Abstract
In some lysosomal storage disorders pathological alterations in the central nervous system (CNS) occur as early as the prenatal period and the neuropathology progresses rapidly soon after birth. In these diseases, postnatal therapies alone are often insufficient. Therefore prenatal gene therapy to the CNS may be necessary. In order to investigate the feasibility of gene transfer to the CNS prenatally, we administered recombinant adenovirus carrying LacZ gene to rat embryos from embryonic day 9 to 12 (E9–E12). Results showed that efficient transduction of the reporter gene to the CNS was achieved when adenoviruses were injected at E12. The regions where the reporter gene was transduced mainly localized at the telencephalon and hypophysis of the embryo, and the gene expression persisted at least 1 week after birth. In addition, when adenoviruses were injected at E9, E10 and E11, no transgene expression was detected in the CNS, but was mainly observed in the liver, the heart and the skin, respectively.
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References
Gravel RA . The GM2 gangliosidoses Scriver CR, Beaudet AL, Sly WS, Valle D (eds); The Metabolic and Molecular Bases of Inherited Disease McGraw-Hill 1995 pp 2839–2879
Beutler E, Grabowski GA . Gaucher disease Scriver CR, Beaudet AL, Sly WS, Valle D (eds); The Metabolic and Molecular Bases of Inherited Disease McGraw-Hill 1995 pp 2641–2670
Suzuki K, Suzuki Y, Suzuki K . Galactosylceramide lipidosis: globoid-cell leukodystrophy (Krabbe disease) Scriver CR, Beaudet AL, Sly WS, Valle D (eds); The Metabolic and Molecular Bases of Inherited Disease McGraw-Hill 1995 pp 2671–2692
Orvisky E et al. Glucosylsphingosine accumulation in mice and patients with type 2 Gaucher disease begins early in gestation Pediatr Res 2000 48: 233–237
Bambach BJ et al. Engraftment following in utero bone marrow transplantation for globoid cell leukodystrophy Bone Marrow Transplant 1997 19: 399–402
Sekhon HS, Larson JE . In utero gene transfer into the pulmonary epithelium Nat Med 1995 1: 1201–1203
Holzinger A et al. Intraamniotic administration of an adenoviral vector for gene transfer to fetal sheep and mouse tissues Pediatr Res 1995 38: 844–850
Douar AM et al. Foetal gene delivery in mice by intra-amniotic administration of retroviral producer cells and adenovirus Gene Therapy 1997 4: 883–890
Turkay A, Saunders TL, Kurachi K . Intrauterine gene transfer: gestational stage-specific gene delivery in mice Gene Therapy 1999 6: 1685–1694
Schachtner SK, Buck CA, Bergelson JM, Baldwin HS . Temporally regulated expression patterns following in utero adenovirus-mediated gene transfer Gene Therapy 1999 6: 1249–1257
Lipshutz GS, Flebbe-Rehwaldt L, Gaensler KM . Adenovirus-mediated gene transfer to the peritoneum and hepatic parenchyma of fetal mice in utero Surgery 1999 126: 171–177
Yang EY et al. Persistent postnatal transgene expression in both muscle and liver after fetal injection of recombinant adenovirus J Pediatr Surg 1999 34: 766–773
Larson JE et al. Reversal of cystic fibrosis phenotype in mice by gene therapy in utero Lancet 1997 349: 619–620
Lipshutz GS et al. Short-term correction of factor VIII deficiency in a murine model of hemophilia A after delivery of adenovirus murine factor VIII in utero Proc Natl Acad Sci USA 1999 96: 13324–13329
Niwa H, Yamamura K, Miyazaki J . Efficient selection for high-expression transfectants with a novel eukaryotic vector Gene 1991 108: 193–199
Niwa H, Yamamura K, Miyazaki J . Efficient selection for high-expression transfectants with a novel eukaryotic vector Rugh R. The Mouse, Its Reproduction and Development. Burgess: Minneapolis, MN 1968, pp 102–207
Jaenisch R . Retrovirus and embryogenesis: microinjection of moloney leukemia virus into midgestation mouse embryos Cell 1980 19: 181–188
Draghia R et al. Gene delivery into the central nervous system by nasal instillation in rats Gene Therapy 1995 2: 418–423
Baldwin HS, Mickanin C, Buck C . Adenovirus-mediated gene transfer during initial organogenesis in the mammalian embryo is promoter-dependent and tissue-specific Gene Therapy 1997 4: 1142–1149
Wickham TJ, Mathias P, Cheresh DA, Nemerow GR . Integrins αvβ3 and αvβ5 promote adenovirus internalization but not virus attachment Cell 1993 73: 309–319
McCray PB Jr et al. Adenoviral-mediated gene transfer to fetal pulmonary epithelia in vitro and in vivo J Clin Invest 1995 95: 2620–2632
Wang G et al. Ultrasound-guided gene transfer to hepatocytes in utero Fetal Diagn Ther 1998 13: 197–205
Mitchell M et al. Long-term gene transfer to mouse fetuses with recombinant adenovirus and adeno-associated virus (AAV) vectors Gene Therapy 2000 7: 1986–1992
Feng M et al. Stable in vivo gene transduction via a novel adenoviral/retroviral chimeric vector Nat Biotechnol 1997 15: 866–870
Zheng C, Baum BJ, Iadarola MJ, O'Connell BC . Genomic integration and gene expression by a modified adenoviral vector Nat Biotechnol 2000 18: 176–180
Brambati B, Tului L . Prenatal genetic diagnosis through chorionic villus sampling Milunsky A (eds); Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment Johns Hopkins 1998 pp 150–178
Kanegae Y et al. Efficient gene activation in mammalian cells by using recombinant adenovirus expressing site-specific cre recombinase Nucleic Acids Res 1995 23: 3816–3821
Kanegae Y, Makimura M, Saito I . A simple and efficient method for purification of infectious recombinant adenovirus Jpn J Med Sci Biol 1994 47: 157–166
Acknowledgements
We would like to thank Dr I Saito and Dr Y Kanegae (University of Tokyo) for kindly providing the adenovirus vector. We also thank Mr Y Kimura (Laboratory Animal Center, The Jikei University School of Medicine) for technical assistance.
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Shen, JS., Meng, XL., Ohashi, T. et al. Adenovirus-mediated prenatal gene transfer to murine central nervous system. Gene Ther 9, 819–823 (2002). https://doi.org/10.1038/sj.gt.3301700
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DOI: https://doi.org/10.1038/sj.gt.3301700