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Systemic administration of naked DNA with targeting specificity to mammalian kidneys

Gene Therapy volume 12, pages 477–486 (2005)Cite this article

Abstract

A major challenge for gene therapy is to be able to deliver efficiently the gene of interest to specific cell types. Here we describe a safe and simple effective naked DNA gene delivery method, via inferior vena cava (IVC) injection, to the recipient's kidneys. It was further demonstrated that gene expression was concentrated in the proximal tubular epithelial cells of the cortico-medullary region of the kidney. Confocal microscopy analyses demonstrated the presence of the exogenous DNA in the renal cell membrane 10 min postgene delivery. However, it was only by 30 min that the presence of the exogenous DNA could be detected in the cell cytoplasm and in the nuclei of the renal cells. Stable expression of the β-galactosidase gene could be detected for up to 35 days and no toxicity or any adverse pathological effect associated with the delivery method could be observed. Importantly, this IVC gene delivery method could promote the targeting of genes to carcinoma established in the kidney of SCID mice. These results provide the first evidence to support that stable gene expression could be achieved in the renal cells of kidney and the established carcinoma in the kidneys following in vivo gene delivery with naked DNA and could therefore provide the potential to design protocols for the gene therapy of the kidney diseases.

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Article 01 December 2022

Zixuan Zhao, Xinyi Chen, … Hanry Yu

References

  1. Christ M . Preclinical evaluation of gene transfer products: safety and immunological aspects. Toxicology 2002; 174: 13–19.

    Article  CAS  PubMed  Google Scholar 

  2. Smith AE . Gene therapy – where are we? Lancet 1999; 354: S11–S14.

    Article  Google Scholar 

  3. Nikitin AY et al. RB-mediated suppression of spontaneous multiple neuroendocrine neoplasia and lung metastases in Rb+/− mice. Proc Natl Acad Sci USA 1999; 96: 3916–3921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Whitmore M et al. LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth. Gene Therapy 1999; 6: 1867–1875.

    Article  CAS  PubMed  Google Scholar 

  5. Kim SI et al. Inhibitory effect of the salmosin gene transferred by cationic liposomes on the progression of B16BL6 tumors. Cancer Res 2003; 63: 6458–6462.

    CAS  PubMed  Google Scholar 

  6. Li S et al. Effect of immune response on gene transfer to the lung via systemic administration of cationic lipidic vectors. Am J Physiol 1999; 276: L796–L804.

    Article  CAS  PubMed  Google Scholar 

  7. Scheule RK et al. Basis of pulmonary toxicity associated with cationic lipid-mediated gene transfer to the mammalian lung. Hum Gene Ther 1999; 10: 689–707.

    Article  Google Scholar 

  8. Krieg AM et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 1995; 374: 546–549.

    Article  CAS  PubMed  Google Scholar 

  9. Klinman DM et al. CpG motifs represent in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon-γ. Proc Natl Acad Sci USA 1996; 93: 2879–2883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Whitmore M et al. Systemic administration of LPD prepared with CpG oligonucleotides inhibits the growth of established pulmonary metastases by stimulating innate and acquired antitumor immune responses. Cancer Immunol Immunother 2001; 50: 503–514.

    Article  CAS  PubMed  Google Scholar 

  11. Wolff JA et al. Direct gene transfer into mouse muscle in vivo. Science 1990; 247: 1465–1468.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang G et al. Expression of naked plasmid DNA injected into the afferent and efferent vessels of rodent and dog livers. Hum Gene Ther 1997; 8: 1763–1772.

    Article  CAS  PubMed  Google Scholar 

  13. Meyer KB et al. Intratracheal gene delivery to the mouse airway: characterization of plasmid DNA expression and pharmacokinetics. Gene Therapy 1995; 2: 450–460.

    CAS  PubMed  Google Scholar 

  14. Li K, Welikson RE, Vikstrom KL, Leinwand LA . Direct gene transfer into the mouse heart. J Mol Cell Cardiol 1997; 29: 1499–1504.

    Article  CAS  PubMed  Google Scholar 

  15. Choate KA, Khavari PA . Direct cutaneous gene delivery in a human genetic skin disease. Hum Gene Ther 1997; 8: 1659–1665.

    Article  CAS  PubMed  Google Scholar 

  16. Liu Y et al. Cationic liposome-mediated intravenous gene delivery. J Biol Chem 1995; 270: 24864–24870.

    Article  CAS  PubMed  Google Scholar 

  17. Benvenuti F, Cesco-Gaspere M, Burrone OR . Anti-idiotypic DNA vaccines for B-cell lymphoma therapy. Front Biosci 2002; 7: d228–d234.

    Article  CAS  PubMed  Google Scholar 

  18. Haupt K, Roggendorf M, Mann K . The potential of DNA vaccination against tumor-associated antigens for antitumor therapy. Exp Biol Med (Maywood) 2002; 227: 227–237.

    Article  CAS  Google Scholar 

  19. Maloy KJ et al. Intralymphatic immunization enhances DNA vaccination. Proc Natl Acad Sci USA 2001; 98: 3299–3303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kwon SS, Kim N, Yoo TJ . The effect of vaccination with DNA encoding murine T-cell epitopes on the Der p 1 and 2 induced immunoglobulin E synthesis. Allergy 2001; 8: 741–748.

    Article  Google Scholar 

  21. Ulmer JB . Tuberculosis DNA vaccines. Scand J Infect Dis 2001; 33: 246–248.

    Article  CAS  PubMed  Google Scholar 

  22. Yoon WS et al. Comparison of responses elicited by immunization with a Legionella species common lipoprotein delivered as naked DNA or recombinant protein. DNA Cell Biol 2002; 21: 99–107.

    Article  CAS  PubMed  Google Scholar 

  23. Kumar V, Sercarz E . Genetic vaccination: the advantages of going naked. Nat Med 1996; 2: 857–859.

    Article  CAS  PubMed  Google Scholar 

  24. Vile RG, Sunassee K, Diaz RM . Strategies for achieving multiple layers of selectivity in gene therapy. Mol Med Today 1998; 4: 84–92.

    Article  CAS  PubMed  Google Scholar 

  25. Yang JP, Huang L . Direct gene transfer to mouse melanoma by intratumor injection of free DNA. Gene Therapy 1996; 3: 542–548.

    CAS  PubMed  Google Scholar 

  26. Budker V et al. The efficient expression of intravascularly delivered DNA in rat muscle. Gene Therapy 1998; 5: 272–276.

    Article  CAS  PubMed  Google Scholar 

  27. Szary J, Szala S . Intra-tumoral administration of naked plasmid DNA encoding mouse endostatin inhibits renal carcinoma growth. Int J Cancer 2001; 92: 835–839.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Kitamura M, Fine LG . Gene transfer into the adult kidney for unravelling disease processes. Exp Nephrol 1998; 6: 429–437.

    Article  CAS  PubMed  Google Scholar 

  30. Kelly VR, Sukhatme VP . Gene transfer in the kidney. Am J Physiol (Renal Physiol 45) 1999; 276: F1–F9.

    Article  Google Scholar 

  31. Moullier P, Salvetti A, Champion-Arnaud P, Ronco PM . Gene transfer into the kidney: current status and limitations. Nephron 1997; 77: 139–151.

    Article  CAS  PubMed  Google Scholar 

  32. Knebelmann B, Antignac C, Gubler M-C, Grunfeld J-P . A molecular approach to inherited kidney disorders. Kidney Int 1993; 44: 1205–1216.

    Article  CAS  PubMed  Google Scholar 

  33. Gregory MC, Atkin CL . Alport syndrome. In: Schrier RW, Gottschalk CW (eds), Disease of the Kidney, 5th edn. Little Brown: Boston, 1993, pp 571–591.

    Google Scholar 

  34. Hostikka SL et al. Identification of a distinct type IV collagen α chain with restricted kidney distribution and assignment of the gene to the locus ox X chromosome-linked Alport syndrome. Proc Natl Acad Sci USA 1990; 87: 1606–1610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tryggvason K, Zhou J, Hostikka SL, Shows TB . Molecular genetics of Alport syndrome. Kidney Int 1993; 43: 38–44.

    Article  CAS  PubMed  Google Scholar 

  36. Antignac C et al. Alport syndrome and diffuse leiomyomatosis: deletions in the 5′ end of the COL4A5 collagen genes. Kidney Int 1992; 42: 1178–1183.

    Article  CAS  PubMed  Google Scholar 

  37. Qin L et al. Retrovirus-mediated transfer of viral IL-10 gene prolongs murine cardiac allograft survival. J Immunol 1996; 156: 2316–2323.

    CAS  PubMed  Google Scholar 

  38. Wissing KM, Morelon E, Legendre C, De Pauw L . A pilot trial of recombinant human interleukin-10 in kidney transplant recipients receiving OKT3 induction therapy. Transplantation 1997; 64: 999–1006.

    Article  CAS  PubMed  Google Scholar 

  39. Marras D et al. Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy. Nat Med 2002; 8: 522–526.

    Article  CAS  PubMed  Google Scholar 

  40. Bosch RJ, Woolf AS, Fine LG . Gene transfer into the mammalian kidney: direct retrovirus-transduction of regenerating tubular epithelial cells. Exp Nephrol 1993; 1: 49–54.

    CAS  PubMed  Google Scholar 

  41. Moullier P et al. Adenoviral-mediated gene transfer to renal tubular cells in vivo. Kidney Int. 1994; 45: 1220–1225.

    Article  CAS  PubMed  Google Scholar 

  42. Zhu G et al. In vivo adenovirus-mediated gene transfer into normal and cystic rat kidneys. Gene Therapy 1996; 3: 298–304.

    CAS  PubMed  Google Scholar 

  43. Langer JC et al. Adeno-associated virus gene transfer into renal cells: potential for in vivo gene delivery. Exp Nephrol 1998; 6: 189–194.

    Article  CAS  PubMed  Google Scholar 

  44. Gusella GL et al. Lentiviral gene transduction of kidney. Hum Gene Ther 2002; 13: 407–414.

    Article  CAS  PubMed  Google Scholar 

  45. Peng KW et al. Organ distribution of gene expression after intravenous infusion of targeted and untargeted lentiviral vectors. Gene Therapy 2001; 8: 1456–1463.

    Article  CAS  PubMed  Google Scholar 

  46. Lai LW et al. Kidney-targeted liposome-mediated gene transfer in mice. Gene Therapy 1997; 4: 426–431.

    Article  CAS  PubMed  Google Scholar 

  47. Ignowski JM, Schaffer DV . Kinetic analysis and modeling of firefly luciferase as a quantitative reporter gene in live mammalian cells. Biotechnol Bioeng 2004; 86: 827–834.

    Article  CAS  PubMed  Google Scholar 

  48. Romen S et al. Pharmacodynamics of geldanamycin using luciferase as a reporter. The 14th Annual UBRP Research Conference 2003, No. 56.

  49. Bao L et al. Stable transgene expression in tumors and metastases after transduction with lentiviral vectors based on human immunodeficiency virus type 1. Hum Gene Ther 2004; 15: 445–456.

    Article  CAS  PubMed  Google Scholar 

  50. Varnavski AN et al. Stable high-level expression of heterologous genes in vitro and in vivo by noncytopathic DNA-based Kunjin virus replicon vectors. J Virol 2000; 74: 4394–4403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Maeda S et al. Expression of Lac Z gene in canine muscle by intramuscular inoculation of a plasmid DNA. J Vet Med Sci 2004; 66: 337–339.

    Article  CAS  PubMed  Google Scholar 

  52. Thompson JF et al. Modulation of firefly luciferase stability and impact on studies of gene regulation. Gene 1991; 103: 171–177.

    Article  CAS  PubMed  Google Scholar 

  53. Hickman MA et al. Gene expression following direct injection of DNA into liver. Hum Gene Ther 1994; 5: 1477–1483.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Medical Research Council of Singapore and A*Star (Agency for Science, Technology and Research), Singapore.

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Author notes

  1. X Wu and H Gao: These authors contributed equally to this work

Authors and Affiliations

  1. Gene Vector Laboratory, Division of Cellular and Molecular Research, National Cancer Center, Singapore

    X Wu, H Gao & K M Hui

  2. Department of General Surgery, Singapore General Hospital, Singapore

    S Pasupathy

  3. Department of Pathology, Singapore General Hospital, Singapore

    P H Tan

  4. Department of Surgical Oncology, National Cancer Center, Singapore

    L L Ooi

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  1. X Wu
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Wu, X., Gao, H., Pasupathy, S. et al. Systemic administration of naked DNA with targeting specificity to mammalian kidneys. Gene Ther 12, 477–486 (2005). https://doi.org/10.1038/sj.gt.3302433

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