Skip to main content
Log in

Gene Therapy for Renal Disorders

What are the Benefits for the Elderly?

  • Leading Article
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

Chronic renal failure is one of the major health problems for the elderly. Currently, about 50% of all patients receiving chronic dialysis for end-stage renal disease (ESRD) are aged 65 years or older. Their first-year mortality rate is as high as 30%. The leading causes of ESRD in the elderly are diabetic nephropathy, hypertension and large vessel diseases, and glomerulonephritis. The elderly are also prone to developing acute renal failure induced by ischaemic injury or nephrotoxic drugs. Gene transfer in experimental animals have been tested in all of these conditions, as well as in animal kidney transplantation models, with various degrees of success. However, there are many obstacles to be overcome before gene therapy can be tested clinically for renal disorders. In particular, the major challenges include determining how to prolong and control transgene expression or antisense inhibition and how to minimise the adverse effects of viral or nonviral vectors. Once these problems are solved, gene therapy will have a role in treating age-related renal impairment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Table I

Similar content being viewed by others

References

  1. US renal data system. USRDS 2000 annual data report: atlas of end stage renal disease in the United States. Bethesda (MD): National Institutes of Health, National Institutes of Diabetes and Digestive and Kidney Diseases, 2000

    Google Scholar 

  2. Lien YH, Lai L. Gene therapy for renal diseases. Kidney Int 1997; 52Suppl. 61: S85–8

    Google Scholar 

  3. Lien YH, Lai L. Renal gene therapy. In: Walker J, editor. Nonviral vectors for gene therapy: methods and protocols, methods in molecular medicine. Cambridge (MA): Praecis Pharmaceuticals, 2001: 370–92

    Google Scholar 

  4. Imai E, Isaka Y. Strategies of gene transfer to the kidney. Kidney Int 1998; 53: 264–72

    Article  PubMed  CAS  Google Scholar 

  5. Imai E. Gene therapy approach in renal disease in the 21st century. Nephrol Dial Transplant 2001; 16Suppl. 5: 26–34

    Article  PubMed  CAS  Google Scholar 

  6. Ylä-Herttuala S, Martin JF. Cardiovascular gene therapy. Lancet 2000; 355: 213–22

    Article  PubMed  Google Scholar 

  7. von der Leyen HE, Dzau VJ. Therapeutic potential of nitric oxide synthase gene manipulation. Circulation 2001; 103: 2760–5

    Article  PubMed  Google Scholar 

  8. Phillips MI. Gene therapy for hypertension: the preclinical data. Hypertension 2001; 38: 543–8

    Article  PubMed  CAS  Google Scholar 

  9. Tomita N, Higaki J, Morishita R, et al. Direct in vivo gene introduction into rat kidney. Biochem Biophys Res Commun 1992; 186: 129–34

    Article  PubMed  CAS  Google Scholar 

  10. Isaka Y, Akagi Y, Ando Y, et al. Application of gene therapy to diabetic nephropathy. Kidney Int 1997; 52Suppl. 60: S100–3

    Google Scholar 

  11. Kimura B, Mohuczy D, Tang X, et al. Attenuation of hypertension and heart hypertrophy by adeno-associated virus delivering angiotensinogen antisense. Hypertension 2001; 37: 376–80

    Article  PubMed  CAS  Google Scholar 

  12. Phillips MI, Kimura B, Zhang YC, et al. Gene therapy for hypertension: recombinant adeno-associated virus vector delivery of angiotensin type I receptor antisense in hypertensive double transgenic mice [abstract]. Hypertension 2000; 36: 204

    Google Scholar 

  13. Yayama K, Wang C, Chao L, et al. Kallikrein gene delivery attenuates hypertension and cardiac hypertrophy and enhances renal function in Goldblatt hypertensive rats. Hypertension 1998; 31: 1104–10

    Article  PubMed  CAS  Google Scholar 

  14. Dobrzynski E, Wang C, Chao J, et al. Adrenomedullin gene delivery attenuates hypertension cardiac remodeling and renal injury in deoxycorticosterone acetate-salt hypertensive rats. Hypertension 2000; 36: 995–1001

    Article  PubMed  CAS  Google Scholar 

  15. Chao J, Jin L, Lin KF, et al. Adrenomedullin gene delivery reduces blood pressure in spontaneously hypertensive rats. Hypertens Res 1997; 20: 269–77

    Article  PubMed  CAS  Google Scholar 

  16. Lin KF, Chao J, Chao L. Atrial natriuretic peptide gene delivery attenuates hypertension, cardiac hypertrophy, and renal injury in salt-sensitive rats. Hum Gene Ther 1998; 9: 1429–38

    Article  PubMed  CAS  Google Scholar 

  17. Lin KF, Chao J, Chao L. Prolonged reduction of high blood pressure with human nitric oxide synthase gene delivery. Hypertension 1997; 30: 307–13

    Article  PubMed  CAS  Google Scholar 

  18. Zhang YC, Kimura B, Shen L, et al. New ß-blocker: prolonged reduction in high blood pressure with ß1 antisense oligodeoxynucleotides. Hypertension 2000; 35: 219–24

    Article  CAS  Google Scholar 

  19. Wang H, Reaves PY, Gardon ML, et al. Angiotensin I converting enzyme antisense gene therapy causes permanent antihypertensive effects in the SHR. Hypertension 2000; 35: 202–8

    Article  PubMed  CAS  Google Scholar 

  20. Reaves PY, Gelband CH, Wang H, et al. Permanent cardiovascular protection from hypertension by the AT(1) receptor antisense gene therapy in hypertensive rat offspring. Circ Res 1999; 85: e44–50

    Article  PubMed  CAS  Google Scholar 

  21. Baumgartner I, Pieczek A, Manor O, et al. Constitutive expression of VEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998; 97: 1114–23

    Article  PubMed  CAS  Google Scholar 

  22. Simovic D, Isner JM, Ropper AH, et al. Improvement in chronic ischemic neuropathy after intramuscular phVEGF165 gene transfer in patients with critical limb ischemia. Arch Neurol 2001; 58: 761–8

    Article  PubMed  CAS  Google Scholar 

  23. von der Leyen HE, Gibbons GH, Morishita R, et al. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer for endothelial-cell nitric oxide synthase gene. Proc Natl Acad Sci U S A 1995; 92: 1137–41

    Article  PubMed  Google Scholar 

  24. Mann MJ, Morishita R, Gibbons GH, et al. DNA transfer into vascular smooth muscle using fusogenic Sendai virus (HVJ)-liposomes. Mol Cell Biochem 1997; 172: 3–12

    Article  PubMed  CAS  Google Scholar 

  25. von der Leyen HE, Muhs A, Shrader J, et al. Inhibition of in-stent plaque formation by inducible nitric oxide synthaselipoplex-mediated gene therapy in a pig femoral artery stent model. J Am Coll Cardiol 2000; 35Suppl A: 280A

    Google Scholar 

  26. Mann MJ, Whittemore AD, Donaldson MC, et al. Ex-vivo gene therapy of human vascular bypass grafts with E2F decoy: the PREVENT single-centre, randomized, controlled trial. Lancet 1999; 354: 1493–8

    Article  PubMed  CAS  Google Scholar 

  27. Mann MJ, Gibbons GH, Tsao PS, et al. Cell cycle inhibition preserves endothelial function in genetically engineered rabbit vein grafts. J Clin Invest 1997; 99: 1295–301

    Article  PubMed  CAS  Google Scholar 

  28. Akagi Y, Isaka Y, Arai M, et al. Inhibition of TGF-beta 1 expression by antisense oligonucleotides suppressed extracellular matrix accumulation in experimental glomerulonephritis. Kidney Int 1996; 50: 148–55

    Article  PubMed  CAS  Google Scholar 

  29. Maeshima Y, Kashihara N, Yasuda T, et al. Inhibition of mesangial cell proliferation by E2F decoy oligodeoxynucleotide in vitro and in vivo. J Clin Invest 1998; 101: 2589–97

    Article  PubMed  Google Scholar 

  30. Tomita N, Morishita R, Lan H, et al. In vivo administration of a nuclear transcription factor-ΚB decoy suppresses experimental crescentic glomerulonephritis. J Am Soc Nephrol 2000; 11: 1244–52

    PubMed  CAS  Google Scholar 

  31. Munger KA, Montero A, Fukunaga M, et al. Transfection of rat kidney with human 15-lipoxygenase suppresses inflammation and preserves function in experimental glomerulonephritis. Proc Natl Acad Sci U S A 1999; 96: 13375–80

    Article  PubMed  CAS  Google Scholar 

  32. Isaka Y, Brees DK, Ikegaya K, et al. Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney. Nat Med 1996; 2: 418–23

    Article  PubMed  CAS  Google Scholar 

  33. Isaka Y, Akagi Y, Ando Y, et al. Gene therapy by transforming growth factor-beta receptor-IgG Fc chimera suppressed extracellular matrix accumulation in experimental glomerulonephritis. Kidney Int 1999; 55: 465–75

    Article  PubMed  CAS  Google Scholar 

  34. Nakamura H, Isaka Y, Tsujie M, et al. Electroporation-mediated PDGF receptor-IgG chimera gene transfer ameliorates experimental glomerulonephritis. Kidney Int 2001; 59: 2134–45

    PubMed  CAS  Google Scholar 

  35. Noiri E, Peresleni T, Miller F, et al. In vivo targeting of inducible NO synthase with oligodeoxynucleotides protects rat kidney against ischemia. J Clin Invest 1996; 97: 2377–83

    Article  PubMed  CAS  Google Scholar 

  36. Haller H, Dragun D, Miethke A, et al. Antisense oligonucleotides for ICAM-1 attenuate reperfusion injury and renal failure in the rat. Kidney Int 1996; 50: 473–80

    Article  PubMed  CAS  Google Scholar 

  37. Murakami H, Yayama K, Chao L, et al. Human kallikrein gene delivery protects against gentamycin-induced nephrotoxicity in rats. Kidney Int 1998; 53: 1305–13

    Article  PubMed  CAS  Google Scholar 

  38. Murakami H, Yayama K, Chao J, et al. Atrial natriuretic peptide gene delivery attenuates gentamycin-induced nephrotoxicity in rats. Nephrol Dial Transplant 1999; 14: 1376–84

    Article  PubMed  CAS  Google Scholar 

  39. Stepkowski SM, Wang ME, Condon TP, et al. Protection against allograft rejection with intercellular adhesion molecule-1 antisense oligodeoxynucleotides. Transplantation 1998; 66: 699–707

    Article  PubMed  CAS  Google Scholar 

  40. Swenson KM, Ke B, Wang T, et al. Fas ligand gene transfer to renal allografts in rats: effect on allograft survival. Transplantation 1998; 65: 155–60

    Article  PubMed  CAS  Google Scholar 

  41. Tomasoni S, Azzollini N, Casiraghi F, et al. CTLA4Ig gene transfer prolongs survival and induces donor-specific tolerance in a rat renal allograft. J Am Soc Nephrol 2000; 11: 747–52

    PubMed  CAS  Google Scholar 

  42. Sonntag KC, Emery DW, Yasumoto A, et al. Tolerance to solid organ transplants through transfer of MHC class II genes. J Clin Invest 2001; 107: 65–71

    Article  PubMed  CAS  Google Scholar 

  43. Schwarz ER, Speakman MT, Patterson M, et al. Evaluation of the effects of intramyocardial injection of DNA expressing vascular endothelial growth factor (VEGF) in a myocardial infarction model in the rat: angiogenesis and angioma formation. J Am Coll Cardiol 2000; 35: 1323–30

    Article  PubMed  CAS  Google Scholar 

  44. Morishita R, Gibbons GH, Horiuchi M, et al. A gene therapy strategy using a transcription factor decoy of the E2F binding site inhibits smooth muscle proliferation in vivo. Proc Natl Acad Sci U S A 1995; 92: 5855–9

    Article  PubMed  CAS  Google Scholar 

  45. Isaka Y, Akagi Y, Kaneda Y, et al. The HVJ liposome method. Exp Nephrol 1998; 6: 144–7

    Article  PubMed  CAS  Google Scholar 

  46. Balter M. Gene therapy on trial. Science 2000; 288: 951–7

    Article  Google Scholar 

  47. Donste A, Volger CA, Muzyczka N, et al. Observed incidence of tumorigenesis in long-term rodent studies of rAA V vectors. Gene Ther 2001; 8: 1343–6

    Article  Google Scholar 

  48. Schwartz DA, Quinn TJ, Thorne PS, et al. CpG motifs in bacterial DNA cause inflammation in the lower respiratory tract. J Clin Invest 1997; 100: 68–73

    Article  PubMed  CAS  Google Scholar 

  49. Stewart MJ, Plautz GE, Buono LD, et al. Gene transfer in vivo with DNA-liposome complexes: safety and acute toxicity in mice. Hum Gene Ther 1992; 3: 267–75

    Article  PubMed  CAS  Google Scholar 

  50. Canonico AE, Plitman JD, Conary JT, et al. No lung toxicity after repeated aerosol or intravenous delivery of plasmidcationic liposome complexes. J Appl Physiol 1994; 77: 415–9

    PubMed  CAS  Google Scholar 

  51. Henry SP, Taylor J, Midgley L, et al. Evaluation ofthe toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a 4-week study in CD-1 mice. Antisense Nucleic Acid Drug Dev 1997; 7: 473–81

    Article  PubMed  CAS  Google Scholar 

  52. Monteith DK, Horner MJ, Gillett NA, et al. Evaluation of the renal effects of an antisense phosphorothioate oligodeoxynucleotide in monkeys. Toxicol Pathol 1999; 27: 307–17

    Article  PubMed  CAS  Google Scholar 

  53. O’Dwyer PJ, Stevenson JP, Gallagher M, et al. c-raf-1 depletion and tumor responses in patients treated with c-raf-1 antisense oligodeoxynucleotide ISIS 5132(CGP69846A). Clin Cancer Res 1999; 5: 3977–82

    PubMed  Google Scholar 

  54. Szebeni J, Fontana JL, Wassef NM, et al. Hemodynamic changes induced by liposomes and liposome-encapsulated hemoglobin in pigs: a model for pseudoallergic cardiopulmonary reactions to liposomes. Role of complement and inhibition by soluble CR1 and anti-C5a antibody. Circulation 1999; 99: 2302–9

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grant RO1DK56660 and a grant from the Dialysis Clinic Inc., a non-profit organisation. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yeong-Hau H. Lien.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lien, YH.H., Lai, LW. Gene Therapy for Renal Disorders. Drugs Aging 19, 553–560 (2002). https://doi.org/10.2165/00002512-200219080-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002512-200219080-00001

Keywords

Navigation