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Hepatic Encephalopathy, Hyperammonemia, and Ammonia Toxicity pp 145–154Cite as

Ornithine Transcarbamylase Deficiency: A Model for Gene Therapy

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 368))

Abstract

Ornithine transcarbamylase (EC 2.1.3.3.) deficiency (OTCD) is the most common and severe defect of the urea cycle disorders. It is an X-linked disorder with a high new mutation rate and variable phenotypic consequences. The enzyme catalyses the condensation of carbamyl phosphate and ornithine to citrulline in the second step of the urea cycle. It is expressed mainly in the liver and intestine (approximately 30% of liver levels), and is targeted to the mitochondria in which it assumes its homotrimeric active form.

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References

  1. Maestri N., Hauser E., Bartholomew D., Brusilow S.W., 1991, Prospective treatment of urea cycle disorder, J. Pediatr. 119:923–928.

    Article  PubMed  CAS  Google Scholar 

  2. Bmsilow, S. W. and Horwich, A. L. In: The metabolic basis of inherited disease, Vol 6 (Scriver CR, Beaudet AL, Sly WS and Valle D, Eds) New York: McGraw-Hill, pp 629–670. (1989)

    Google Scholar 

  3. Finkelstein J., Hauser E., Leonard C., Brusilow S., 1990, Late-onset ornithine transcarbamylase deficiency in male patients, J. Pediatr. 117(6):(6)897–902.

    PubMed  CAS  Google Scholar 

  4. Batshaw M., Msall M., Beaudate A., Trojak J., 1986, Risk of serious illness in heterozygotes for Ornithin Transcarbamylase deffeciency, J. Pediatr. 108:236–241.

    Article  PubMed  CAS  Google Scholar 

  5. Rowe P., Newman S., Brusilow S.W., 1986, Natural history of symptomatic partial ornithine transcarbamylase deficiency, New Engl Med, 314:541–547.

    Article  CAS  Google Scholar 

  6. Arn P.H., Hauser E.R., Thomas G.H., Herman G., Hess D., Brusilow S.W., 1990, Hyperammonemia in women with a mutation in the ornithine transcarbamylase locus: a cause of postpartum coma., New Engl J Med, 322:1652–1655.

    Article  PubMed  CAS  Google Scholar 

  7. Morsy M.A., Mitani K., Clemens P., Caskey C.T., 1993, Progress towards human gene therapy,JAMA, 270:2338–2345.

    Article  PubMed  CAS  Google Scholar 

  8. Ponder K.P., Gupta S., Leland F., Darlington G., Finegold M., DeMayo J., Ledley F.D., Chowdhury J.R., Woo S.L.C., 1991, Mouse hepatocytes migrate to liver parenchyma and function indefinitely after intrasplenic transplantation. Proc. Natl. Acad. Sci. USA, 88:1217–1221.

    Article  PubMed  CAS  Google Scholar 

  9. Chowdhury J.R., Grossman M., Gupta S., Chowdhury N.R., Baker J.R. Jr., Wilson J.M., 1991,Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits, Science, 254:1802–1805.

    Article  PubMed  CAS  Google Scholar 

  10. Ledley F.D., Woo S.L.C., Ferry G.D., Whisennand H.H., Brandt M.L., Darlington G.J., Demmler G.J., Finegold M.J., Pokorny W.J., Rosenblatt H., Schwart P., Anderson W.F., Moen R.C., 1991, Clinical protocol: hepatocellular transplantation in acute hepatic failure and targeting genetic markers to hepatic cells, Hum. Gene. Ther., 2:331–358.

    Article  PubMed  CAS  Google Scholar 

  11. Wilson J., Grossman M., Raper S., Baker J.J., Newton R., Thoene J., 1992, Ex vivo gene therapy of familial hypercholesterolemia, Hum. Gene. Ther., 3:179–222.

    Article  PubMed  CAS  Google Scholar 

  12. Cristiano R., Smith L., Kay M., Brinkley B., Woo S., 1993, Hepatic gene therapy: efficient gene delivery and expression in primary hepatocytes utilizing a conjugated adenovirus-DNA complex, Proc. Natl. Acad. Sci. USA, 90:11548–11552.

    Article  PubMed  CAS  Google Scholar 

  13. Human gene marker/therapy clinical protocols, 1994, Hum. Gene Ther., 5(2):271–280.

    Article  Google Scholar 

  14. Graham, F. L. and Prevec, L. Manipulation of adenovirus vectors. In: Methods in Molecular Biology, edited by E.J.Clifton, NJ: The Humana Press Inc., 1991, p. 109–128.

    Google Scholar 

  15. Horwitz, M. S. Field’s Virology (2nd), edited by B. N. Fields and D. M. Knipe, NY: Raven Press,1990, p. 1679–1721.

    Google Scholar 

  16. Quantin, B., Perricaudet, L.D., Tajbakhsh, S., Mandel. J.L., 1992, Adenovirus as an expression vector in muscle cells in vivo, Proc. Natl. Acad. Sci. USA. 89:2581–2584.

    Article  PubMed  CAS  Google Scholar 

  17. Stratford-Perricaudet, L., Makeh, I., Perricaudet, M., Briand, P., 1992, Widespread long-term gene transfer to mouse skeletal muscles and heart, J. Clin. Invest., 90:626–630.

    Article  PubMed  CAS  Google Scholar 

  18. Ragot, T., Vincent, N., Chafey, P., Vigne, E., Gilgenk-Rantz, H., Couton, D., Cartaud, J., Briand,P., Kaplan, J.-C., Perricaudet, M., Kahn, A., 1993, Efficient adenovirus-mediated transfer of a human minidystrophin gene to skeletal muscle of mdx mice, Nature, 361:647–650.

    Article  PubMed  CAS  Google Scholar 

  19. Bout, A., Perricaudet, M., Baskin, G., Imler, J.-L., Scholte, B.J., Pavirani, A., Valerio, D., 1994,Lung gene therapy: in vivo adenovirus-mediated gene transfer to Rhesus monkey airway epithelium, Hum. Gene Ther., 5(1):3–10.

    Article  PubMed  CAS  Google Scholar 

  20. Rich, D.P., Anderson, M.P., Gregory, S.H., Cheng, S.H., Paul, S., Jefferson, D.M., McCann, J.D., Klinger, K.W., Smith, A.E., Welsh, M.J., 1990, Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulator in cystic fibrosis airway epithelial cells. Nature, 347:358–363.

    Article  PubMed  CAS  Google Scholar 

  21. Rosenfeld, M.A., Yoshimura, K., Trapnell, B.C., Yoneyama, K., Rosenthal, W., Dalemans, W.,Fukayama, M., Bargon, J., Stier, L.E., Stratford-Perricaudet, L., et al. ., 1992, In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epitheluim. Cell, 68:143–155.

    Article  PubMed  CAS  Google Scholar 

  22. Stratford-Perricaudet, L.D., Levrero, M., Chasse, J.-F., Perricaudet, M., Briand, P., 1990,Evaluation of the Transfer and Expression in Mice of an Enzyme-Encoding Gene Using a Human Adenovirus Vector. Hum. Gene Ther., 1:241–256.

    Article  PubMed  CAS  Google Scholar 

  23. Kozarsky K., Grossman M., Wilson J.M., 1993, Adenovirus-mediated correction of the genetic defect in hepatocytes from pateints with familial hypercholesterolemia, Somat. Cell Mol. Genet, 19:449–458.

    Article  PubMed  CAS  Google Scholar 

  24. Ishibashi S., Brown M.S., Goldstein J.L., Gerard R.D., Hammer R.E., Herz J., 1993,Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery, J. Clin. Invest., 92:883–893.

    Article  PubMed  CAS  Google Scholar 

  25. Kay M.A., Landen C.N., Rothenberg S.R., Taylor LA., Leland F., Wiehle S., Fang B., Bellinger D., Finegold M., Thompson A.R., Read M., Brinkhous K.M., Woo S.L., 1994, In vivo hepetic gene therapy: complete albeit transeint correction of factor IX deficiency in hemophilia B dogs, Proc. Natl. Acad. Sci. USA, 91:2353–2357.

    Article  PubMed  CAS  Google Scholar 

  26. Gushiken T., Yoshimura N., Saheki T., 1985, Transient hyperammonemia during ageing in ornithine transcarbamylase-deficient, sparse-fur mice, Biochem. Int., 11:637–643.

    PubMed  CAS  Google Scholar 

  27. DeMars R., LeVan S.L., Trend B.L., Russell L.B., 1976, Abnormal ornithine carbamoyltransferase in mice having the sparse-fur mutation, Proc. Natl. Acad. Sci. USA, 73:1693–1697.

    Article  PubMed  CAS  Google Scholar 

  28. Briand P., Cathelineau L., Kamoun P., Gigot D., Penninckx M., 1981, Increase in ornithine transcarbamylase protein in sparse-fur mice with ornithine transcarbamylase deficiency, FEBS lett., 130:65–68.

    Article  PubMed  CAS  Google Scholar 

  29. Hulbert, L., Cordy, C. & Doolittle, D., 1974, A new allele of the sparse fur gene in the mouse,J. Hered., 65:194–195.

    PubMed  Google Scholar 

  30. Hodges, P. E. & Rosenberg, L. E., 1989, The spfash mouse: A missence mutation in the ornithine transcarbamylase gene also causes aberrant mRNA splicing, Proc. Natl. Acad. Sci. USA, 86:4142–4146.

    Article  PubMed  CAS  Google Scholar 

  31. Jones S.N., Grompe M., Munir M.I., Veres G., Craigen W.J., Caskey C.T., 1990, Ectopic correction of ornithine transcarbamylase deficiency in sparse fur mice, J. Biol. Chem., 265:14684–14690.

    PubMed  CAS  Google Scholar 

  32. Carvard C., Grimber G., Dubois N., Chasse J.F., Bennoun M., Minet T.M., Kamoun P., Briand P., 1988, Correction of mouse ornithine transcarbamylase deficiency by gene transfer into the germ line, Nucl. Acids. Res., 16:2099–2110.

    Article  Google Scholar 

  33. Grompe M., Jones S.N., Loulseged H., Caskey C.T., 1992, Retroviral-mediated gene transfer of human ornithine transcarbamylase into primary hepatocytes of spf and spf-ash mice, Hum. Gene Ther., 3:35–44.

    Article  PubMed  CAS  Google Scholar 

  34. Takebe Y., Seiki M., J.-I. F., P. H., Yokota K., Arai K.-I., Yoshida M., Arai M., SRa promoter:an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-US segment of human T-cell leukemia virus type-1 long terminal repeat, Mol. Cell. Biol., 8:466–472.

    Google Scholar 

  35. Morsy M.A., Alford E.L., Bett A., Graham F.L., Caskey C.T., 1993, Efficient adenoviral-mediated OTC expression in deficient mouse and human hepatocytes, J. Clin. Invest., 92:1580–1586.

    Article  PubMed  CAS  Google Scholar 

  36. MacGregor, G. R. and Caskey, C. T., 1989, Construction of plasmids that express E. coli ß-galactosidase in mammalian cells, Nucl. Acids. Res., 17:2365.

    Article  PubMed  CAS  Google Scholar 

  37. Quershi, I. A., Letarte, J., Ouellet, R., 1979, Ornithine transcarbamylase deficiency in mutant mice:Studies on the charecterization of enzyme defect and suitability as animal models of human disease, Pediatr. Res., 13:807–811.

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA

    Manal A. Morsy & C. Thomas Caskey

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  1. Manal A. Morsy
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  2. C. Thomas Caskey
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Editors and Affiliations

  1. Instituto de Investigaciones Citologicas de la F. I. B., Valencia, Spain

    Vicente Felipo  & Santiago Grisolia  & 

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Morsy, M.A., Caskey, C.T. (1994). Ornithine Transcarbamylase Deficiency: A Model for Gene Therapy. In: Felipo, V., Grisolia, S. (eds) Hepatic Encephalopathy, Hyperammonemia, and Ammonia Toxicity. Advances in Experimental Medicine and Biology, vol 368. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1989-8_15

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  • DOI: https://doi.org/10.1007/978-1-4615-1989-8_15

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5820-6

  • Online ISBN: 978-1-4615-1989-8

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