GTMB 7 - Gene Therapy & Molecular Biology

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Maruyama et al: Kidney-targeted plasmid DNA transferTable 2. Gene transfer via renal veinEpo, erythropoietin; MCP-1, Anti-monocyte chemoattractanttubulointerstitial renal injury induced by protein-overloadproteinuria.IV. Kidney-targeted gene transfer viathe urinary tractTable 3 provides an overview of studies of kidneytargetedplasmid DNA transfer in a retrograde manner viathe urinary tract. Two kinds of liposomes have been usedin retrograde gene transfer via the pelvis or ureter. Usingthem, investigators can target tubules and other interstitialfibroblasts.A. Lipofectin via the pelvisAfter the intrarenal pelvic injection of pCMV-β-gal-Lipofectin, lacZ was expressed mainly in the cytoplasm ofrenal tubular cells in the outer medulla with some stainingin the cortex (Lai et al, 1997). The transgene expressionsite accessed by this route was similar to that accessed bythe intrarenal arterial route, as described above. Lai et al(1997) speculated that the difference in themicroenvironments of the inner and outer medulla mightaffect the interactions between the DNA and the liposome,therefore preventing gene uptake by the papillary cells,and resulting in a lack of staining in the inner medulla.Alternatively, the transgene taken up by the papillary cellsmay not have been expressed properly, owing to factorssuch as limited promoter efficiency and specificity, earlydegradation of the DNA, and altered half-life of themRNA and/or protein synthesized from transgene.Intrarenal pelvic injection is more feasible than intra-renalarterialinjection in mice, because it is difficult to inject anadequate amount of plasmid DNA-Lipofectin complexinto the renal artery, and because intrarenal-arterialinjection has a high incidence of renal ischemic injury (Laiet al, 1997).Lai et al, (1998) also demonstrated a transientphysiological effect of gene delivery into the kidney by theretrograde injection of a cationic liposome complexed witha carbonic anhydrase (CA) II chimeric gene, pCMV-CAII-Lipofectin into the renal pelvis of CAII-deficient mice.The CAII-deficiency was produced by introducing a pointmutation into the CAII gene, and it manifested as renaltubular acidosis. The delivery of the CAII gene correctedthe renal tubular acidosis of the CAII-deficient mousemodel. Immunohistochemistry studies using anti-CAIIantibodies showed that CAII was expressed in the tubularcells of the outer medulla and corticomedullary junction.The gene therapy was not associated with nephrotoxicity,as assessed by evaluating the blood urea nitrogen levelsand the renal histology. This is the first successful genetherapy of a genetic renal disease.B. Naked plasmid DNA via pelvisIt has not been possible to express transgenes in thekidney by injecting naked plasmid DNA via the pelvis(Lai et al, 1997).C. AVE-type HVJ-liposome viaTo examine the pattern of transgene-expressing cells,Tsujie et al (2000) used the N-lacF fragment containingthe SV40 nuclear transport signal at the N terminus of thelacZ gene, which limits the β-galactosidase proteinlocalization to the nucleus of transfected cells and can bedistinguished from endogeneous β-galactosidase. pEBAct-NlacF was introduced into the kidney of normal ratsretrogradely via the ureter using the AVE-type HVJliposomemethod (Tsujie et al, 2000). Nuclear β-galactosidase activity was observed in interstitialfibroblasts for 2 weeks. After the introduction of thepEBActN-lacF expression vector into kidneys with anobstructed ureter, Tsujie et al, (2000) observed a greatlyexpanded interstitium with marked cell proliferation ondays 7 and 14. In contrast, no pathological changes norincreased numbers of infiltrated cells were observed in thetreated kidneys 1 day after the transfection, suggesting thatthere was no interstitial damage from the HVJ-liposomesolution, but that the damage was caused by ureteralobstruction. It has been speculated that the AVE-typeHVJ-liposome may reach interstitial fibroblasts byslipping between either tubular epithelial cells or papillaepithelial cells; gene transfer could then occur via thefusion activity of the HVJ-liposome.Gene transfer targeting interstitial fibroblasts might beexplained by the possibility that glycol-type sialic acids,the receptors for HVJ, are abundant in fibroblasts but rarein endothelial or epithelial cells (Tsujie et al, 2000).However, the precise mechanism remains to be elucidated.226
Gene Therapy and Molecular Biology Vol 7, page 227Table 3 Gene transfer via urinary tractCAII, carbonic anhydrase II; Nlac F, containing nuclear transport signal, which resulted in the specific and exclusive nuclear localizationof the protein, was inserted into the plasmid at the N terminus of the LacZ geneV. Direct injectionIntrarenal parenchymal injection of a plasmid DNA-Lipofectin complex did not result in gene transfer into thekidney (Lai et al, 1997). Direct injection caused focalinfiltration of inflammatory cells. On the other hand, theintrarenal parenchymal injection of naked plasmid DNAled to gene expression in the tubules (Lai et al, 1997). Thegene expression was limited to small areas near or deeperthan the injection site. The transfection efficiency of nakedplasmid DNA via intrarenal parenchymal injection ismuch less than that of liposome-mediated plasmid DNAtransfer via intrarenal pelvic or intrarenal arterialinjections.VI. SystemicAlthough the kidney can be targeted by a systemicintravenous route (tail vein injection), the gene transferefficiency is not sufficient for the specific transfection ofthe kidney. The plasmid DNA:cationic liposome(DOTMA:DOPE) complex becomes trapped in thepulmonary tissue and vascular endothelial cells (Zhu et al,1993), resulting in the highest expression in the lungs.Compared with plasmid DNA:cationic liposome 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)complexes, liposome-polycation-DNA complexes (LPD),such as DOTAP-protamine-plasmid DNA complexes,offer better protection of the plasmid DNA fromenzymatic digestion and give higher gene expression inthe mouse kidney following tail vein injection (Li andHuang, 1997). When Li and Huang (1997) used aluciferase reporter gene with this technique, they foundgene expression in all the tissues examined, includinglungs, heart, spleen, liver, and kidney, with the highestexpression in the lungs.These organs can also be transfected byhydrodynamics-based naked plasmid DNA transfectionvia tail vein injection. In this case, the highest level oftransgene expression observed is in the liver (Liu et al,1999; Zhang et al, 1999; Maruyama et al, 2002b; Higuchiet al, 2003).Thus, the transgene expression that results from thesystemic injection of a gene is not confined to the kidney.VII. Future clinical applicationsAlthough the precise mechanisms of the genetransfer into cells induced by the nonviral techniques hasnot yet been clarified, recent progress in kidney-targetedgene transfer is promising for future clinical applications.High transfection efficiency and long-term transgeneexpression are required for clinical applications.Nephrotoxicity attributable to gene transfer is obviouslyundesirable. An ischemic period is caused by theinterruption of renal blood flow during the injection andthe following incubation time, in the case of sometechniques. The shortest ischemic duration possible isdesirable because of safety concerns. For clinical uses, thenonviral techniques should confine transgene expressionto the injected kidney, without aberrant expression innontarget organs. Urinary tract infection attributable togene transfer via the retrograde urinary tract route isundesirable.A. In vivo catheter-mediated genetherapyPutting the catheter technique to practical use, theabove-mentioned gene transfer techniques via threedifferent routes, renal artery anterogradely, renal veinretrogradely, the urinary tract (ureter or pelvis)retrogradely, can deliver therapeutic genes to the kidneyless invasively than techniques that do not use cathetersand therefore require an abdominal incision. Therefore, thedevelopment of catheters that are exclusively for genetransfer is key to the progress of catheter-mediated genetherapy. Similarly, ureterorenoscopes can be used todeliver therapeutic genes and specific adaptations tooptimize their use should be undertaken (Lai et al, 1998).B. Ex vivo gene therapy for kidneytransplantationTo obtain successful outcomes following kidneytransplantation, we need to overcome the common227
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