The Potential of Gene Therapy as a Treatment Strategy for Intra-uterine Growth Restriction



Intra-uterine growth restriction (IUGR) is a major cause of perinatal morbidity and mortality. Growth-restricted fetuses are also at higher risk for developing diabetes, obesity, hypertension, coronary artery disease, and dyslipidemia later in adult life. Placental insufficiency, or abnormal placental vascular development or function, accounts for up to two-thirds of IUGR. Despite the relatively high prevalence of IUGR and the frequent perinatal morbidity and mortality and the potential for serious long-term sequelae, there is still no effective treatment for IUGR due to placental insufficiency. However, placental gene therapy that aims to overexpress transgene to compensate for deficient native gene expression in placenta tissues is a potential new therapeutic strategy. Placental gene therapy has numerous advantages including gene transfer to discarded tissue at the end of gestation, avoidance of fetal and maternal gene transfer, high level of transgene levels in target cells in placenta for duration of pregnancy, and the potential for long-term reprogramming of the fetal metabolic response to prevent long-term sequelae of IUGR. There are, however, a number of obstacles to be overcome before clinical translation of placental gene transfer can be considered as short- and long-term safety, efficacy, potential of germ line gene transfer, and insertional mutagenesis. In this chapter we review the etiologies of IUGR, management and treatment options, and the potential for gene therapy as treatment strategy.


Fetal Growth Fetal Growth Restriction Insertional Mutagenesis Placental Insufficiency Placenta Growth Factor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Adeno-associated virus vectors


Adeno virus vectors






Basic fibroblast growth factor


Coxsackie–adenovirus receptor


Insulin-like growth factor-binding proteins


Hepatocyte growth factor


Simplex virus


Insulin-like growth factor


Insulin-like growth factor receptor


Intra-uterine growth restriction


Platelet-derived growth factor B


Placental insufficiency


Placenta growth factor


Vascular endothelial growth factor-121


  1. Alsat E, Guibourdenche, Couturier A, et al. Physiological role of human placental growth hormone. Mol Cell Endocrinol. 1998;140:121–7.PubMedCrossRefGoogle Scholar
  2. American College of Obstetricians and Gynecologists. Intrauterine growth restriction (January 2000, Reaffirmed 2010). ACOG practice bulletin no. 12; 2000.Google Scholar
  3. Arechavaleta-Velasco F, Ma Y, Zhang J, McGrath CM, Parry S. Adeno-associated virus-2 (AAV-2) causes trophoblast dysfunction, and placental AAV-2 infection is associated with preeclampsia. Am J Pathol. 2006;168:1951–9.PubMedCrossRefGoogle Scholar
  4. Ashton IK, Spencer EM. Effect of partially purified human somatomedin on human fetal and postnatal cartilage in vitro. Early Hum Dev. 1983;8:135–40.PubMedCrossRefGoogle Scholar
  5. Baker J, Liu JP, Robertson EJ, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 1993;75:73–82.PubMedGoogle Scholar
  6. Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. The Vermont Oxford Network. Am J Obstet Gynecol. 2000;182:198–206.PubMedCrossRefGoogle Scholar
  7. Charnock-Jones DS. Soluble flt-1 and the angiopoietins in the development and regulation of placental vasculature. J Anat. 2002;200:607–15.PubMedCrossRefGoogle Scholar
  8. Collet M, Beillard C. Consequences of smoking on fetal development and risk of intra-uterine growth retardation or in utero fetal death. J Gynecol Obstet Biol Reprod (Paris). 2005;34 Spec No. 1:3S135–45.Google Scholar
  9. Constancia M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A, Fundele R, Stewart F, Kelsey G, Fowden A, Sibley C, Reik W. Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature. 2002;417:945–8.PubMedCrossRefGoogle Scholar
  10. Coutelle C, Douar AM, Colledge WH, Froster U. The challenge of fetal gene therapy. Nat Med. 1995;1:864–6.PubMedCrossRefGoogle Scholar
  11. Creasy RK, Resnik R. Intrauterine growth restriction. In: Creasy RK, Resnik R, editors. Maternal-fetal medicine: principles and practice. 4th ed. Philadelphia, PA: Saunders; 2004. pp. 495–512.Google Scholar
  12. DeChiara TM, Efstratiadis A, Robertson EJ. A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature. 1990;345:78–80.PubMedCrossRefGoogle Scholar
  13. Gilbert WM, Danielsen B. Pregnancy outcomes associated with intrauterine growth restriction. Am J Obstet Gynecol. 2003;188:1596–601.PubMedCrossRefGoogle Scholar
  14. Giudice LC, de Zegher F, Gargosky SE, Dsupin BA, de las Fuentes L, Crystal RA, Hintz RL, Rosenfeld RG. Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth. J Clin Endocrinol Metab. 1995;80:1548–55.PubMedCrossRefGoogle Scholar
  15. Godfrey KM, Barker DJP. Fetal nutrition and adult disease. Am J Clin Nutr. 2000;71 Suppl:1344S–52S.PubMedGoogle Scholar
  16. Gulmezoglu AM, Hofmeyr GJ. Bed rest in hospital for suspected impaired fetal growth (Systematic Review). Cochrane Pregnancy and Childbirth Group. Cochrane Database Syst Rev. 2000;3. Oxford: Update Software.Google Scholar
  17. Hinchliffe SA, Lynch MR, Sargent PH, Howard CV, Van Velzen D. The effect of intrauterine growth retardation on the development of renal nephrons. Br J Obstet Gynaecol. 1992;99:296–301.PubMedCrossRefGoogle Scholar
  18. Jansson T, Scholtbach V, Powell TL. Placental transport of leucine and lysine is reduced in intrauterine growth restriction. Pediatr Res. 1998;44:532–7.PubMedCrossRefGoogle Scholar
  19. Jauniaux E, Burton GJ. Morphological and biological effects of maternal exposure to tobacco smoke on the fetoplacental unit. Early Hum Dev. 2007;83(11):699–706.PubMedCrossRefGoogle Scholar
  20. Kanaka-Gantenbein C, Mastorakos G, Chrousos GP. Endocrine-related causes and consequences of intrauterine growth retardation. Ann N Y Acad Sci. 2003;997:150–7.PubMedCrossRefGoogle Scholar
  21. Katz AB, Keswani SG, Habli M, et al. Placental gene transfer: transgene screening in mice for trophic effects on the placenta. Am J Obstet Gynecol. 2009;201:499(5):e1–8.CrossRefGoogle Scholar
  22. Kauma S, Hayes N, Weatherford S. The differential expression of hepatocyte growth factor and met in human placenta. J Clin Endocrinol Metab. 1997;82:949–4.PubMedCrossRefGoogle Scholar
  23. Kniss DA, Shubert PJ, Zimmerman PD, Landon MB, Gabbe SG. Insulinlike growth factors. Their regulation of glucose and amino acid transport in placental trophoblasts isolated from first-trimester chorionic villi. J Reprod Med. 1994;39:249–56.PubMedGoogle Scholar
  24. Kramer MS, McLean FH, Olivier M, Willis DM, Usher RH. Body proportionality and head and length ‘sparing’ in growth-retarded neonates: a critical reappraisal. Pediatrics. 1989;84:717–23.PubMedGoogle Scholar
  25. Laurin J, Persson PH. The effect of bedrest in hospital on fetal outcome in pregnancies complicated by intrauterine growth retardation. Acta Obstet Gynecol Scand. 1987;66:407–11.PubMedCrossRefGoogle Scholar
  26. Leger J, Oury JF, Noel M, Baron S, Benali K, Blot P, Czernichow P. Growth factors and intrauterine growth retardation. I. Serum growth hormone, insulin-like growth factor (IGF)-I, IGF-II, and IGF binding protein 3 levels in normally grown and growth-retarded human fetuses during the second half of gestation. Pediatr Res. 1996;40(1):94–100.PubMedCrossRefGoogle Scholar
  27. MacKenzie T, et al. Efficient transduction of liver and muscle after in utero injection of lentiviral vectors with different pseudotypes. Mol Ther. 2002;6:349.PubMedCrossRefGoogle Scholar
  28. Manning FA. Fetal growth restriction. In: Manning FA, editor. Fetal medicine: principles and practice. Norwalk, CT: Appleton and Lange; 1995. pp. 395–412.Google Scholar
  29. Patel Y, Kim H, Rappolee DA. A role for hepatocyte growth factor during early postimplantation growth of the placental lineage in mice. Biol Reprod. 2000;62:904–12.PubMedCrossRefGoogle Scholar
  30. Say L, Gulmezoglu AM, Hofmeyr GJ. Maternal oxygen administration for suspected impaired fetal growth (Systematic Review). Cochrane Pregnancy and Childbirth Group. Cochrane Database Syst Rev. 2003;3. Oxford: Update Software.Google Scholar
  31. Sferruzzi Perri AN, et al. Early pregnancy maternal endocrine IGF-I programs the placenta for increased functional capacity throughout gestation. Endocrinology. 2007;148(9):4362–70.PubMedCrossRefGoogle Scholar
  32. Skarsgard ED, Amii LA, Dimmitt RA, et al. Fetal therapy with rhIGF-1 in a rabbit model of intrauterine growth restriction. J Surg Res. 2001;99:142–6.PubMedCrossRefGoogle Scholar
  33. Taylor R, Williams L. Developmental expression of platelet-derived growth factor and its receptor in the human placenta. Mol Endocrinol. 1998;2:627–32.CrossRefGoogle Scholar
  34. Thakur A, Sase M, Lee JJ, et al. Ontogeny of insulin-like growth factor I in a rabbit model of growth retardation. J Surg Res. 2000;91:135–40.PubMedCrossRefGoogle Scholar
  35. Volpers C, Kochanek S. Adenoviral vectors for gene transfer and therapy. J Gene Med. 2004;6 Suppl 1:S164–71.PubMedCrossRefGoogle Scholar
  36. Vonnahme KA, Ford SP. Placental vascular endothelial growth factor receptor system mRNA expression in pigs selected for placental efficiency. J Physiol. 2004;554:194–201.PubMedCrossRefGoogle Scholar
  37. Waddington SN, et al. Long-term transgene expression by administration of a lentivirus-based vector to the fetal circulation of immuno-competent mice. Gene Ther. 2003a;10:1234–40.PubMedCrossRefGoogle Scholar
  38. Waddington SN, et al. In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor. Blood. 2003b;101:1359–66.PubMedCrossRefGoogle Scholar
  39. Waddington SN, et al. Permanent phenotypic correction of Haemophilia B in immunocompetent mice by prenatal gene therapy. Blood. 2004;104:2714–21.PubMedCrossRefGoogle Scholar
  40. Zapf J, Rinderknecht E, Humbel RE, Froesch ER. Nonsuppressible insulin-like activity (NSILA) from human serum: recent accomplishments and their physiologic implications. Metabolism. 1978;27:1803–28.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of Pediatric General, Thoracic and Fetal SurgeryThe Fetal Care Center of Cincinnati, Cincinnati Children’s Hospital Medical Center, University HospitalCincinnatiUSA

Personalised recommendations