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Liver-directed gene therapy for dyslipidemia and diabetes

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Abstract

This article provides an update of liver-directed gene therapy for dyslipidemia, reviewing papers published since 2002 and summarizing progress in gene transfer vectors. Despite the availability of polypharmacy and other therapeutic interventions, the treatment of severe dyslipidemia remains a challenge and continues to be an important target for experimental gene therapy. Gene therapy strategies that focus on long-term therapeutic efficacy of different regimens are emerging from small animal experiments, and new therapeutic genes and/or new approaches have been developed. A novel strategy for gene therapy for diabetes was published recently. Gene therapy for dyslipidemia and diabetes is still in its infancy. Nonetheless, recent progress in this area is encouraging and bodes well for the future.

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References and Recommended Reading

  1. Pearson TA, Blair SN, Daniels SR, et al.: AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation 2002, 106:388–391.

    Article  PubMed  Google Scholar 

  2. Grundy SM: Alternative approaches to cholesterol-lowering therapy. Am J Cardiol 2002, 90:1135–1138.

    Article  PubMed  Google Scholar 

  3. Oka K, Chan L: Recent advances in liver-directed gene therapy for dyslipidemia. Curr Atheroscler Rep 2002, 4:199–207.

    PubMed  Google Scholar 

  4. Niidome T, Huang L: Gene therapy progress and prospects: nonviral vectors. Gene Ther 2002, 9:1647–1652.

    Article  PubMed  CAS  Google Scholar 

  5. Thomas CE, Ehrhardt A, Kay MA: Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet 2003, 4:346–358.

    Article  PubMed  CAS  Google Scholar 

  6. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al.: LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003, 302:415–419.

    Article  PubMed  CAS  Google Scholar 

  7. Williams DA, Baum C: Medicine. Gene therapy-new challenges ahead. Science 2003, 302:400–401.

    Article  PubMed  CAS  Google Scholar 

  8. Schroder AR, Shinn P, Chen H, et al.: HIV-1 integration in the human genome favors active genes and local hotspots. Cell 2002, 110:521–529.

    Article  PubMed  CAS  Google Scholar 

  9. Hillgenberg M, Tonnies H, Strauss M: Chromosomal integration pattern of a helper-dependent minimal adenovirus vector with a selectable marker inserted into a 27.4-kilobase genomic stuffer. J Virol 2001, 75:9896–9908.

    Article  PubMed  CAS  Google Scholar 

  10. Harui A, Suzuki S, Kochanek S, Mitani K: Frequency and stability of chromosomal integration of adenovirus vectors. J Virol 1999, 73:6141–6146.

    PubMed  CAS  Google Scholar 

  11. Gaspar HB, Howe S, Thrasher AJ: Gene therapy progress and prospects: gene therapy for severe combined immunodeficiency. Gene Ther 2003, 10:1999–2004.

    Article  PubMed  CAS  Google Scholar 

  12. Gao GP, Alvira MR, Wang L, et al.: Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci U S A 2002, 99:11854–11859.

    Article  PubMed  CAS  Google Scholar 

  13. McCarty DM, Monahan PE, Samulski RJ: Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis. Gene Ther 2001, 8:1248–1254.

    Article  PubMed  CAS  Google Scholar 

  14. Nakai H, Iwaki Y, Kay MA, Couto LB: Isolation of recombinant adeno-associated virus vector-cellular DNA junctions from mouse liver. J Virol 1999, 73:5438–5447.

    PubMed  CAS  Google Scholar 

  15. Duan D, Sharma P, Yang J, et al.: Circular intermediates of recombinant adeno-associated virus have defined structural characteristics responsible for long-term episomal persistence in muscle tissue. J Virol 1998, 72:8568–8577.

    PubMed  CAS  Google Scholar 

  16. Nakai H, Montini E, Fuess S, et al.: AAV serotype 2 vectors preferentially integrate into active genes in mice. Nat Genet 2003, 34:297–302.

    Article  PubMed  CAS  Google Scholar 

  17. Schnell MA, Zhang Y, Tazelaar J, et al.: Activation of innate immunity in nonhuman primates following intraportal administration of adenoviral vectors. Mol Ther 2001, 3:708–722.

    Article  PubMed  CAS  Google Scholar 

  18. Liu Q, Muruve DA: Molecular basis of the inflammatory response to adenovirus vectors. Gene Ther 2003, 10:935–940.

    Article  PubMed  CAS  Google Scholar 

  19. Schiedner G, Hertel S, Johnston M, et al.: Selective depletion or blockade of Kupffer cells leads to enhanced and prolonged hepatic transgene expression using high-capacity adenoviral vectors. Mol Ther 2003, 7:35–43.

    Article  PubMed  CAS  Google Scholar 

  20. Eastman SJ, Baskin KM, Hodges BL, et al.: Development of catheter-based procedures for transducing the isolated rabbit liver with plasmid DNA. Hum Gene Ther 2002, 13:2065–2077.

    Article  PubMed  CAS  Google Scholar 

  21. Sakhuja K, Reddy PS, Ganesh S, et al.: Optimization of the generation and propagation of gutless adenoviral vectors. Hum Gene Ther 2003, 14:243–254.

    Article  PubMed  CAS  Google Scholar 

  22. Palmer D, Ng P: Improved system for helper-dependent adenoviral vector production. Mol Ther 2003, 8:846–852.

    Article  PubMed  CAS  Google Scholar 

  23. Belalcazar LM, Merched A, Carr B, et al.: Long-term stable expression of human apolipoprotein A-I mediated by helper-dependent adenovirus gene transfer inhibits atherosclerosis progression and remodels atherosclerotic plaques in a mouse model of familial hypercholesterolemia. Circulation 2003, 107:2726–2732.

    Article  PubMed  CAS  Google Scholar 

  24. Libby P: Inflammation in atherosclerosis. Nature 2002, 420:868–874.

    Article  PubMed  CAS  Google Scholar 

  25. Hopkins PN: Familial hypercholesterolemia-improving treatment and meeting guidelines. Int J Cardiol 2003, 89:13–23.

    Article  PubMed  Google Scholar 

  26. Lebherz C, Gao G, Louboutin J, et al.: AAV2/7 and AAV2/8 mediated liver directed gene therapy enables long-term expression of the human LDL receptor and substantially diminishes atherosclerosis in LDL receptor deficient mice. Circulation 2003, 108:IV-143.

    Google Scholar 

  27. Chen SJ, Rader DJ, Tazelaar J, et al.: Prolonged correction of hyperlipidemia in mice with familial hypercholesterolemia using an adeno-associated viral vector expressing very-low-density lipoprotein receptor. Mol Ther 2000, 2:256–261.

    Article  PubMed  CAS  Google Scholar 

  28. Oka K, Nomura S, Merched A, et al.: In-vivo LDL receptor gene therapy is highly effective in reversing hypercholesterolemia in a mouse model of familial hypercholesterolemia. Mol Ther 2003, 7:S246.

    Google Scholar 

  29. Liu G, Ashbourne Excoffon KJ, Wilson JE, et al.: Phenotypic correction of feline lipoprotein lipase deficiency by adeno-viral gene transfer. Hum Gene Ther 2000, 11:21–32.

    Article  PubMed  CAS  Google Scholar 

  30. Ross C, Meulenberg J, Twisk J, et al.: Long-term correction of murine lipoprotein lipase deficiency by single intramuscular administration of AAV1-LPLS447X. Mol Ther 2003, 7:S22.

    Google Scholar 

  31. Rip J, Nierman M, Sierts J, et al.: Working towards clinical application of gene therapy for LPL deficiency. Circulation 2003, 108:IV-133.

    Google Scholar 

  32. Zsigmond E, Kobayashi K, Tzung KW, et al.: Adenovirus-mediated gene transfer of human lipoprotein lipase ameliorates the hyperlipidemias associated with apolipoprotein E and LDL receptor deficiencies in mice. Hum Gene Ther 1997, 8:1921–1933.

    PubMed  CAS  Google Scholar 

  33. Heistad DD: Unstable coronary-artery plaques. N Engl J Med 2003, 349:2285–2287.

    Article  PubMed  CAS  Google Scholar 

  34. Naghavi M, Libby P, Falk E, et al.: From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 2003, 108:1664–1672.

    Article  PubMed  Google Scholar 

  35. Rust S, Rosier M, Funke H, et al.: Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 1999, 22:352–355.

    Article  PubMed  CAS  Google Scholar 

  36. Remaley AT, Rust S, Rosier M, et al.: Human ATP-binding cassette transporter 1 (ABC1): genomic organization and identification of the genetic defect in the original Tangier disease kindred. Proc Natl Acad Sci U S A 1999, 96:12685–12690.

    Article  PubMed  CAS  Google Scholar 

  37. Joyce CW, Amar MJ, Lambert G, et al.: The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice. Proc Natl Acad Sci U S A 2002, 99:407–412.

    Article  PubMed  CAS  Google Scholar 

  38. Singaraja RR, Fievet C, Castro G, et al.: Increased ABCA1 activity protects against atherosclerosis. J Clin Invest 2002, 110:35–42.

    Article  PubMed  CAS  Google Scholar 

  39. Su YR, Ishiguro H, Major AS, et al.: Macrophage apolipoprotein A-I expression protects against atherosclerosis in ApoE-deficient mice and up-regulates ABC transporters. Mol Ther 2003, 8:576–583.

    Article  PubMed  CAS  Google Scholar 

  40. Basso F, Freeman L, Knapper CL, et al.: Role of the hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma HDL cholesterol concentrations. J Lipid Res 2003, 44:296–302.

    Article  PubMed  CAS  Google Scholar 

  41. Wellington CL, Brunham LR, Zhou S, et al.: Alterations of plasma lipids in mice via adenoviral-mediated hepatic over-expression of human ABCA1. J Lipid Res 2003, 44:1470–1480.

    Article  PubMed  CAS  Google Scholar 

  42. Mertens A, Verhamme P, Bielicki JK, et al.: Increased low-density lipoprotein oxidation and impaired high-density lipoprotein antioxidant defense are associated with increased macrophage homing and atherosclerosis in dyslipidemic obese mice: LCAT gene transfer decreases atherosclerosis. Circulation 2003, 107:1640–1646.

    Article  PubMed  CAS  Google Scholar 

  43. Jaye M, Lynch KJ, Krawiec J, et al.: A novel endothelial-derived lipase that modulates HDL metabolism. Nat Genet 1999, 21:424–428.

    Article  PubMed  CAS  Google Scholar 

  44. Ma K, Cilingiroglu M, Otvos JD, et al.: Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism. Proc Natl Acad Sci U S A 2003, 100:2748–2753.

    Article  PubMed  CAS  Google Scholar 

  45. Ishida T, Choi S, Kundu RK, et al.: Endothelial lipase is a major determinant of HDL level. J Clin Invest 2003, 111:347–355.

    Article  PubMed  CAS  Google Scholar 

  46. Maugeais C, Tietge UJ, Broedl UC, et al.: Dose-dependent acceleration of high-density lipoprotein catabolism by endothelial lipase. Circulation 2003, 108:2121–2126.

    Article  PubMed  CAS  Google Scholar 

  47. Broedl UC, Maugeais C, Marchadier D, et al.: Effects of non-lipolytic ligand function of endothelial lipase on high density lipoprotein metabolism in vivo. J Biol Chem 2003, 278:40688–40693.

    Article  PubMed  CAS  Google Scholar 

  48. Kawashiri M, Zhang Y, Usher D, et al.: Effects of coexpression of the LDL receptor and apoE on cholesterol metabolism and atherosclerosis in LDL receptor-deficient mice. J Lipid Res 2001, 42:943–950.

    PubMed  CAS  Google Scholar 

  49. Kawashiri MA, Zhang Y, Pure E, Rader DJ: Combined effects of cholesterol reduction and apolipoprotein A-I expression on atherosclerosis in LDL receptor deficient mice. Atherosclerosis 2002, 165:15–22.

    Article  PubMed  CAS  Google Scholar 

  50. Jalkanen J, Leppanen P, Pajusola K, et al.: Adeno-associated virus-mediated gene transfer of a secreted decoy human macrophage scavenger receptor reduces atherosclerotic lesion formation in LDL receptor knockout mice. Mol Ther 2003, 8:903–910.

    Article  PubMed  CAS  Google Scholar 

  51. Ouchi N, Kihara S, Funahashi T, et al.: Obesity, adiponectin and vascular inflammatory disease. Curr Opin Lipidol 2003, 14:561–566.

    Article  PubMed  CAS  Google Scholar 

  52. Okamoto Y, Kihara S, Ouchi N, et al.: Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 2002, 106:2767–2770.

    Article  PubMed  CAS  Google Scholar 

  53. Chan L, Fujimiya M, Kojima H: In vivo gene therapy for diabetes mellitus. Trends Mol Med 2003, 9:430–435.

    Article  PubMed  CAS  Google Scholar 

  54. Kojima H, Fujimiya M, Matsumura K, et al.: NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nat Med 2003, 9:596–603.

    Article  PubMed  CAS  Google Scholar 

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Oka, K., Chan, L. Liver-directed gene therapy for dyslipidemia and diabetes. Curr Atheroscler Rep 6, 203–209 (2004). https://doi.org/10.1007/s11883-004-0033-6

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