Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Paper
  • Published:

Restoration of adrenal steroidogenesis by adenovirus-mediated transfer of human cytochromeP450 21-hydroxylase into the adrenal gland of21-hydroxylase-deficient mice

Gene Therapy volume 6, pages 1898–1903 (1999)Cite this article

Abstract

21-Hydroxylase deficiency, a potentially fatal disease due to deletions or mutations of the cytochrome P450 21-hydroxylase gene (CYP21), causes congenital adrenal hyperplasia (CAH) with low or absent glucocorticoid and mineralocorticoid production. The feasibility of gene therapy for CAH was studied using 21OH-deficient mice (21OH−) and a replication-deficient adenovirus containing the genomic sequence of human CYP21 (hAdCYP21). Intra-adrenal injection of hAdCYP21 in 21OH− mice induced hCYP21 mRNA with the highest expression from 2 to 7 days before a gradual decline. 21OH activity measured in adrenal tissue increased from undetectable to levels found in wild-type mice 2 to 7 days after AdhCYP21 injection. Adrenal morphology of 21OH− mice showed lack of zonation, and hypertrophy and hyperplasia of adrenocortical mitochondria with few tubulovesicular christae. These morphological abnormalities were markedly improved 7 days after hAdCYP21 gene therapy. Plasma corticosterone increased from undetectable levels to values similar in wild-type mice by 7 and 14 days, declining over the next 40 days. This is the first demonstration that a single intra-adrenal injection of an adenoviral vector encoding CYP21 can compensate for the biochemical, endocrine and histological alterations in 21OH-deficient mice, and shows that gene therapy could be a feasible option for treatment of CAH.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. New MI . Diagnosis and management of congenital adrenal hyperplasia Annu Rev Med 1998 49: 311–328

    Article  CAS  Google Scholar 

  2. Pang S . Congenital adrenal hyperplasia Endocrinol Metab Clin N Am 1997 26: 853–889

    Article  CAS  Google Scholar 

  3. Cutler GB Jr, Laue L . Congenital adrenal hyperplasia due to 21-hydroxylase deficiency New Engl J Med 1990 223: 1806–1813

    Google Scholar 

  4. Cutler GB Jr . Treatment of congenital adrenal hyperplasia: the case for new medical approaches J Clin Endocrinol Metab 1996 81: 3185–3186

    Google Scholar 

  5. Migeon CJ . Can the long range results of the treatment of congenital adrenal hyperplasia be improved? J Clin Endocr Metab 1996 81: 3187–3189

    Google Scholar 

  6. Shiroishi T, Sagai T, Natsume-Sakai S, Moriwaki K . Lethal deletion of the complement component C4 and steroid 21-hydroxylase genes in the mouse H-2 class III region caused by meiotic recombination Proc Natl Acad Sci USA 1987 84: 2819–2823

    Article  CAS  Google Scholar 

  7. Gotoh H et al. Steroid 21-hydroxylase deficiency in mice Endocrinology 1988 123: 1923–1927

    Article  CAS  Google Scholar 

  8. Robbins PD, Ghivizzani SC . Viral vectors for gene therapy Pharmacol Ther 1998 80: 35–47

    Article  CAS  Google Scholar 

  9. Vincent N et al. Long term correction of mouse dystrophic degeneration by adenovirus-mediated transfer of a minidistrophin gene Nat Genet 1993 5: 130–134

    Article  CAS  Google Scholar 

  10. Jaffe AH et al. Adenovirus-mediated in vivo gene transfer and expression in normal rat liver Nat Genet 1992 1: 372–378

    Article  CAS  Google Scholar 

  11. Ye X et al. Prolonged metabolic correction in adult ornithine transcarbamylase-deficient mice with adenoviral vectors J Biol Chem 1996 271: 3639–3646

    Article  CAS  Google Scholar 

  12. Ginsberg HS . The ups and downs of adenovirus vectors Bull NY Acad Med 1996 72: 53–58

    Google Scholar 

  13. Paltekian E et al. Adenovirus mediated gene transfer into the brain: methodological assessment J Neurosci Meth 1997 71: 77–84

    Article  Google Scholar 

  14. Munch A, Guyre PM, Holbrook NJ . Physiological functions of glucocorticoids in stress and their relation to pharmacological action Endocrine Rev 1984 5: 25–44

    Article  Google Scholar 

  15. Tajima T, Ma X-M, Bornstein SR, Aguilera G . Prenatal treatment does not prevent alterations of the hypothalamic pituitary adrenal axis in steroid 21-hydroxylase deficient mice Endocrinology 1999 140: 3354–3362

    Article  CAS  Google Scholar 

  16. Geddes BJ et al. Persistent transgene expression in the hypothalamus following stereotaxic delivery of a recombinant adenovirus: suppression of the immune response with cyclosporin Endocrinology 1996 137: 5166–5169

    Article  CAS  Google Scholar 

  17. Bornstein S et al. Adrenomedullary function is severely impaired in 21-hydroxylase deficient mice FASEB J 1999 13: 1185–1194

    Article  CAS  Google Scholar 

  18. Bornstein SR et al. Ultrastructural dynamics of mitochondrial morphology in varying functional forms of human adrenal cortical carcinoma Horm Metab Res 1996 28: 177–182

    Article  CAS  Google Scholar 

  19. Nussdorfer GG et al. Investigations on the turnover of adrenocortical mitochondria. XI A stereological study of the effects of chronic treatment with ACTH on the size and number of mitochondria from adult human adrenocortical cells cultured in vitro Cell Tissue Res 1977 182: 145–150

    Article  CAS  Google Scholar 

  20. Bornstein SR, Ehrhart-Bornstein M, Guse-Behling H, Scherbaum WA . Structure and dymnamics of adrenal mitochondria following stimulation with corticotropin releasing hormone Anat Record 1997 234: 255–262

    Article  Google Scholar 

  21. Okada T et al. Efficient directional cloning of recombinant adenovirus vectors using DNA–protein complex Nucleic Acids Res 1998 26: 1947–1950

    Article  CAS  Google Scholar 

  22. Graham FL, Prevec L . Adenovirus based expression vectors and recombinant vaccines Biotechnology 1992 20: 363–390

    CAS  PubMed  Google Scholar 

  23. McGrory WJ, Bautista DS, Graham FL . A simple technique for the rescue of early region I mutations into infectious human adenovirus type 5 Virology 1988 163: 614–617

    Article  CAS  Google Scholar 

  24. Jones N, Shenk T . Isolation of adenovirus type 5 host range deletion mutants defective for transformation of rat embryo cells Cell 1979 17: 683–689

    Article  CAS  Google Scholar 

  25. Smith TA et al. Adenovirus mediated expression of therapeutic plasma levels of human factor IX in mice Nat Genet 1993 5: 397–402

    Article  CAS  Google Scholar 

  26. Stojilkovic SS, Chang JP, Ngo D, Catt KJ . Evidence for a role of protein kinase C in luteinizing hormone synthesis and secretion: impared responses to gonadotropin releasing hormone in protein kinase C depleted cells J Biol Chem 1988 263: 17307–17311

    CAS  PubMed  Google Scholar 

  27. Fukushi M et al. A method for quantitative analysis of adrenal steroids with high-performance-liquid-chromatography for diagnosis of congenital adrenal hyperplasia. In: Therrel BL (ed) . Advances in Neonatal Screening Elsevier Science Publishers BV: New York 1987 303–308

    Google Scholar 

  28. Aguilera G, Lightman SL, Kiss A . Regulation of the hypothalamic-pituitary-adrenal axis during water deprivation Endocrinology 1993 132: 241–248

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Developmental Endocrinology Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA

    T Tajima, X-M Ma, S R Bornstein & G Aguilera

  2. Clinical Gene Therapy Branch, National Human Genome Research Center, NIH, Bethesda, MD, USA

    T Okada & W J Ramsey

Authors
  1. T Tajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X-M Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W J Ramsey
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S R Bornstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G Aguilera
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tajima, T., Okada, T., Ma, XM. et al. Restoration of adrenal steroidogenesis by adenovirus-mediated transfer of human cytochromeP450 21-hydroxylase into the adrenal gland of21-hydroxylase-deficient mice. Gene Ther 6, 1898–1903 (1999). https://doi.org/10.1038/sj.gt.3301018

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301018

Keywords

This article is cited by

Search

Advanced search

Quick links