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Angiographically guided utero-placental gene transfer in rabbits with adenoviruses, plasmid/liposomes and plasmid/polyethyleneimine complexes

Gene Therapy volume 8, pages 784–788 (2001)Cite this article

Abstract

We examined the feasibility of gene transfer to rabbit placenta using adenoviruses, plasmid/liposomes and plasmid/polyethyleneimine (PEI) complexes. Pregnant New Zealand White rabbits (n = 17) were anesthetized and local gene transfer was done via a catheter inserted in uterine arteries under direct angiographic control. Either nuclear targeted LacZ adenoviruses (1.0 × 1010 p.f.u.), nuclear targeted LacZ plasmid (500 μg)/liposome (DOTMA:DOPE 1:1) complexes or nuclear targeted LacZ plasmid (250 μg)/PEI (25 kDa) complexes (charge ratio ±4) were used. Animals were killed 3 days later and detection of the transgene expression was done by X-gal staining and RT-PCR. Adenovirus-mediated gene transfer resulted in a high transfection efficiency (34 ± 10%) in placental trophoplastic cells. Very little, if any, transfection was seen in fetal membranes. Plasmid/liposomes and plasmid/PEI complexes led to a very low (<0.01%) transfection efficiency in trophoblastic cells, but some transfection was seen in fetal membranes. A total of 25 fetuses were analyzed for the presence of transgene at the time of death. In most fetuses expression of the LacZ gene was below the sensitivity of the X-gal staining, but expression was detected by PCR in 50%, 50% and 42% of the analyzed fetuses after adenoviral, plasmid/PEI and plasmid/liposome gene transfer, respectively. No major inflammatory changes were present in the transfected placentas as analyzed by general histology and macrophage- and T cell-specific immunostainings. We conclude that catheter-mediated intravascular gene transfer with adenoviruses can be used for the transfection of placental trophoplastic cells, but plasmid complexes are inefficient for this purpose. However, selective angiographically guided gene transfer also led to leakage of the vector to fetuses. Therefore, if gene therapy is developed for the treatment of placental disorders, the gene-vector combination should not be harmful to the fetus and the expression of the transgene should only occur in placenta.

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Acknowledgements

This study was supported by grants from Finnish Academy, Sigrid Juselius Foundation, Kuopio University Hospital (EVO grant 5130) and The Finnish Cultural Foundation of Northern Savo. The authors want to thank Dr Jeff Bergelson for providing CAR receptor antibody, Ms Mervi Nieminen, Ms Eila Pelkonen and Ms Maiju Jääskeläinen for technical assistance and Ms Marja Poikolainen for preparing the manuscript.

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Authors and Affiliations

  1. AI Virtanen Institute, University of Kuopio, Kuopio, Finland

    A Heikkilä, M O Hiltunen, M P Turunen, A-M Turunen, T T Rissanen & S Ylä-Herttuala

  2. Department of Gynecology and Obstetrics, University of Kuopio, Kuopio, Finland

    L Keski-Nisula & S Heinonen

  3. Department of Radiology, University of Kuopio, Kuopio, Finland

    H Räsänen & H Manninen

  4. Department of Pathology and Forensic Medicine, University of Kuopio, Kuopio, Finland

    V-M Kosma

  5. Department of Medicine, University of Kuopio, Kuopio, Finland

    S Ylä-Herttuala

  6. Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland

    S Ylä-Herttuala

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  1. A Heikkilä
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  2. M O Hiltunen
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Heikkilä, A., Hiltunen, M., Turunen, M. et al. Angiographically guided utero-placental gene transfer in rabbits with adenoviruses, plasmid/liposomes and plasmid/polyethyleneimine complexes. Gene Ther 8, 784–788 (2001). https://doi.org/10.1038/sj.gt.3301444

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