Einfluß einer Virusdosiseskalation beim adenoviralen LDL-Rezeptorgentransfer im KaninchenmodellNicole GreweI1.11.1234399#469567456#315891.2101.2.111624#8651.2.212275#27513623#866141.2.3151.2.41617604#562181.2.51.2.619266#3642021603#4421.3221.3.12324604#37925261.3.21.3.327282.293.303.13.1.1556#3473.1.2313.1.332333#5893.23.2.133560#408343.2.23.2.2.1353.2.2.2363.33.3.13.3.23.3.33.3.4373.43.4.1383.4.239403.4.3468#45480#59504#58588#59413.4.4540#59504#58588#59423.4.5434.444.145397#570464.24.347607#4124.4484.5494.5.14.5.2504#3534.5.350604#2104.5.45152462#9514.5.553604#685544.64.6.14.6.255510#3404.6.356608#36757603#364584.6.45960605#58661504#58062505#5814.6.55.63646566676869707172736.7475 ABKÜRZUNGSVERZEICHNIS767778 LITERATURVERZEICHNIS7980818283848586878889909192ERKLÄRUNG AN EIDES STATTDANKSAGUNGdeInhaltsverzeichnisHilfe LITERATURVERZEICHNIS 1. Karlson, P., Doenecke, D., Koolman, J. Kurzes Lehrbuch der Biochemie für Mediziner und Naturwissenschaftler. 14. Aufl. Thieme,

Stuttgart, New York

, 1994, 103-164 2. Morgan, R. A., Anderson, W. F. Human Gene Therapy. Annu Rev Biochem, 1993, 62:191-217 3. Grabowski, G. A., Whitsett, J. A. Gene Therapy. In: Nelson, W. E., Behrmann, R. E., Kliegman, R. M., Arvin, A. M., Nelson Textbook of Pediatrics. W. B. Saunders Company,

Philadelphia

, 1996, 321-326 4. Vesting, J.-W. Legal Aspects of Genetic Therapies in Germany. In: Müller, S., Simon, J. W., Vesting, J.-W., Interdisciplinary approaches to gene therapy: legal, ethical and scientific aspects. Springer-Verlag, 1997, 91-97 5. Tzeng, E., Shears, L., Lotze, M., Billiar, T. Gene Therapy. In: Tzeng, E., Shears, L., Lotze, M., Billiar, T. Current Problems in Surgery. Mosby-Year Book,

St. Louis

, December 1996, 963-1041 6. Büttner, C. A. Entwicklung eines in vivo Scan-Verfahrens zur Detektion des LDL-Rezeptor Gentransfers im Kaninchenmodell.

Hannover

, Med. Hochsch., Abtlg. für Gastroenterologie und Hepatologie, Diss., 1999 7. Sakata, H., Taketazu, G., Nagaya, K., Shirai, M., Sugai, R., Ikegami, K., Maruyama, S. Outbreak of severe infection due to adenovirus type 7 in a paediatric ward in Japan. In: J Hosp Infect, 1998, 39: 207-211 8. Abzug, M. J., Levin, M. J. Neonatal Adenovirus Infection: Four Patients and Review of the Literature. In: Pediatrics, 1991, 87: 890-896 9. Lynch, C. M., Hara, P. S., Leonard, J. C., Williams, J. K., Dean, R. H., Geary, R. L. Adeno-Associated Virus Vectors for Vascular Gene Delivery . In: Circ Res, 1997; 80: 497-505 10. Löffler, G., Petrides, P. E. Biochemie und Pathobiochemie. Springer-Verlag, 1997, 350-354, 463-480 11. Dargel, R. Biochemie und Pathobiochemie der Lipoproteine: Lipoproteine und Atherosklerose. Akademie-Verlag,

Berlin

, 1991, 1-71 12. Havel, R. J., Goldstein, J. L., Brown, M. S. Lipoproteins and Lipid Transport. In Bondy, P. K., Rosenberg, L. E. Metabolic Control and Diasease, Saunders Company,

Philadelphia

, 1980, 393-433 13. Schwandt, P., Richter, W. O. Handbuch der Fettstoffwechselstörungen. Schattauer-Verlag,

Stuttgart, New York

, 1995, Seite 1-33, 41-47, 145-158 14. Darnell, J. E., Lodish, H., Baltimore, D. Transport durch Zellmembranen. In: Darnell, J., Lodish, H., Baltimore, D. Molekulare Zellbiologie. Walter de Gruyter & Co-Verlag,

Berlin, New York

, 1993, 650-661 15. Stryer, L. Biosynthese der Bausteine. In: Biochemie. Spektrum-Verlag,

Heidelberg, Berlin, Oxford,

1996, 733-744 16. Schmidt, H., Kostner, G. M. Hypercholesterinämien. In: Wien Med Wochenschr, Themenheft Hypercholesterinämie, Heft 12/13, 1994, 312-319 17. Südhof, T. C., Goldstein, J. L., Brown, M. S., Russel, D. W. The LDL receptor gene: A mosaic of exons shared with different proteins. In: Science, 1985; 228: 815-822 18. Hobbs, H. H., Russell, D. W., Brown, M. S., Goldstein, J. L. The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. In: Annu Rev Genet, 1990; 24: 133-170 19. Hobbs, H. H., Brown, M. S., Goldstein, J. L. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia . In: Hum Mutat, 1992; 1: 445-466 20. Reshef, A., Nissen, H., Triger, L., Hensen, T. S., Eliav, O., Schurr, D., Safadi, R., Gare, M., Leitersdorf, E. Molecular genetics of familial hypercholesterolemia in Israel. In: Hum Genet, 1996; 98: 581-586 21. Schmidt, H. H.-J., Hill, S., Makariou, E. V., Feuerstein, I. M., Dugi, K. A., Hoeg, J. M. Relation of Cholesterol-Year Score to Severity of Calcific Atherosclerosis and Tissue Deposition in Homozygous Familial Hypercholesterolemia . In: Am J Cardiol, 1996; 77: 575-580 22. Goldstein, J. L., Hobbs, H. H., Brown, M. S., Havel, R. J., Kane, J. P. Lipoprotein and lipid metabolism disorders . In: Stanbury, J. B., Wyngaarden, J. B., Fredrickson, D. S. The Metabolic and Molecular Bases of Inherited Disease. 7/e, Mc Graw Hill, 1995, 1840-1885, 1981-2030 23. Goldstein, J. L., Brown, M. S. Atherosclerosis: The low-density lipoprotein receptor hypothesis . In: Metabolism, 1977; 26: 1257 24. Rose, V., Wilson, G., Steiner, G. Familial hypercholesterolemia: Report of coronary death at age 3 in a homozygous child and prenatal diagnosis in a heterozygous sibling .In: J Pediatr, 1982; 100: 757 25. Hobbs, H. H., Brown, M. S., Russell, D. W., Davignon, J., Goldstein, J. L. Deletion in the gene for the LDL receptor in majority of French Canadians with familial hypercholesterolemia . In: N Engl J Med, 1987; 317: 734 26. Gagné, C., Moorjani, S., Brun, D., Toussaint, M., Lupien, P.-J. Heterozygous familial hypercholesterolemia: Relationship between plasma lipids, lipoproteins, clinical manifestations and ischaemic heart disease in men and women . In: Atherosclerosis, 1979; 34: 13-24 27. Kwiterovich, P. O., Fredrickson, D. S., Levy, R. I. Familial Hypercholesterolemia (One Form of Familial Type II Hyperlipoproteinemia). In: J Clin Invest, 1974; 53: 1237-1249 28. Hoeg, J. M., Demosky, S. J., Schaefer, E. J., Starzl, T. E., Brewer, H. B. Characterization of Hepatic Low Density Lipoprotein Binding and Cholesterol Metabolism in Normal and Homozygous Familial Hypercholesterolemic Subjects. In: J Clin Invest, 1984; 73: 429-436 29. Hoeg, J. M., Edge, S. B., Demosky, S. J., Starzl, T. E., Triche, T., Gregg, R. E., Brewer, H. B. Metabolism of low-density lipoproteins by cultured hepatocytes from normal and homozygous familial hypercholesterolemic subjects. In: Biochim Biophys Acta, 1986; 876: 646-657 30. Top, B., Uitterlinden, A. G., Van der Zee, A., Kastelein, J. J. P., Gevers Leuven, J. A., Havekes, L. M., Frants, R. R. Absence of mutations in the promoter region of the low density lipoprotein receptor gene in a large number of familial hypercholesterolemia patients as revealed by denaturing gradient gel electrophoresis. In: Hum Genet, 1992; 89: 561-565 31. Edge, S. E., Hoeg, J. M., Triche, T., Schneider, P. D., Brewer, H. B. Cultured human hepatocytes. Evidence for metabolism of low density lipoproteins by a pathway independent of the classical low density lipoprotein receptor . In: J Biol Chem, 1986; 261: 3800-3806 32. Strachan, T., Read, A. P. Molekulare Humangenetik. Spektrum-Verlag,

Heidelberg, Berlin, Oxford

, 1996, 661-704 33. Fan, J., Watanabe, T. Cholesterol-fed and transgenic rabbit models for the study of atherosclerosis . In: J Atheroscler Thromb 2000; 7(1): 26-32 34. Buja, L. M., Clubb, F. J., Bilheimer, D. W., Willerson, J. T. Pathobiology of human familial hypercholesterolemia and a related animal model, the Watanabe heritable hyperlipidemic rabbit. In: Eur Heart J, 1990, Aug 11; Suppl. E: 41-52 35. Carranza-Bencano, A., Fernádez-Centeno, M., Leal-Cerro, A., Duque-Jimeno, V., Gornez-Arroyo, J. A., Zurita-Gutierrez, M. Xanthomas of the achilles tendon: report of a bilateral case and review of the literature . In: Foot Ankle Int, 1999 May; 20(5): 314-16 36. Stefanutti, C., Lucani, G., Vivenzio, A., Di Giacomo, S. Diet only and diet plus simvastatin in the treatment of heterozygous familial hypercholesterolemia in childhood . In: Drugs Exp Clin Res, 1999; 25(1): 23-28 37. Schwandt, P., Richter, W. O. Medikamentöse Therapie der Hypercholesterinämie . In: Wien Klin Wochenschr, 1995; 107(18): 544-8 38. Connor, W. E., Connor, S. L. Dietary treatment of familial hypercholesterolemia . In: Arteriosclerosis, 1989 Jan-Feb; 9(1): I91-I105 39. Illingworth, D. R., Bacon, S. Treatment of heterozygous familial hypercholesterolemia with lipid-lowering drugs. In: Arteriosclerosis, 1989 Jan-Feb; 9(1): I121-I134 40. Kajinami, K., Mabuchi, H. Therapeutic effects of LDL apheresis in the prevention of atherosclerosis. In: Curr Opin Lipidol, 1999 Okt; 10(5): 401-6 41. Thompson, G. R., Barbir, M., Okabayashi, K., Trayner, I., Larkin, S. Plasmapheresis in familial hypercholesterolemia. In: Arteriosclerosis, 1989 Jan-Feb; 9(1): I152-I157 42. Bilheimer, D. W. Portacaval shunt and liver transplantation in treatment of familial hypercholesterolemia. In: Arteriosclerosis, 1989 Jan-Feb; 9(1): I158-I163 43. Starzl, T. E., Bahnson, H. T., Hardesty, R. L., Iwatsuki, S., Gartner jr., J. C., Bilheimer, D. W., Shaw jr., B. W., Griffith, B. P., Zitelli, B. J., Malatack, J. J., Urbach, A. H. Heart-liver transplantation in a patient with familial hypercholesterolemia. In: Lancet, 1984; 1: 1382-1383 44. Offstad, J., Schrumpf, E., Geiran, O., Søreide, O., Simonsen, S. Plasma exchange and heart-liver transplantation in a patient with homozygous familial hypercholesterolemia. In: Clin Transplant, 2001; 15(6): 432-436 45. Culver, K. W. The potential for genetic healing. In: JAMA, 1992; 268(13): 1768 46. Rüger, R. Leberzell-Gentherapie – Perspektiven nach einem heroischen Start. In: Fortschr Med, 1995; 24: 341/25 47. Raper, S. E. Hepatocyte tranplantation and gene therapy . In: Clin Tranplant, 1995; 9(3 Pt 2): 249-54 48. Wilson, J. M., Johnston, D. E., Jefferson, D. M., Mulligan, R. C. Correction of the genetic defect in hepatocytes from the Watanabe heritable hyperlipidemic rabbit . In: Proc Natl Acad Sci USA, 1988; 85: 4421-4425 49. Wilson, J. M., Johnston, D. E., Jefferson, D. M., Mulligan, R. C. Correction of metabolic defect by gene transfer into isolated hepatocytes. In: J Gastroenterol Hepatol, 1989; 4: 585-587 50. Wilson, J. M., Chowdhury, N. R., Grossman, M., Wajsman, R., Epstein, A., Mulligan, R. C., Chowdhury, J. R. Temporary amelioration of hyperlipidemia in low density lipoprotein receptor-deficient rabbits transplanted with genetically modified hepatocytes . In: Proc Natl Acad Sci USA, 1990; 87: 8437-8441 51. Chowdhury, J. R., Grossman, M., Gupta, S., Chowdhury, N. R., Baker jr., J. R., Wilson, J. M. Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits . In: Science, 1991; 254: 1802-1805 52. Grossman, M., Rader, D. J., Muller, D. W. M., Kolansky, D. M., Kozarsky, K., Clark III, B. J., Stein, E. A., Lupien, P. J., Brewer jr., H. B., Raper, S. E., Wilson, J. M. A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolemia. In: Nat Med, 1995; 1(11): 1148-1154 53. Watanabe, Y. Serial imbreeding of rabbits with hereditary hyperlipidemia (WHHL-rabbit); incidence and development of atherosclerosis and xanthoma. In: Atherosclerosis, 1980; 36: 261-268 54. Havel, R. J., Yamada, N., Shames, D. M. Watanabe heritable hyperlipidemic rabbit: animal model for familial hypercholesterolemia. In: Arteriosclerosis, 1989 Jan-Feb; 9(1): I33-I38 55. Buja, L. M., Kita, T., Goldstein, J. L., Watanabe, Y., Brown, M. S. Cellular pathology of progressive atherosclerosis in the WHHL rabbit: an animal model of familial hypercholesterolemia . In: Arteriosclerosis, 1983 Jan-Feb; 3(1): 87-101 56. Havel, R. J., Kita, T., Kotite, L., Kane, J. P., Hamilton, R. L., Goldstein, J. L., Brown, M. S. Concentration and composition of lipoproteins in blood plasma of the WHHL rabbit. In: Arteriosclerosis, 1982 Nov-Dec; 2(6): 467-474 57. Kita, T., Brown, M. S., Watanabe, Y., Goldstein, J. L. Deficiency of low density lipoprotein receptors in liver and adrenal gland of the WHHL rabbit, an animal model of familial hypercholesterolemia . In: Proc Natl Acad Sci USA, 1981; 78(4): 2268-2272 58. Dichek, D. A., Bratthauer, G. L., Beg, Z. H., Anderson, K. D., Newman, K. D., Zwiebel, J. A., Hoeg, J. M., Anderson, W. F. Retroviral vector-mediated in vivo expression of low-density-lipoprotein receptors in the Watanabe heritable hyperlipidemic rabbit. In: Somat Cell Mol Genet, 1991; 17(3): 287-301 59. Wilson, J. M., Grossman, M., Wu, C. H., Chowdhury, N. R., Wu, G. Y., Chowdhury, J. R. Hepatocyte-directed gene transfer in vivo leads to transient improvement of hypercholesterolemia in low density lipoprotein receptor-deficient rabbits . In: J Biol Chem, 1992; 267(2): 963-967 60. Kozarsky, K. F., McKinley, D. R., Austin, L. L., Raper, S. E., Stratford-Perricaudet, L. D., Wilson, J. M. In vivo correction of low density lipoprotein receptor deficiency in the Watanabe heritable hyperlipidemic rabbit with recombinant adenoviruses . In: J Biol Chem; 1994; 269(18): 13695-13702 61. Li, J., Fang, B., Eisensmith, R. C., Li, X. H. C., Nasonkin, I., Lin-Lee, Y.-C., Mims, M. P., Hughes, A., Montgomery, C. D., Roberts, J. D., Parker, T. S., Levine, D. M., Woo, S. L. C. In vivo gene therapy for hyperlipidemia: phenotypic correction in Watanabe rabbits by hepatic delivery of the rabbit LDL receptor gene. In: J Clin Invest, 1995; 95: 768-773 62. Brown, D. R., Brousseau, M. E., Shamburek, R. D., Talley, G. D., Meyn, S., Demosky jr., S. J., Santamarina-Fojo, S., Brewer jr., H. B., Hoeg, J. M. Adenoviral delivery of low-density lipoprotein receptors to hyperlipidemic rabbits: receptor expression modulates high-density lipoproteins. In: Metabolism, 1996; 45(12): 1447-1457 63. Herz, J., Gerard, R. D. Adenovirus-mediated transfer of low density lipoprotein receptor gene acutely accelerates cholesterol clearance in normal mice . In: Proc Natl Acad Sci USA, 1993; 90: 2812-2816 64. Yamamoto, T., Davis, C. G., Brown, M. S., Schneider, W. J., Casey, M. L., Goldstein, J. L., Russell, D. W. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. In: Cell, 1984; 39(1): 27-38 65. Brewer, H. B., Ronan, R., Meng, M., Bishop, C. Isolation and characterization of apolipoproteins A-I, A-II, and A-IV . Methods Enzymol, 1986; 128: 223-246 66. Mac Farlane, A. S. Efficient trace-labeling of proteins with iodine. In: Nature, 1958; 182: 53-55 67. Langer, T., Strober, W., Levy, R. I. The metabolism of low density lipoproteins in familial type II hyperlipoproteinemia: In: J Clin Invest, 1972; 51: 1528-1536 68. Lees, R. S., Lees, A. M., Strauss, H. W. External imaging of human atherosclerosis . J Nucl Med, 1983; 24: 154-156 69. Hoffmann, P., Lieser, K. H. Methoden der Kern- und Radiochemie. 1991,

Weinheim

, VCH Verlagsgesellschaft 70. Gansow, O. A. Newer approaches to the radiolabeling of monoclonal antibodies by use of metal chelates. In: Nucl Med Biol, 1991; 18(4): 369-381 71. Rosen, J. M., Butler, S. P., Meinken, G. E., Wang, T. S. T., Ramakrishnan, R., Srivastava, S. C., Alderson, P. O., Ginsberg, H. N. Indium-111-labeled LDL: a potential agent imaging atherosclerotic disease and lipoprotein distribution. In: J Nucl Med, 1990; 31: 343-350 72. Virgolini, I., Angelberger, P., Li, S. R., Koller, F., Koller, E., Pidlich, J., Lupattelli, G., Sinzinger, H. Indium-111-labeled low-density lipoprotein binds with higher affinity to the human liver as compared to iodine-123-low-density-labeled lipoprotein. In: J Nucl Med, 1991; 32: 2132-2138 73. Hnatowich, D. J., McGann, J. DTPA-coupled proteins – procedures and precautions . In: Int J Rad Appl Instrum, Part B, 1987; 14(6): 563-568 74. Hnatowich, D. J. Label stability in serum of four radionuclides on DTPA-coupled antibodies – an evaluation. In: Int J Rad Appl Instrum, Part B, 1986; 13(4): 353-358 75. Najafi, A., Childs, R. L., Hnatowich, D. J. Coupling antibody with DTPA – an alternative to the cyclic anhydride . In: Int J Appl Rad Isotopes, 1984; 35(6): 554-557 76. Hnatowich, D. J., Childs, R. L., Lanteigne, D., Najafi, A. The preparation of DTPA-coupled antibodies radiolabeled with metallic radionuclides: an improved method. In: J Immunol Methods, 1983; 65(1-2): 147-157 77. Hnatowich, D. J., Layne, W. W., Childs, R. L., Lanteigne, D., Davis, M. A., Griffin, T. W., Doherty, P. W. Radioactive labeling of antibody: a simple and efficient method. In: Science, 1983; 220(4597): 613-615 78. Markwell, A. K., Haas, S. M., Biebler, L. L., Tolbert, N. E. A modification of the lowry procedure to simplify protein determination in membrane and lipoprotein samples. In: Anal Biochem, 1978; 87: 206-210 79. Kobayashi, K., Oka, K., Forte, T., Ishida, B., Teng, B., Ishimura-Oka, K., Nakamuta, M., Chan., L. Reversal of hypercholesterolemia in low density lipoprotein receptor knockout mice by adenovirus-mediated gene transfer of the very low density lipoprotein receptor . In: J Biol Chem, 1996; 271(12): 6852-6860 80. Ishibashi, S., Brown, M. S., Goldstein, J. L., Gerard, R. D., Hammer, R. E., Herz, J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. In: J Clin Invest, 1993; 92: 883-893 81. Kozarsky, K. F., Jooss, K., Donahee, M., Strauss III, J. F., Wilson, J. M. Effective treatment of familial hypercholesterolaemia in the mouse model using adenovirus-mediated transfer of the VLDL receptor gene . In: Nat Genet, 1996; 13: 54-62 82. Lupattelli, G., Virgolini, I., Li, S. R., Sinzinger, H. Low density lipoprotein receptors: preliminary results on „in vivo“ study . In: Wien Klin Wochenschr, 1991; 103(15): 462-465 83. Banyai, M., Lupattelli, G., Li, S. R., Pongratz, S., Yang, Q., Böck, P., Angelberger, P., Virgolini, I. Comparison of iodine-123 low-density lipoprotein (LDL) and indium-111 LDL binding to mononuclear cells of healthy normolipaemic controls and patients with heterozygous familial hypercholesterolemia. In: Eur J Nucl Med, 1994; 21(7): 634-639 84. Leitha, T., Hermann, M., Hüttinger, M., Angelberger, P., Dudczak, R. Technetium-99m labelled LDL as a tracer for quantitative LDL scintigraphy. I. Tracer purification, in vitro and in vivo long-term stability, in vitro validation and biodistribution. In: Eur J Nucl Med, 1993; 20(8): 667-673 85. Leitha, T., Staudenherz, A., Gmeiner, B., Hermann, M., Hüttinger, M., Dudczak, R. Technetium-99m labelled LDL as a tracer for quantitative LDL scintigraphy. II. In vivo validation, LDL receptor-dependent and unspecific hepatic uptake and scintigraphic results. In: Eur J Nucl Med, 1993; 20(8): 674-679 86. Leitha, T., Staudenherz, A., Hermann, M., Hüttinger, M., Gmeiner, B. Parenchymal and nonparenchymal uptake of technetium-99m, indium-111, and iodine-125 low-density lipoprotein in the normal and estradiol-stimulated rat liver: tracer validation for quantitative low-density lipoprotein scintigraphy . In: Hepatology, 1995; 22: 1289-1295 87. Virgolini, I., Angelberger, P., O´Grady, J., Sinzinger, H. Low density lipoprotein labelling characterizes experimentally induced atherosclerotic lesions in rabbits in vivo as to presence of foam cells and endothelial coverage . In: Eur J Nucl Med, 1991; 18: 944-947 88. Virgolini, I., Rauscha, F., Lupattelli, G., Angelberger, P., Ventura, A., O´Grady, J., Sinzinger, H. Autologous low-density lipoprotein labelling allows characterization of human atherosclerotic lesions in vivo as to presence of foam cells and endothelial coverage . In: Eur J Nucl Med, 1991; 18: 948-951 89. Hüttinger, M., Corbett, J. R., Schneider, W. J., Willerson, J. T., Brown, M. S., Goldstein, J. L. Imaging of hepatic low density lipoprotein receptors by radionuclide scintiscanning in vivo. In: Proc Natl Acad Sci USA, 1984; 81(23): 7599-7603 90. Chang, M. Y., Lees, A. M., Lees, R. S. Low-density lipoprotein modification and arterial wall accumulation in a rabbit model of atherosclerosis. In: Biochemistry, 1993; 32: 8518-8524 91. Lorberboym, M., Vallabhajosula, S., Lipszyc, H., Pastores, G. Scintigraphic evaluation of Tc-99m-low-density lipoprotein (LDL) distribution in patients with Gaucher disease . In: Clin Genet, 1997; 52(1): 7-11 92. Virgolini, I., Angelberger, P., Lupattelli, G., Li, S. R., Pidlich, J., Molinari, E., Sinzinger, H. Comparison of different methods for LDL isolation and radioiodination on liver LDL receptor binding in vitro. In: Int J Rad Appl Intrum, Part B, 1991; 18(5): 513-517 93. Billington, D., Jayson, G. G., Maltby, P. J. Radioisotopes. Introduction to Biotechniques, ed. Graham, J. M., and Billington, D. 1992,

Oxford

: Bios Scientific Publishers: 143-144 94. Vasile, E., Antohe, F. An ultrastructural study of β -very low density lipoprotein uptake and transport by valvular endothelium of hyperlipidemic rabbits. In: J Submicrosc Cytol Pathol, 1991; 23(2): 279-287 95. Patsch, W., Gotto, A. M., jr., Alaupovic, P. Characterization of Plasma Lipoproteins. In: Methods Enzymol, 1996; 263: 3-60 96. Mahley, R. W., Hui, D. Y., Innerarity, T. L., Beisiegel, U. Chylomicron Remnant Metabolism: Role of Hepatic Lipoprotein Receptors in Mediating Uptake. In: Arteriosclerosis, 1989 Jan-Feb; Supplement I (9): I14-I18 97. Dominiczak, M. H. Lipid metabolism. In: Curr Opin Lipidol, 1996; 7: U85-U91 98. Goldstein, J. L., Anderson, R. G. W., Brown, M. S. Coated pits, coated vesicles, and receptor-mediated endocytosis . In: Nature, 1979; 279: 679-685 99. Basu, S. K., Goldstein, J. L., Brown, M. S. Characterization of the Low Density Lipoprotein Receptor in Membranes Prepared from Human Fibroblasts. In: J Biol Chem, 1978; 253 (11): 3852-3856 100. Brown, M. S., Goldstein, J. L. Lipoprotein Receptors in the Liver: Control Signals for Plasma Cholesterol Traffic . In: J Clin Invest, 1983; 72: 743-747 101. Jackson, R. L., Morrisett, J. D., Gotto, A. M., Jr. The Mechanism of Lipid Binding by Plasma Lipoproteins .In: Mol Cell Biochem, 1975; 6(1): 43-49 102. Schaefer, E. J., Eisenberg, S., Levy, R. I. Lipoprotein apoprotein metabolism. In: J Lipid Res, 1978; 19:667-682 103. Schmidt, H. H.-J., Tietge, U. J. F., Manns, M. P. Perspectives of Liver Cell Transplantation: A Review . In: Hepatogastroenterology, 1997; 44: 1013-1018 104. Hoeg, J., Starzl, T., Brewer H. J. Liver transplantation for treatment of cardiovascular disease: Comparison with medication and plasma exchange in homozygous familial hypercholesterolemia . In: Am J Cardiol, 1987; 59: 705-707 105. Bilheimer, D., Goldstein, J., Grundy, S., Starzl, T., Brown, M. Liver transplantation to provide low-density-lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia . In: N Engl J Med, 1984; 311: 1658-1664 106. Tanzawa, K., Shimada, Y., Kuroda, M., Tsujita, Y., Arai, M., Watanabe, M. WHHL-rabbit: a low density lipoprotein receptor-deficient animal model for familial hypercholesterolemia. In: FEBS Lett, 1980; 25118 (1): 81-84 107. Watanabe, Y., Ito, T., Saeki, M., Kuroda, M., Tanzawa, K., Mochizuki, M., Tsujita, Y., Arai, M. Hypolipidemic effects of CS-500 (ML-236B) in WHHL-rabbit, a heritable animal model for hypercholesterolemia. In: Atherosclerosis, 1981; 38 (1-2): 27-31 108. Zsigmond, E., Kobayashi, K., Tzung, K.-W., Li, L., Fuke, Y., Chan, L. Adenovirus-Mediated Gene Transfer of Human Lipoprotein Lipase Ameliorates the Hyperlipidemias Associated with Apolipoprotein E and LDL Receptor Deficiencies in Mice. In: Hum Gene Ther; 8: 1921-1933 109. Van Dijk, K. W., Van Vlijmen, B. J. M., Van der Zee, A., Van´t Hof, B., Van der Boom, H., Kobayashi, K., Chan, L., Havekes, L. M., Hofker, M. H. Reversal of Hypercholesterolemia in Apolipoprotein E2 and Apolipoprotein E3-Leiden Transgenic Mice by Adenovirus-Mediated Gene Transfer of the VLDL Receptor . In: Arterioscler Thromb Vasc Biol; 18(1): 7-12 110. Chan, L., Use of somatic gene transfer to study lipoprotein metabolism in experimental animals in vivo . In: Curr Opin Lipidol, 1995; 6(5): 335-340 111. Schneider, D. B., Fly, C. A., Dichek, D. A., Geary, R. L. Adenoviral Gene Transfer in Arteries of Hypercholesterolemic Nonhuman Primates . In: Human Gene Therapy, 1998; 9: 815-821 112. Sullivan, D. E., Dash, S., Du, H., Hiramatsu, N., Aydin, F., Kolls, J., Blanchard, J., Baskin, G., Gerber, M. A. Liver-Directed Gene Transfer in Non-Human Primates. In: Hum Gene Ther, 1997; 8: 1195-1206 113. Raper, S. E., Haskal, Z. J., Ye, X., Pugh, C., Furth, E. E., Gao, G.-P., Wilson, J. M. Selective Gene Transfer into the Liver of Non-Human Primates with E1-Deleted, E2A-Defective, or E1-E4 Deleted Recombinant Adenoviruses. In: Hum Gene Ther, 1998; 9: 671-679 114. Gunsalus, J. R., Brady, D. A., Coulter, S. M., Gray, B. M., Edge, S. B. Reduction of serum cholesterol in Watanabe rabbits by xenogenic hepatocellular transplantation. In: Nat Med, 1997; 3(1): 48-53 115. Schmidt, H.-J., Sturmann, M., Shamburek, R., Schewe, C., Ebhardt, M., La, Z., Büttner, C., Wendt, M., Beisiegel, U., Brewer H. et al. Delayed catabolism despite a functional intact LDL-apolipoprotein B particle and LDL-receptor in a subject with clinical homozygous familial hypercholesterolemia. In: J Clin Endocrinol Metab, 1998; 83: 2167-2174 116. Knoell, D. L., Yiu, I. M. Human gene therapy for hereditary diseases: A review of trials. In: Am J Health Syst Pharm, 1998; 55: 899-904 117. Raper, S. E., McClane, S. J. Gene Transfer Strategies for Metabolic Diseases. In: World J Surg, 2002; 26(7): 838-842 118. Wilson, J. M., Grossman, M. Therapeutic strategies for familial hypercholesterolemia based on somatic gene transfer. In: Am J Cardiol, 1993; 72: 59D-63D 119. Grasso, A. W., Wu, G. Y. Therapeutic Implications of Delivery and Expression of Foreign Genes in Hepatocytes. In: Adv Pharmacol, 1994; 28: 169-192 120. Kozarsky, K., Grossman, M., Wilson, J. M. Adenovirus-Mediated Correction of the Genetic Defect in Hepatocytes from Patients with Familial Hypercholesterolemia. In: Somat Cell Mol Genet, 1993; 19(5): 449-458 121. Gerard, R. D., Chan, L. Adenovirus-mediated gene transfer: strategies and applications in lipoprotein research. In: Curr Opin Lipidol, 1996; 7(105): 105-111 122. Ilan, Y., Prakash, R., Davidson, A., Jona, V., Droguett, G., Horwitz, M. S., Chowdhury, N. R., Chowdhury, J. R. Oral tolerization to adenoviral antigens permits long-term gene expression using recombinant adenoviral vectors . J Clin Invest, 1997; 99(5): 1098-1106 123. Morral, N., O´Neal, W., Zhou, H., Langston, C., Beaudet, A. Immune responses to reporter proteins and high viral dose limit duration of expression with adenoviral vectors: comparison of E2a wild type and E2a deleted vectors. In: Hum Gene Ther, 1997; 8: 1275-1286 124. Smith, T. A. G., White, B. D., Gardner, J. M., Kaleko, M., McClelland, A. Transient immunosuppression permits successful repetitive intravenous administration of an adenovirus vector . Gene Ther, 1996; 3: 496-502 125. Marshall, E. Gene therapy death prompts review of adenovirus vector. Science, 1999; 286(5448): 2244-2245 126. Hollon, T. Researchers and regulators reflect on first gene therapy death. Nat Med, 2000; 6(1): 6 127. Sibbald, B. Death but one unintended consequence of gene-therapy trial. CMAJ, 2001; 164(11): 1612