Animal Models for Prenatal Gene Therapy: Rodent Models for Prenatal Gene Therapy

  • Jessica L. Roybal
  • Masayuki Endo
  • Suzanne M. K. Buckley
  • Bronwen R. Herbert
  • Simon N. Waddington
  • Alan W. Flake
Part of the Methods in Molecular Biology book series (MIMB, volume 891)

Abstract

Fetal gene transfer has been studied in various animal models, including rabbits, guinea pigs, cats, dogs, and nonhuman primate; however, the most common model is the rodent, particularly the mouse. There are numerous advantages to mouse models, including a short gestation time of around 20 days, large litter size usually of more than six pups, ease of colony maintenance due to the small physical size, and the relatively low expense of doing so. Moreover, the mouse genome is well defined, there are many transgenic models particularly of human monogenetic disorders, and mouse-specific biological reagents are readily available. One criticism has been that it is difficult to perform procedures on the fetal mouse with suitable accuracy. Over the past decade, accumulation of technical expertise and development of technology such as high-frequency ultrasound have permitted accurate vector delivery to organs and tissues. Here, we describe our experiences of gene transfer to the fetal mouse with and without ultrasound guidance from mid to late gestation. Depending upon the vector type, the route of delivery and the age of the fetus, specific or widespread gene transfer can be achieved, making fetal mice excellent models for exploratory biodistribution studies.

Key words

Rodents In utero gene delivery Fetal gene therapy Mating Injection procedures Tissue and biological fluid sampling Biodistribution 

References

  1. 1.
    Waddington SN, Kramer MG, Hernandez-Alcoceba R et al (2005) In utero gene therapy: current challenges and perspectives. Mol Ther 11:661–676PubMedCrossRefGoogle Scholar
  2. 2.
    Haynes BF, Martin ME, Kay HH et al (1988) Early events in human T cell ontogeny. Phenotypic characterization and immunohistologic localization of T cell precursors in early human fetal tissues. J Exp Med 168:1061–1080PubMedCrossRefGoogle Scholar
  3. 3.
    Takahama Y (2006) Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol 6:127–135PubMedCrossRefGoogle Scholar
  4. 4.
    Hagberg H, Peebles D, Mallard C (2002) Models of white matter injury: comparison of infectious, hypoxic-ischemic, and excitotoxic insults. Ment Retard Dev Disabil Res Rev 8:30–38PubMedCrossRefGoogle Scholar
  5. 5.
    Seppen J, van der Rijt R, Looije N et al (2003) Long-term correction of bilirubin UDP glucuronyltransferase deficiency in rats by in utero lentiviral gene transfer. Mol Ther 8:593–599PubMedCrossRefGoogle Scholar
  6. 6.
    Waddington SN, Mitrophanous KA, Ellard F et al (2003) Long-term transgene expression by administration of a lentivirus-based vector to the fetal circulation of immuno-competent mice. Gene Ther 10:1234–1240PubMedCrossRefGoogle Scholar
  7. 7.
    Dejneka NS, Surace EM, Aleman TS et al (2004) In utero gene therapy rescues vision in a murine model of congenital blindness. Mol Ther 9:182–188PubMedCrossRefGoogle Scholar
  8. 8.
    Rucker M, Fraites TJ Jr, Porvasnik SL et al (2004) Rescue of enzyme deficiency in embryonic diaphragm in a mouse model of metabolic myopathy: Pompe disease. Development 131: 3007–3019PubMedCrossRefGoogle Scholar
  9. 9.
    Karolewski BA, Wolfe JH (2006) Genetic correction of the fetal brain increases the lifespan of mice with the severe multisystemic disease mucopolysaccharidosis type VII. Mol Ther 14:14–24PubMedCrossRefGoogle Scholar
  10. 10.
    Sabatino DE, Mackenzie TC, Peranteau W et al (2007) Persistent expression of hF.IX after tolerance induction by in utero or neonatal administration of AAV-1-F.IX in hemophilia B mice. Mol Ther 15:1677–1685PubMedCrossRefGoogle Scholar
  11. 11.
    Niiya M, Endo M, Shang D et al (2008) Correction of ADAMTS13 deficiency by in utero gene transfer of lentiviral vector encoding ADAMTS13 genes. Mol Ther 17:34–41PubMedCrossRefGoogle Scholar
  12. 12.
    Koppanati BM, Li J, Reay DP et al (2010) Improvement of the mdx mouse dystrophic phenotype by systemic in utero AAV8 delivery of a mini dystrophin gene. Gene Ther 17(11):1355–1362PubMedCrossRefGoogle Scholar
  13. 13.
    Schachtner S, Buck C, Bergelson J et al (1999) Temporally regulated expression patterns following in utero adenovirus-mediated gene transfer. Gene Ther 6:1249–1257PubMedCrossRefGoogle Scholar
  14. 14.
    Endo M, Henriques-Coelho T, Zoltick PW et al (2010) The developmental stage determines the distribution and duration of gene expression after early intra-amniotic gene transfer using lentiviral vectors. Gene Ther 17:61–71PubMedCrossRefGoogle Scholar
  15. 15.
    Endo M, Zoltick PW, Chung DC et al (2007) Gene transfer to ocular stem cells by early gestational intraamniotic injection of lentiviral vector. Mol Ther 15:579–587PubMedCrossRefGoogle Scholar
  16. 16.
    Endo M, Zoltick PW, Peranteau WH et al (2007) Efficient in vivo targeting of epidermal stem cells by early gestational intraamniotic injection of lentiviral vector driven by the keratin 5 promoter. Mol Ther 16:131–137PubMedCrossRefGoogle Scholar
  17. 17.
    Stitelman DH, Endo M, Bora A et al (2010) Robust in vivo transduction of nervous system and neural stem cells by early gestational intra amniotic gene transfer using lentiviral vector. Mol Ther 18:1615–1623PubMedCrossRefGoogle Scholar
  18. 18.
    Roybal JL, Endo M, Radu A et al (2011) Early gestational gene transfer of IL-10 by systemic administration of lentiviral vector can prevent arthritis in a murine model. Gene Ther 18:719–726PubMedCrossRefGoogle Scholar
  19. 19.
    Henriques-Coelho T, Gonzaga S, Endo M et al (2007) Targeted gene transfer to fetal rat lung interstitium by ultrasound-guided intrapulmonary injection. Mol Ther 15: 340–347PubMedCrossRefGoogle Scholar
  20. 20.
    Gonzaga S, Henriques-Coelho T, Davey M et al (2008) Cystic adenomatoid malformations are induced by localized FGF10 overexpression in fetal rat lung. Am J Respir Cell Mol Biol 39:346–355PubMedCrossRefGoogle Scholar
  21. 21.
    Diehl KH, Hull R, Morton D et al (2001) A good practice guide to the administration of substances and removal of blood, including routes and volumes. J Appl Toxicol 21: 15–23PubMedCrossRefGoogle Scholar
  22. 22.
    Buckley SMK, Rahim AA, Chan JKY et al (2011) Recent advances in fetal gene therapy. Ther Deliv 2:461–469PubMedCrossRefGoogle Scholar
  23. 23.
    Roybal JL, Santore MT, Flake AW (2010) Stem cell and genetic therapies for the fetus. Semin Fetal Neonatal Med 15:46–51PubMedCrossRefGoogle Scholar
  24. 24.
    Rahim AA, Wong AM, Ahmadi S, et al (2011) In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression. Gene Ther (in press)Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Jessica L. Roybal
    • 1
  • Masayuki Endo
    • 1
  • Suzanne M. K. Buckley
    • 2
  • Bronwen R. Herbert
    • 1
  • Simon N. Waddington
    • 3
  • Alan W. Flake
    • 4
  1. 1.Department of Surgery, Children’s Center for Fetal Research and Center for Fetal Diagnosis and TreatmentChildren’s Hospital of PhiladelphiaPhiladelphiaUSA
  2. 2.Gene Transfer Technology Group, Institute for Women’s HealthUniversity College LondonLondonUK
  3. 3.Institute for Women’s Health, Gene Transfer Technology GroupUniversity College LondonLondonUK
  4. 4.Department of SurgeryChildren’s Hospital of PhiladelphiaPhiladelphiaUSA

Personalised recommendations