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Adeno-associated Virus as a Gene Therapy Vector: Vector Development, Production and Clinical Applications

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Gene Therapy and Gene Delivery Systems

Part of the book series: Advances in Biochemical Engineering/Biotechnology ((ABE,volume 99))

Abstract

Adeno-associated virus (AAV) has emerged as an attractive vector for gene therapy. AAV vectors have successfully been utilized to promote sustained gene expression in a variety of tissues such as muscle, eye, brain, liver, and lung [1, 2, 3, 4, 5, 6, 7]. As the significance of AAV as a gene therapy vector has been realized over the past years, recent developments in recombinant AAV (rAAV) production and purification have revolutionized the AAV field. It is now possible to produce high yields of vector (1012–1013 genome-containing particles per mL) that are free of contaminating cellular and helper virus proteins. Such vectors have been successfully used in preclinical applications in animal models such as those of hemophilia, lysosomal storage diseases and vision deficiency, all of which have shown therapeutic benefits from rAAV treatment. Clinical trials using rAAV2 for the treatment of hemophilia B, cystic fibrosis, alpha-1-antitrypsin deficiency, and Canavan disease have begun, and reports from these phase I trials support the safety seen in preclinical trials. Eventually, tissue-specific vectors that can potentially evade the immune system will be required to optimize success in gene therapy. In recent years, this has led to the development of retargeted rAAV2 vectors and the identification and characterization of new serotypes from human and nonhuman primates that could potentially achieve these goals. AAV virologists and gene therapists alike have just begun to scratch the surface in terms of the utility of this small virus in a clinical setting. In this chapter, we will provide a comprehensive overview of the recent advances in rAAV vector production and purification, vector development, and clinical applications.

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References

  1. Xiao X, Li J, McCown TJ, Samulski RJ (1997) Exp Neurol 144:113

    Article  CAS  Google Scholar 

  2. Snyder RO, Miao CH, Patijn GA, Spratt SK, Danos O, Nagy D, Gown AM, Winther B, Meuse L, Cohen LK, Thompson AR, Kay MA (1997) Nat Genet 16:270

    Article  CAS  Google Scholar 

  3. Flotte TR, Afione SA, Conrad C, McGrath SA, Solow R, Oka H, Zeitlin PL, Guggino WB, Carter BJ (1993) P Natl Acad Sci USA 90:10613

    Article  CAS  Google Scholar 

  4. Fisher KJ, Jooss K, Alston J, Yang Y, Haecker SE, High K, Pathak R, Raper SE, Wilson JM (1997) Nat Med 3:306

    Article  CAS  Google Scholar 

  5. Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, Pearce-Kelling SE, Anand V, Zeng Y, Maguire AM, Jacobson SG, Hauswirth WW, Bennett J (2001) Nat Genet 28:92

    Article  CAS  Google Scholar 

  6. Auricchio A (2003) Vision Res 43:913

    Article  CAS  Google Scholar 

  7. Rabinowitz JE, Rolling F, Li C, Conrath H, Xiao W, Xiao X, Samulski RJ (2002) J Virol 76:791

    Article  CAS  Google Scholar 

  8. Atchison RW, Casto BC, Hammon WM (1965) Science 149:754

    Article  CAS  Google Scholar 

  9. Buller RM, Janik JE, Sebring ED, Rose JA (1981) J Virol 40:241

    CAS  Google Scholar 

  10. Srivastava A, Lusby EW, Berns KI (1983) J Virol 45:555

    CAS  Google Scholar 

  11. Lusby E, Fife KH, Berns KI (1980) J Virol 34:402

    CAS  Google Scholar 

  12. King JA, Dubielzig R, Grimm D, Kleinschmidt JA (2001) Embo J 20:3282

    Article  CAS  Google Scholar 

  13. Chejanovsky N, Carter BJ (1989) Virology 173:120

    Article  CAS  Google Scholar 

  14. Girod A, Wobus CE, Zadori Z, Ried M, Leike K, Tijssen P, Kleinschmidt JA, Hallek M (2002) J Gen Virol 83:973

    CAS  Google Scholar 

  15. Zadori Z, Szelei J, Lacoste MC, Li Y, Gariepy S, Raymond P, Allaire M, Nabi IR, Tijssen P (2001) Dev Cell 1:291

    Article  CAS  Google Scholar 

  16. Warrington KH Jr, Gorbatyuk OS, Harrison JK, Opie SR, Zolotukhin S, Muzyczka N (2004) J Virol 78:6595

    Article  CAS  Google Scholar 

  17. Muzyczka N (1992) Curr Top Microbiol Immunol 158:97

    CAS  Google Scholar 

  18. Berns KI, Linden RM (1995) Bioessays 17:237

    Article  CAS  Google Scholar 

  19. Samulski RJ, Zhu X, Xiao X, Brook JD, Housman DE, Epstein N, Hunter LA (1991) Embo J 10:3941

    CAS  Google Scholar 

  20. Kotin RM, Berns KI (1989) Virology 170:460

    Article  CAS  Google Scholar 

  21. Cheung AK, Hoggan MD, Hauswirth WW, Berns KI (1980) J Virol 33:739

    CAS  Google Scholar 

  22. Laughlin CA, Cardellichio CB, Coon HC (1986) J Virol 60:515

    CAS  Google Scholar 

  23. McLaughlin SK, Collis P, Hermonat PL, Muzyczka N (1988) J Virol 62:1963

    CAS  Google Scholar 

  24. Chang LS, Shi Y, Shenk T (1989) J Virol 63:3479

    CAS  Google Scholar 

  25. Samulski RJ, Shenk T (1988) J Virol 62:206

    CAS  Google Scholar 

  26. Janik JE, Huston MM, Rose JA (1981) P Natl Acad Sci USA 78:1925

    Article  CAS  Google Scholar 

  27. Laughlin CA, Jones N, Carter BJ (1982) J Virol 41:868

    CAS  Google Scholar 

  28. Richardson WD, Westphal H (1984) J Virol 51:404

    CAS  Google Scholar 

  29. Carter BJ, Antoni BA, Klessig DF (1992) Virology 191:473

    Article  CAS  Google Scholar 

  30. Chang LS, Shenk T (1990) J Virol 64:2103

    CAS  Google Scholar 

  31. Weindler FW, Heilbronn R (1991) J Virol 65:2476

    CAS  Google Scholar 

  32. Samulski RJ, Chang LS, Shenk T (1989) J Virol 63:3822

    CAS  Google Scholar 

  33. Vincent KA, Piraino ST, Wadsworth SC (1997) J Virol 71:1897

    CAS  Google Scholar 

  34. Ogasawara Y, Urabe M, Ozawa K (1998) Microbiol Immunol 42:177

    CAS  Google Scholar 

  35. Li J, Samulski RJ, Xiao X (1997) J Virol 71:5236

    CAS  Google Scholar 

  36. Grimm D, Kern A, Rittner K, Kleinschmidt JA (1998) Hum Gene Ther 9:2745

    Article  CAS  Google Scholar 

  37. Collaco RF, Cao X, Trempe JP (1999) Gene 238:397

    Article  CAS  Google Scholar 

  38. Xiao X, Li J, Samulski RJ (1998) J Virol 72:2224

    CAS  Google Scholar 

  39. Clark KR, Voulgaropoulou F, Fraley DM, Johnson PR (1995) Hum Gene Ther 6:1329

    Article  CAS  Google Scholar 

  40. Ruffing M, Zentgraf H, Kleinschmidt JA (1992) J Virol 66:6922

    CAS  Google Scholar 

  41. Chen C, Okayama H (1987) Mol Cell Biol 7:2745

    CAS  Google Scholar 

  42. Ferrari FK, Samulski T, Shenk T, Samulski RJ (1996) J Virol 70:3227

    CAS  Google Scholar 

  43. McCarty DM, Christensen M, Muzyczka N (1991) J Virol 65:2936

    CAS  Google Scholar 

  44. Pereira DJ, McCarty DM, Muzyczka N (1997) J Virol 71:1079

    CAS  Google Scholar 

  45. Pereira DJ, Muzyczka N (1997) J Virol 71:4300

    CAS  Google Scholar 

  46. Pereira DJ, Muzyczka N (1997) J Virol 71:1747

    CAS  Google Scholar 

  47. Matsushita T, Elliger S, Elliger C, Podsakoff G, Villarreal L, Kurtzman GJ, Iwaki Y, Colosi P (1998) Gene Ther 5:938

    CAS  Google Scholar 

  48. Salvetti A, Oreve S, Chadeuf G, Favre D, Cherel Y, Champion-Arnaud P, David-Ameline J, Moullier P (1998) Hum Gene Ther 9:695

    Article  CAS  Google Scholar 

  49. Zhang X, De Alwis M, Hart SL, Fitzke FW, Inglis SC, Boursnell ME, Levinsky RJ, Kinnon C, Ali RR, Thrasher AJ (1999) Hum Gene Ther 10:2527

    Article  CAS  Google Scholar 

  50. Clark KR (2002) Kidney Int 61 Suppl 1:9

    Article  Google Scholar 

  51. Clark KR, Liu X, McGrath JP, Johnson PR (1999) Hum Gene Ther 10:1031

    Article  CAS  Google Scholar 

  52. Gao GP, Qu G, Faust LZ, Engdahl RK, Xiao W, Hughes JV, Zoltick PW, Wilson JM (1998) Hum Gene Ther 9:2353

    Article  CAS  Google Scholar 

  53. Zhang X, Li CY (2001) Mol Ther 3:787

    Article  CAS  Google Scholar 

  54. Conway JE, Rhys CM, Zolotukhin I, Zolotukhin S, Muzyczka N, Hayward GS, Byrne BJ (1999) Gene Ther 6:986

    CAS  Google Scholar 

  55. Qiao C, Wang B, Zhu X, Li J, Xiao X (2002) J Virol 76:13015

    Article  CAS  Google Scholar 

  56. Inoue N, Russell DW (1998) J Virol 72:7024

    CAS  Google Scholar 

  57. Urabe M, Ding C, Kotin RM (2002) Hum Gene Ther 13:1935

    Article  CAS  Google Scholar 

  58. Sambrook J, Russell DW (eds)(2001) Cesium chloride and cesium chloride equilibrium density gradients. In: Molecular cloning: A laboratory manual, 3rd edn. Cold Spring Harbor Laboratory Press, New York, pp 1.154–155

    Google Scholar 

  59. Wistuba A, Kern A, Weger S, Grimm D, Kleinschmidt JA (1997) J Virol 71:1341

    CAS  Google Scholar 

  60. Zolotukhin S, Byrne BJ, Mason E, Zolotukhin I, Potter M, Chesnut K, Summerford C, Samulski RJ, Muzyczka N (1999) Gene Ther 6:973

    CAS  Google Scholar 

  61. Summerford C, Samulski RJ (1998) J Virol 72:1438

    CAS  Google Scholar 

  62. Gao G, Qu G, Burnham MS, Huang J, Chirmule N, Joshi B, Yu QC, Marsh JA, Conceicao CM, Wilson JM (2000) Hum Gene Ther 11:2079

    Article  CAS  Google Scholar 

  63. Kaludov N, Handelman B, Chiorini JA (2002) Hum Gene Ther 13:1235

    Article  CAS  Google Scholar 

  64. Xie Q, Bu W, Bhatia S, Hare J, Somasundaram T, Azzi A, Chapman MS (2002) P Natl Acad Sci USA 99:10405

    Article  CAS  Google Scholar 

  65. Rabinowitz JE, Xiao W, Samulski RJ (1999) Virology 265:274

    Article  CAS  Google Scholar 

  66. Wu P, Xiao W, Conlon T, Hughes J, Agbandje-McKenna M, Ferkol T, Flotte T, Muzyczka N (2000) J Virol 74:8635

    Article  CAS  Google Scholar 

  67. Girod A, Ried M, Wobus C, Lahm H, Leike K, Kleinschmidt J, Deleage G, Hallek M (1999) Nat Med 5:1052

    Article  CAS  Google Scholar 

  68. Grifman M, Trepel M, Speece P, Gilbert LB, Arap W, Pasqualini R, Weitzman MD (2001) Mol Ther 3:964

    Article  CAS  Google Scholar 

  69. Tsao J, Chapman MS, Agbandje M, Keller W, Smith K, Wu H, Luo M, Smith TJ, Rossmann MG, Compans RW et al. (1991) Science 251:1456

    Article  CAS  Google Scholar 

  70. Hileman RE, Fromm JR, Weiler JM, Linhardt RJ (1998) Bioessays 20:156

    Article  CAS  Google Scholar 

  71. Mulloy B, Linhardt RJ (2001) Curr Opin Struct Biol 11:623

    Article  CAS  Google Scholar 

  72. Opie SR, Warrington KH Jr, Agbandje-McKenna M, Zolotukhin S, Muzyczka N (2003) J Virol 77:6995

    Article  CAS  Google Scholar 

  73. Kern A, Schmidt K, Leder C, Muller OJ, Wobus CE, Bettinger K, Von der Lieth CW, King JA, Kleinschmidt JA (2003) J Virol 77:11072

    Article  CAS  Google Scholar 

  74. Buning H, Ried MU, Perabo L, Gerner FM, Huttner NA, Enssle J, Hallek M (2003) Gene Ther 10:1142

    CAS  Google Scholar 

  75. Bartlett JS, Kleinschmidt J, Boucher RC, Samulski RJ (1999) Nat Biotechnol 17:181

    Article  CAS  Google Scholar 

  76. Ponnazhagan S, Mahendra G, Kumar S, Thompson JA, Castillas M Jr (2002) J Virol 76:12900

    Article  CAS  Google Scholar 

  77. Girod A, Ried M, Wobus C, Lahm H, Leike K, Kleinschmidt J, Deleage G, Hallek M (1999) Nat Med 5:1438

    Article  CAS  Google Scholar 

  78. Nicklin SA, Buening H, Dishart KL, de Alwis M, Girod A, Hacker U, Thrasher AJ, Ali RR, Hallek M, Baker AH (2001) Mol Ther 4:174

    Article  CAS  Google Scholar 

  79. Shi W, Bartlett JS (2003) Mol Ther 7:515

    Article  CAS  Google Scholar 

  80. Work LM, Nicklin SA, Brain NJ, Dishart KL, Von Seggern DJ, Hallek M, Buning H, Baker AH (2004) Mol Ther 9:198

    Article  CAS  Google Scholar 

  81. White SJ, Nicklin SA, Buning H, Brosnan MJ, Leike K, Papadakis ED, Hallek M, Baker AH (2004) Circulation 109:513

    Article  CAS  Google Scholar 

  82. Shi W, Arnold GS, Bartlett JS (2001) Hum Gene Ther 12:1697

    Article  CAS  Google Scholar 

  83. Loiler SA, Conlon TJ, Song S, Tang Q, Warrington KH, Agarwal A, Kapturczak M, Li C, Ricordi C, Atkinson MA, Muzyczka N, Flotte TR (2003) Gene Ther 10:1551

    CAS  Google Scholar 

  84. Nicklin SA, Dishart KL, Buening H, Reynolds PN, Hallek M, Nemerow GR, von Seggern DJ, Baker AH (2003) Cancer Lett 201:165

    CAS  Google Scholar 

  85. Muller OJ, Kaul F, Weitzman MD, Pasqualini R, Arap W, Kleinschmidt JA, Trepel M (2003) Nat Biotechnol 21:1040

    Article  CAS  Google Scholar 

  86. Perabo L, Buning H, Kofler DM, Ried MU, Girod A, Wendtner CM, Enssle J, Hallek M (2003) Mol Ther 8:151

    Article  CAS  Google Scholar 

  87. Duan D, Yue Y, Yan Z, Yang J, Engelhardt JF (2000) J Clin Invest 105:1573

    Article  CAS  Google Scholar 

  88. Qing K, Hansen J, Weigel-Kelley KA, Tan M, Zhou S, Srivastava A (2001) J Virol 75:8968

    Article  CAS  Google Scholar 

  89. Thomas CE, Storm TA, Huang Z, Kay MA (2004) J Virol 78:3110

    Article  CAS  Google Scholar 

  90. Bantel-Schaal U, Hub B, Kartenbeck J (2002) J Virol 76:2340

    Article  CAS  Google Scholar 

  91. Gao G, Alvira MR, Somanathan S, Lu Y, Vandenberghe LH, Rux JJ, Calcedo R, Sanmiguel J, Abbas Z, Wilson JM (2003) P Natl Acad Sci USA 100:6081

    Article  CAS  Google Scholar 

  92. Gao G, Vandenberghe LH, Alvira MR, Lu Y, Calcedo R, Zhou X, Wilson JM (2004) J Virol 78:6381

    Article  CAS  Google Scholar 

  93. Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM (2002) P Natl Acad Sci USA 99:11854

    Article  CAS  Google Scholar 

  94. Hildinger M, Auricchio A, Gao G, Wang L, Chirmule N, Wilson JM (2001) J Virol 75:6199

    Article  CAS  Google Scholar 

  95. Xiao W, Chirmule N, Berta SC, McCullough B, Gao G, Wilson JM (1999) J Virol 73:3994

    CAS  Google Scholar 

  96. Erles K, Sebokova P, Schlehofer JR (1999) J Med Virol 59:406

    Article  CAS  Google Scholar 

  97. Georg-Fries B, Biederlack S, Wolf J, zur Hausen H (1984) Virology 134:64

    Article  CAS  Google Scholar 

  98. Xiao X, Li J, Samulski RJ (1996) J Virol 70:8098

    CAS  Google Scholar 

  99. Hernandez YJ, Wang J, Kearns WG, Loiler S, Poirier A, Flotte TR (1999) J Virol 73:8549

    CAS  Google Scholar 

  100. Brockstedt DG, Podsakoff GM, Fong L, Kurtzman G, Mueller-Ruchholtz W, Engleman EG (1999) Clin Immunol 92:67

    Article  CAS  Google Scholar 

  101. Kaspar BK, Vissel B, Bengoechea T, Crone S, Randolph-Moore L, Muller R, Brandon EP, Schaffer D, Verma IM, Lee KF, Heinemann SF, Gage FH (2002) P Natl Acad Sci USA 99:2320

    Article  CAS  Google Scholar 

  102. Chao H, Monahan PE, Liu Y, Samulski RJ, Walsh CE (2001) Mol Ther 4:217

    Article  CAS  Google Scholar 

  103. Chao H, Liu Y, Rabinowitz J, Li C, Samulski RJ, Walsh CE (2000) Mol Ther 2:619

    Article  CAS  Google Scholar 

  104. Grimm D, Zhou S, Nakai H, Thomas CE, Storm TA, Fuess S, Matsushita T, Allen J, Surosky R, Lochrie M, Meuse L, McClelland A, Colosi P, Kay MA (2003) Blood 102:2412

    Article  CAS  Google Scholar 

  105. Mingozzi F, Schuttrumpf J, Arruda VR, Liu Y, Liu YL, High KA, Xiao W, Herzog RW (2002) J Virol 76:10497

    Article  CAS  Google Scholar 

  106. Flotte T, Agarwal A, Wang J, Song S, Fenjves ES, Inverardi L, Chesnut K, Afione S, Loiler S, Wasserfall C, Kapturczak M, Ellis T, Nick H, Atkinson M (2001) Diabetes 50:515

    Article  CAS  Google Scholar 

  107. Prasad KM, Yang Z, Bleich D, Nadler JL (2000) Gene Ther 7:1553

    CAS  Google Scholar 

  108. Wang AY, Peng PD, Ehrhardt A, Storm TA, Kay MA (2004) Hum Gene Ther 15:405

    Article  CAS  Google Scholar 

  109. Du L, Kido M, Lee DV, Rabinowitz JE, Samulski RJ, Jamieson SW, Weitzman MD, Thistlethwaite PA (2004) Mol Ther 10:604

    Article  CAS  Google Scholar 

  110. Beck SE, Jones LA, Chesnut K, Walsh SM, Reynolds TC, Carter BJ, Askin FB, Flotte TR, Guggino WB (1999) J Virol 73:9446

    CAS  Google Scholar 

  111. Halbert CL, Rutledge EA, Allen JM, Russell DW, Miller AD (2000) J Virol 74:1524

    Article  CAS  Google Scholar 

  112. Halbert CL, Allen JM, Miller AD (2001) J Virol 75:6615

    Article  CAS  Google Scholar 

  113. Zabner J, Seiler M, Walters R, Kotin RM, Fulgeras W, Davidson BL, Chiorini JA (2000) J Virol 74:3852

    Article  CAS  Google Scholar 

  114. Flotte T, Carter B, Conrad C, Guggino W, Reynolds T, Rosenstein B, Taylor G, Walden S, Wetzel R (1996) Hum Gene Ther 7:1145

    Article  CAS  Google Scholar 

  115. Wagner JA, Reynolds T, Moran ML, Moss RB, Wine JJ, Flotte TR, Gardner P (1998) Lancet 351:1702

    Article  CAS  Google Scholar 

  116. Wagner JA, Messner AH, Moran ML, Daifuku R, Kouyama K, Desch JK, Manley S, Norbash AM, Conrad CK, Friborg S, Reynolds T, Guggino WB, Moss RB, Carter BJ, Wine JJ, Flotte TR, Gardner P (1999) Laryngoscope 109:266

    Article  CAS  Google Scholar 

  117. Wagner JA, Nepomuceno IB, Messner AH, Moran ML, Batson EP, Dimiceli S, Brown BW, Desch JK, Norbash AM, Conrad CK, Guggino WB, Flotte TR, Wine JJ, Carter BJ, Reynolds TC, Moss RB, Gardner P (2002) Hum Gene Ther 13:1349

    Article  CAS  Google Scholar 

  118. Flotte TR, Brantly ML, Spencer LT, Byrne BJ, Spencer CT, Baker DJ, Humphries M (2004) Hum Gene Ther 15:93

    Article  CAS  Google Scholar 

  119. Manno CS, Chew AJ, Hutchison S, Larson PJ, Herzog RW, Arruda VR, Tai SJ, Ragni MV, Thompson A, Ozelo M, Couto LB, Leonard DG, Johnson FA, McClelland A, Scallan C, Skarsgard E, Flake AW, Kay MA, High KA, Glader B (2003) Blood 101:2963

    Article  CAS  Google Scholar 

  120. Vincent KA, Moore GK, Haigwood NL (1990) Vaccine 90:353

    Google Scholar 

  121. Edelstein M (2005) The Journal of Gene Medicine clinical trial website. Wiley, New York (see http://www.wiley.co.uk/wileychi/genmed/clinical , last accessed 19th September 2005)

  122. Avigen, Inc. (2005) Website. Avigen Inc., Alameda, CA (see http://www.avigen.com , last accessed 19th September 2005)

  123. Neurologix, Inc. (2005) Website. Neurologix, Inc., Fort Lee, NJ (see http://www.neurologix.net , last accessed 19th September 2005)

  124. Flotte TR (2004) Preclinical and phase I/II clinical trials of recombinant adeno-associated virus (rAAV)-alpha-1 antitrypsin vectors. In: Xth Parvovirus Workshop, 8–12 September 2004, St. Petersburg, FL

    Google Scholar 

  125. Ceregene, Inc. (2005) Website. Ceregene, Inc., San Diego, CA (see http://www.ceregene.com , last accessed 19th September 2005)

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  1. University of North Carolina Gene Therapy Center, Thurston Bowles Bldg. Rm. 7119 CB 7352, NC 27599, Chapel Hill, USA

    Joshua C. Grieger & Richard J. Samulski

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  1. Joshua C. Grieger
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  2. Richard J. Samulski
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Correspondence to Richard J. Samulski .

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David V. Schaffer Weichang Zhou

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Grieger, J.C., Samulski, R.J. Adeno-associated Virus as a Gene Therapy Vector: Vector Development, Production and Clinical Applications. In: Schaffer, D.V., Zhou, W. (eds) Gene Therapy and Gene Delivery Systems. Advances in Biochemical Engineering/Biotechnology, vol 99. Springer, Berlin, Heidelberg. https://doi.org/10.1007/10_005

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