It has been suggestedthat this is because the long-term gene expression is notrequired for therapeutic vascular growth and the currentgene therapy vectors induce at least some physiologicalimprovement (Yla-Herttuala et al, 2003). Over 23 clinicaltrials have been initiated; approximately half are forperipheral disease and the other half for coronary heartdisease. The first set of clinical trials involved pioneeringattempts to overexpress VEGF165 with naked DNA (Isneret al, 1996; Baumgartner et al, 1998; Losordo et al, 1998)and adenoviruses (Rosengart et al, 1999). The secondphase of trials were small, uncontrolled trials using nakedDNA and adenoviruses to overexpress VEGF165 andVEGF121; many of these had positive results (Symes etal, 1999; Laitinen et al, 2000; Rajagopalan et al, 2001).Only recently, the third set of clinical trials has begun totest the potential of this gene therapy fully. Theserandomised, controlled and blinded trials have involvedlarger numbers of patients and defined primary andsecondary endpoints (Grines et al, 2002; Makinen et al,2002; Stewart et al, 2002; Hedman et al, 2003;Rajagopalan et al, 2003). Several of these have beenjudged positive according to primary and secondaryendpoints but it has been suggested that this may not betransferable to a clear-cut clinical benefit (Yla-Herttuala etal, 2003).Critically ischaemic lower limbs from diabetes thatare not suitable candidates for surgical endovascularapproaches may be amenable to gene therapy fortherapeutic angiogenesis. Diabetes impairs endogenousneovascularization of ischaemic tissues due to a reducedexpression of VEGF (Rivard et al, 1999) and HGF(Taniyama et al, 2001). Consequently Ad-mediatedoverexpression of VEGF and plasmid HGF restoredneovascularization in mouse and rat models of diabetes,respectively (Rivard et al, 1999; Taniyama et al, 2001).Enhanced angiogenesis by such strategies also improvesneuropathy both when growth factors including VEGF, aregiven alone (Rissanen et al, 2001) or in conjunction withthe prostacyclin synthase gene (Koike et al, 2003).Furthermore, a small clinical trial which included 6diabetic patients with critical leg ischaemia, observedneurologic improvement and therapeutic angiogenesisafter plasmid injections of VEGF165 in the muscles of theischaemic limb (Simovic et al, 2001). Inhibition ofangiogenesis may also have therapeutic potential for thetreatment of retinopathy, since lentiviral delivery ofangiostatin inhibited neovascularization in a murineproliferative retinopathy model (Igarashi et al, 2003).Although, this strategy has made great progress inthe last decade there are still some unresolved issues. Forexample is administration of a single angiogenic moleculesufficient? Will administration of VEGF lead to toxiceffects such as oedema? Will an angiogenic factor besuitable for myocardial and peripheral angiogenesis? Sincethe same adenoviral VEGF121 gave positive effects in themyocardium (Stewart et al, 2002) but failed in peripheralvascular disease (Rajagopalan et al, 2003), will VEGF beproven clinically benefial? Some caution has been cast onthe potential of VEGF gene therapy by the observationthat VEGF enhances atherosclerotic plaque progression inboth mice and rabbits (Celletti et al, 2001). Are otherVEGF homologues safer options? Increasedlymphogenesis and reduced oedema is observed withVEGFC and VEGFD (Yla-Herttuala et al, 2003).VII. Future directionsRecent advances through preclinical studies haveraised the profile of gene therapy in some vasculardiseases, particularly with respect to angiogenic genetherapy in the myocardium and peripheral vasculature aswell as in vein graft disease. These studies, presently inphase II, highlight the potential of the technology forrelieving symptoms of human vascular diseases.Despite the lack of dramatic cures, a decade ofclinical trials has provided important news about thestrengths and weaknesses of current vectors. Bothadenoviruses and liposomal vectors have been shown to beable to transduce transgenes in patients with a variety ofdisorders. From this work, it is now extremely clear thatthe expression is temporary and is associated with aninflammatory response. However, there are someimportant points to consider. First, with respect tomyocardial and peripheral vascular gene transfer clinicaltrials, these have been performed with single proangiogenicgenes with gene delivery using sub-optimalvector systems (e.g. naked DNA/adenoviral vectors). With143
Page 7 and 8:
Instructions to authors:Gene Therap
Page 9:
Please submit an electronic version
Page 12:
103-111 ResearchArticle113-133 Revi
Page 17 and 18:
Gene Therapy and Molecular Biology
Page 19 and 20:
Page 21 and 22:
Page 23 and 24:
Page 25 and 26:
Page 27 and 28:
Page 29 and 30:
Page 31 and 32:
Page 33 and 34:
Page 35 and 36:
Page 37 and 38:
Page 39 and 40:
Page 41 and 42:
Page 43 and 44:
Page 45 and 46:
Page 47 and 48:
Page 49 and 50:
Page 51 and 52:
Page 53 and 54:
Page 55 and 56:
Page 57 and 58:
Page 59 and 60:
Page 61 and 62:
Page 63 and 64:
Page 65 and 66:
Page 67 and 68:
Page 69 and 70:
Page 71 and 72:
Page 73 and 74:
Page 75 and 76:
Page 77:
Page 80 and 81:
Epperly et al: Late injection of Mn
Page 82 and 83:
Epperly et al: Late injection of Mn
Page 84 and 85:
Goldberg-Cohen et al: Regulation of
Page 86 and 87:
Page 88 and 89:
Page 90 and 91:
Gascón-Irún et al: Gene therapy a
Page 92 and 93:
Page 94 and 95:
Page 96 and 97:
Page 98 and 99:
Page 100 and 101:
Page 102 and 103:
Page 104 and 105:
Page 106 and 107: Suzuki et al: Regulation of the Sp/
Page 114 and 115: Li et al: MET amplification in live
Page 116 and 117: Li et al: MET amplification in live
Page 118 and 119: Chavakis et al: Leukocyte adhesion
Page 128 and 129: Sanlioglu et al: Adenovirus mediate
Page 150 and 151: George et al: Gene therapy for vasc
Page 168 and 169: Zhang et al: Angiogenic Gene Therap
Page 182 and 183: Xu et al: G-CSF receptor-mediated S
Page 188 and 189: Burek et al: Calcium induced cell d
Page 196 and 197: David et al: Current status and fut
Page 206 and 207:
David et al: Current status and fut
Page 208 and 209:
Page 210 and 211:
Page 212 and 213:
Page 214 and 215:
Page 216 and 217:
Page 218 and 219:
Page 220 and 221:
Page 222 and 223:
Page 224 and 225:
Page 226 and 227:
Stoll et al: The role of EBV and ge
Page 228 and 229:
Page 230 and 231:
Page 232 and 233:
Page 234 and 235:
Page 236 and 237:
Maruyama et al: Kidney-targeted pla
Page 238 and 239:
Page 240 and 241:
Page 242 and 243:
Page 244 and 245:
Kren et al: Hepatocyte-targeted del
Page 246 and 247:
Page 248 and 249:
Page 250 and 251:
Page 252 and 253:
Page 254 and 255:
Zeng: PRL-3 as a target for cancer
Page 256 and 257:
Page 258 and 259:
Page 260 and 261:
Latchman: Protective effect of heat
Page 262 and 263:
Page 264 and 265:
Page 266 and 267:
Page 268 and 269:
Page 270 and 271:
Cai et al: Lung cancer gene therapy
Page 272 and 273:
Page 274 and 275:
Page 276 and 277:
Page 278 and 279:
Page 280:
Page 283 and 284:
Page 285 and 286:
Page 287 and 288:
Page 289 and 290:
Page 291 and 292:
Page 293 and 294:
Page 295 and 296:
Page 297 and 298:
Page 299 and 300:
Page 301 and 302:
Page 303 and 304:
Page 305 and 306:
Page 307 and 308:
Page 309:
show all

GTMB 7 - Gene Therapy & Molecular Biology

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?