Abstract
In utero somatic gene therapy in the later stages of pregnancy may allow targeting of organ systems which are difficult to reach later in life and to prevent the development of tissue damage otherwise caused by the early onset of inherited diseases. We report here on the percutaneous delivery of two adenoviral vectors, containing the β-galactosidase reporter gene and the human Factor IX gene respectively, to the fetal liver and circulation by ultrasound-guided umbilical vein puncture similar to procedures used in human pregnancy. Vector spread, as detected by PCR analysis for the β-galactosidase encoding vector, was found in almost all fetal and neonatal organs and in the maternal liver. Expression of the β-galactosidase transgene was detected in many fetal tissues by RT-PCR. High β-galactosidase production was shown by immuno-histochemistry predominantly in the liver, where about 30% of the hepatocytes stained positive, and in the adrenal cortex. Production of factor IX was determined by ELISA in the plasma of treated fetuses and newborn lambs and reached at birth up to 80% of the normal human plasma concentration. This demonstrates a very hopeful proof of principle for the development of prenatal treatment of many genetic diseases but also requires more detailed investigations with respect to the observed systemic spread of the vector.
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Acknowledgements
This work was supported by grants from SPARKS and the Leopold Muller Bequest/CF Trust. MT is funded by the Leopold Muller Bequest/CF Trust, SJ by the MRC, SA by the Sir Jules Thorne Charitable Trust and HS by the Deutsche Forschungsgemeinschaft. We wish to express our gratitude to Ms Irene Hopton-Scott, Dr Hidenori Nishina, Dr Takashi Ozaki, Mr James Newman, Ms Suzy Buckley and Ms Henrietta Price for their much appreciated organisational or experimental support during this experiment.
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Themis, M., Schneider, H., Kiserud, T. et al. Successful expression of β-galactosidase and factor IX transgenes in fetal and neonatal sheep after ultrasound-guided percutaneous adenovirus vector administration into the umbilical vein. Gene Ther 6, 1239–1248 (1999). https://doi.org/10.1038/sj.gt.3300970
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DOI: https://doi.org/10.1038/sj.gt.3300970
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