rAAV Human Trial Experience

  • Katherine A. HighEmail author
  • Patrick Aubourg
Part of the Methods in Molecular Biology book series (MIMB, volume 807)


Recombinant AAV vectors have been used in clinical trials since the mid-1990s, with over 300 subjects enrolled in studies. Although there are not yet licensed AAV products, there are several clear examples of clinical efficacy, and recombinant AAV vectors have a strong safety record after administration both locally and systemically. This chapter provides a review of two types of studies that have shown efficacy, including studies for Leber’s congenital amaurosis, a hereditary retinal degenerative disorder in which subretinal administration of AAV has shown efficacy in terms of improvement in multiple measures of visual/retinal function; and of Parkinson’s disease which has also shown improvement in clinical and imaging studies after gene transfer to the CNS. The chapter also provides a detailed review of the results of studies of gene therapy for hemophilia, in which short-term efficacy was achieved, but expression of the donated gene failed to persist, likely due to an immune response to the vector. Safety issues relating to AAV-mediated gene transfer are discussed, including a detailed review of the single death to have occurred in an AAV gene therapy trial (likely unrelated to the AAV vector), and of issues related to integration and insertional mutagenesis, risk of germline transmission, and risks related to immune responses to either vector or transgene product. Finally, protocols for determining the presence of vector DNA in body fluids using real-time quantitative PCR, and for isolating, cryopreserving, and testing peripheral blood mononuclear cells for interferon-γ (IFN-γ) responses to capsid are described in detail.

Key words

AAV Hemophilia B Leber’s congenital amaurosis Parkinson’s disease Rheumatoid arthritis Disseminated histoplasmosis Hepatocellular carcinoma IFN-γ ELISpot PBMCs 


  1. 1.
    Bainbridge, J. W., Smith, A. J., Barker, S. S., Robbie, S., Henderson, R., Balaggan, K., Viswanathan, A., Holder, G. E., Stockman, A., Tyler, N., Petersen-Jones, S., Bhattacharya, S. S., Thrasher, A. J., Fitzke, F. W., Carter, B. J., Rubin, G. S., Moore, A. T., and Ali, R. R. (2008) Effect of gene therapy on visual function in Leber’s congenital amaurosis, N Engl J Med 358, 2231–2239.PubMedCrossRefGoogle Scholar
  2. 2.
    Maguire, A. M., High, K. A., Auricchio, A., Wright, J. F., Pierce, E. A., Testa, F., Mingozzi, F., Bennicelli, J. L., Ying, G. S., Rossi, S., Fulton, A., Marshall, K. A., Banfi, S., Chung, D. C., Morgan, J. I., Hauck, B., Zelenaia, O., Zhu, X., Raffini, L., Coppieters, F., De Baere, E., Shindler, K. S., Volpe, N. J., Surace, E. M., Acerra, C., Lyubarsky, A., Redmond, T. M., Stone, E., Sun, J., McDonnell, J. W., Leroy, B. P., Simonelli, F., and Bennett, J. (2009) Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial, Lancet 374, 1597–1605.PubMedCrossRefGoogle Scholar
  3. 3.
    Maguire, A. M., Simonelli, F., Pierce, E. A., Pugh, E. N., Jr., Mingozzi, F., Bennicelli, J., Banfi, S., Marshall, K. A., Testa, F., Surace, E. M., Rossi, S., Lyubarsky, A., Arruda, V. R., Konkle, B., Stone, E., Sun, J., Jacobs, J., Dell’Osso, L., Hertle, R., Ma, J. X., Redmond, T. M., Zhu, X., Hauck, B., Zelenaia, O., Shindler, K. S., Maguire, M. G., Wright, J. F., Volpe, N. J., McDonnell, J. W., Auricchio, A., High, K. A., and Bennett, J. (2008) Safety and efficacy of gene transfer for Leber’s congenital amaurosis, N Engl J Med 358, 2240–2248.PubMedCrossRefGoogle Scholar
  4. 4.
    Hauswirth, W. W., Aleman, T. S., Kaushal, S., Cideciyan, A. V., Schwartz, S. B., Wang, L., Conlon, T. J., Boye, S. L., Flotte, T. R., Byrne, B. J., and Jacobson, S. G. (2008) Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial, Hum Gene Ther 19, 979–990.PubMedCrossRefGoogle Scholar
  5. 5.
    Christine, C. W., Starr, P. A., Larson, P. S., Eberling, J. L., Jagust, W. J., Hawkins, R. A., VanBrocklin, H. F., Wright, J. F., Bankiewicz, K. S., and Aminoff, M. J. (2009) Safety and tolerability of putaminal AADC gene therapy for Parkinson disease, Neurology 73, 1662–1669.PubMedCrossRefGoogle Scholar
  6. 6.
    Eberling, J. L., Jagust, W. J., Christine, C. W., Starr, P., Larson, P., Bankiewicz, K. S., and Aminoff, M. J. (2008) Results from a phase I safety trial of hAADC gene therapy for Parkinson disease, Neurology 70, 1980–1983.PubMedCrossRefGoogle Scholar
  7. 7.
    Kaplitt, M. G., Feigin, A., Tang, C., Fitzsimons, H. L., Mattis, P., Lawlor, P. A., Bland, R. J., Young, D., Strybing, K., Eidelberg, D., and During, M. J. (2007) Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: an open label, phase I trial, Lancet 369, 2097–2105.PubMedCrossRefGoogle Scholar
  8. 8.
    (2010) AMT submits its lead product Glybera® application for marketing authorisation to EMA. Available at: Accessed on: 1/23/2011.
  9. 9.
    Manno, C. S., Pierce, G. F., Arruda, V. R., Glader, B., Ragni, M., Rasko, J. J., Ozelo, M. C., Hoots, K., Blatt, P., Konkle, B., Dake, M., Kaye, R., Razavi, M., Zajko, A., Zehnder, J., Rustagi, P. K., Nakai, H., Chew, A., Leonard, D., Wright, J. F., Lessard, R. R., Sommer, J. M., Tigges, M., Sabatino, D., Luk, A., Jiang, H., Mingozzi, F., Couto, L., Ertl, H. C., High, K. A., and Kay, M. A. (2006) Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response, Nat Med 12, 342–347.PubMedCrossRefGoogle Scholar
  10. 10.
    Mount, J. D., Herzog, R. W., Tillson, D. M., Goodman, S. A., Robinson, N., McCleland, M. L., Bellinger, D., Nichols, T. C., Arruda, V. R., Lothrop, C. D., Jr., and High, K. A. (2002) Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy, Blood 99, 2670–2676.PubMedCrossRefGoogle Scholar
  11. 11.
    Niemeyer, G. P., Herzog, R. W., Mount, J., Arruda, V. R., Tillson, D. M., Hathcock, J., van Ginkel, F. W., High, K. A., and Lothrop, C. D., Jr. (2009) Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy, Blood 113, 797–806.PubMedCrossRefGoogle Scholar
  12. 12.
    Nathwani, A. C., Gray, J. T., McIntosh, J., Ng, C. Y., Zhou, J., Spence, Y., Cochrane, M., Gray, E., Tuddenham, E. G., and Davidoff, A. M. (2007) Safe and efficient transduction of the liver after peripheral vein infusion of self-complementary AAV vector results in stable therapeutic expression of human FIX in nonhuman primates, Blood 109, 1414–1421.PubMedCrossRefGoogle Scholar
  13. 13.
    Nathwani, A. C., Gray, J. T., Ng, C. Y., Zhou, J., Spence, Y., Waddington, S. N., Tuddenham, E. G., Kemball-Cook, G., McIntosh, J., Boon-Spijker, M., Mertens, K., and Davidoff, A. M. (2006) Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver, Blood 107, 2653–2661.PubMedCrossRefGoogle Scholar
  14. 14.
    Pien, G. C., Basner-Tschakarjan, E., Hui, D. J., Mentlik, A. N., Finn, J. D., Hasbrouck, N. C., Zhou, S., Murphy, S. L., Maus, M. V., Mingozzi, F., Orange, J. S., and High, K. A. (2009) Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors, J Clin Invest 119, 1688–1695.PubMedCrossRefGoogle Scholar
  15. 15.
    Finn, J. D., Hui, D., Downey, H. D., Dunn, D., Pien, G. C., Mingozzi, F., Zhou, S., and High, K. A. Proteasome inhibitors decrease AAV2 capsid derived peptide epitope presentation on MHC class I following transduction, Mol Ther 18, 135–142.Google Scholar
  16. 16.
    Nony, P., Chadeuf, G., Tessier, J., Moullier, P., and Salvetti, A. (2003) Evidence for packaging of rep-cap sequences into adeno-associated virus (AAV) type 2 capsids in the absence of inverted terminal repeats: a model for generation of rep-positive AAV particles, J Virol 77, 776–781.PubMedCrossRefGoogle Scholar
  17. 17.
    Hauck, B., Murphy, S. L., Smith, P. H., Qu, G., Liu, X., Zelenaia, O., Mingozzi, F., Sommer, J. M., High, K. A., and Wright, J. F. (2009) Undetectable transcription of cap in a clinical AAV vector: implications for preformed capsid in immune responses, Mol Ther 17, 144–152.PubMedCrossRefGoogle Scholar
  18. 18.
    Li, C., Goudy, K., Hirsch, M., Asokan, A., Fan, Y., Alexander, J., Sun, J., Monahan, P., Seiber, D., Sidney, J., Sette, A., Tisch, R., Frelinger, J., and Samulski, R. J. (2009) Cellular immune response to cryptic epitopes during therapeutic gene transfer, Proc Natl Acad Sci U S A 106, 10770–10774.PubMedCrossRefGoogle Scholar
  19. 19.
    Nathwani, A. C., Tuddenham, E., Rosales, C., McIntosh, J., Riddell, A., Rustagi, P., Glader, B., Kay, M., Allay, J., Coleman, J., Sleep, S., High, K. A., Mingozzi, F., Gray, J. T., Reiss, U. M., Nienhuis, A. W., and Davidoff, A. (2010) Early clinical trial results following administration of a low dose of a novel self complementary adeno-associated viral vector encoding human Factor IX in two subjects with severe hemophilia B., in 52nd ASH Annual Meeting, Orlando, FL.Google Scholar
  20. 20.
    Frank, K. M., Hogarth, D. K., Miller, J. L., Mandal, S., Mease, P. J., Samulski, R. J., Weisgerber, G. A., and Hart, J. (2009) Investigation of the cause of death in a gene-therapy trial, N Engl J Med 361, 161–169.PubMedCrossRefGoogle Scholar
  21. 21.
    Meetings of the NIH Recombinant DNA Advisory Committee, September 2007 and January 2008. Available at: Accessed on: 1/23/2011.
  22. 22.
    (2006) Guidance for Industry: Gene Therapy Clinical Trials--Observing Subjects for Delayed Adverse Events. Available at: Accessed on: 1/23/2011.
  23. 23.
    Miller, D. G., Petek, L. M., and Russell, D. W. (2004) Adeno-associated virus vectors integrate at chromosome breakage sites, Nat Genet 36, 767–773.PubMedCrossRefGoogle Scholar
  24. 24.
    Lin, Y., and Waldman, A. S. (2001) Capture of DNA sequences at double-strand breaks in mammalian chromosomes, Genetics 158, 1665–1674.PubMedGoogle Scholar
  25. 25.
    Donsante, A., Vogler, C., Muzyczka, N., Crawford, J. M., Barker, J., Flotte, T., Campbell-Thompson, M., Daly, T., and Sands, M. S. (2001) Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors, Gene Ther 8, 1343–1346.PubMedCrossRefGoogle Scholar
  26. 26.
    Donsante, A., Miller, D. G., Li, Y., Vogler, C., Brunt, E. M., Russell, D. W., and Sands, M. S. (2007) AAV vector integration sites in mouse hepatocellular carcinoma, Science 317, 477.PubMedCrossRefGoogle Scholar
  27. 27.
    Li, H., Malani, N., Hamilton, S. R., Schlachterman, A., Bussadori, G., Edmonson, S. E., Shah, R., Arruda, V. R., Mingozzi, F., Wright, J. F., Bushman, F. D., and High, K. A. (2011) Assessing the potential for AAV vector genotoxicity in a murine model, Blood 117, 3311–3319.Google Scholar
  28. 28.
    Nichols, T. C., Dillow, A. M., Franck, H. W., Merricks, E. P., Raymer, R. A., Bellinger, D. A., Arruda, V. R., and High, K. A. (2009) Protein replacement therapy and gene transfer in canine models of hemophilia A, hemophilia B, von willebrand disease, and factor VII deficiency, ILAR J 50, 144–167.PubMedGoogle Scholar
  29. 29.
    Arruda, V. R., Fields, P. A., Milner, R., Wainwright, L., De Miguel, M. P., Donovan, P. J., Herzog, R. W., Nichols, T. C., Biegel, J. A., Razavi, M., Dake, M., Huff, D., Flake, A. W., Couto, L., Kay, M. A., and High, K. A. (2001) Lack of germline transmission of vector sequences following systemic administration of recombinant AAV-2 vector in males, Mol Ther 4, 586–592.PubMedCrossRefGoogle Scholar
  30. 30.
    Schuettrumpf, J., Liu, J. H., Couto, L. B., Addya, K., Leonard, D. G., Zhen, Z., Sommer, J., and Arruda, V. R. (2006) Inadvertent germline transmission of AAV2 vector: findings in a rabbit model correlate with those in a human clinical trial, Mol Ther 13, 1064–1073.PubMedCrossRefGoogle Scholar
  31. 31.
    Favaro, P., Downey, H. D., Zhou, J. S., Wright, J. F., Hauck, B., Mingozzi, F., High, K. A., and Arruda, V. R. (2009) Host and vector-dependent effects on the risk of germline transmission of AAV vectors, Mol Ther 17, 1022–1030.PubMedCrossRefGoogle Scholar
  32. 32.
    Herzog, R. W., Mount, J. D., Arruda, V. R., High, K. A., and Lothrop, C. D., Jr. (2001) Muscle-directed gene transfer and transient immune suppression result in sustained partial correction of canine hemophilia B caused by a null mutation, Mol Ther 4, 192–200.PubMedCrossRefGoogle Scholar
  33. 33.
    Wang, Z., Kuhr, C. S., Allen, J. M., Blankinship, M., Gregorevic, P., Chamberlain, J. S., Tapscott, S. J., and Storb, R. (2007) Sustained AAV-mediated dystrophin expression in a canine model of Duchenne muscular dystrophy with a brief course of immunosuppression, Mol Ther 15, 1160–1166.PubMedGoogle Scholar
  34. 34.
    Mingozzi, F., Hasbrouck, N. C., Basner-Tschakarjan, E., Edmonson, S. A., Hui, D. J., Sabatino, D. E., Zhou, S., Wright, J. F., Jiang, H., Pierce, G. F., Arruda, V. R., and High, K. A. (2007) Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver, Blood 110, 2334–2341.PubMedCrossRefGoogle Scholar
  35. 35.
    Mavilio, F., Pellegrini, G., Ferrari, S., Di Nunzio, F., Di Iorio, E., Recchia, A., Maruggi, G., Ferrari, G., Provasi, E., Bonini, C., Capurro, S., Conti, A., Magnoni, C., Giannetti, A., and De Luca, M. (2006) Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells, Nat Med 12, 1397–1402.PubMedCrossRefGoogle Scholar
  36. 36.
    Mingozzi, F., Liu, Y. L., Dobrzynski, E., Kaufhold, A., Liu, J. H., Wang, Y., Arruda, V. R., High, K. A., and Herzog, R. W. (2003) Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer, J Clin Invest 111, 1347–1356.PubMedGoogle Scholar
  37. 37.
    Ziegler, R. J., Lonning, S. M., Armentano, D., Li, C., Souza, D. W., Cherry, M., Ford, C., Barbon, C. M., Desnick, R. J., Gao, G., Wilson, J. M., Peluso, R., Godwin, S., Carter, B. J., Gregory, R. J., Wadsworth, S. C., and Cheng, S. H. (2004) AAV2 vector harboring a liver-restricted promoter facilitates sustained expression of therapeutic levels of alpha-galactosidase A and the induction of immune tolerance in Fabry mice, Mol Ther 9, 231–240.PubMedCrossRefGoogle Scholar
  38. 38.
    Hudig, D., Greee, N. J., C-M., K., and Powers, J. C. (1987) Lymphocyte granule-mediated cytolysis requires serine protease activity., Biochem Biophys Res Commun 149, 882–888.Google Scholar
  39. 39.
    Chang, T. W., and Eisen, H. N. (1980) Effects of N alpha-tosyl-L-lysyl-chloromethylketone on the activity of cytotoxic T lymphocytes, J Immunol 124, 1028–1033.PubMedGoogle Scholar
  40. 40.
    Stroes, E. S., Nierman, M. C., Meulenberg, J. J., Franssen, R., Twisk, J., Henny, C. P., Maas, M. M., Zwinderman, A. H., Ross, C., Aronica, E., High, K. A., Levi, M. M., Hayden, M. R., Kastelein, J. J., and Kuivenhoven, J. A. (2008) Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients, Arterioscler Thromb Vasc Biol 28, 2303–2304.PubMedCrossRefGoogle Scholar
  41. 41.
    Mingozzi, F., Meulenberg, J. J., Hui, D. J., Basner-Tschakarjan, E., Hasbrouck, N. C., Edmonson, S. A., Hutnick, N. A., Betts, M. R., Kastelein, J. J., Stroes, E. S., and High, K. A. (2009) AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells, Blood 114, 2077–2086.PubMedCrossRefGoogle Scholar
  42. 42.
    Velazquez, V. M., Bowen, D. G., and Walker, C. M. (2009) Silencing of T lymphocytes by antigen-driven programmed death in recombinant adeno-associated virus vector-mediated gene therapy, Blood 113, 538–545.PubMedCrossRefGoogle Scholar
  43. 43.
    Lin, S. W., Hensley, S. E., Tatsis, N., Lasaro, M. O., and Ertl, H. C. (2007) Recombinant adeno-associated virus vectors induce functionally impaired transgene product-specific CD8+ T cells in mice, J Clin Invest 117, 3958–3970.PubMedGoogle Scholar
  44. 44.
    Mendell, J. R., Rodino-Klapac, L. R., Rosales-Quintero, X., Kota, J., Coley, B. D., Galloway, G., Craenen, J. M., Lewis, S., Malik, V., Shilling, C., Byrne, B. J., Conlon, T., Campbell, K. J., Bremer, W. G., Viollet, L., Walker, C. M., Sahenk, Z., and Clark, K. R. (2009) Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins, Ann Neurol 66, 290–297.PubMedCrossRefGoogle Scholar
  45. 45.
    Brantly, M. L., Chulay, J. D., Wang, L., Mueller, C., Humphries, M., Spencer, L. T., Rouhani, F., Conlon, T. J., Calcedo, R., Betts, M. R., Spencer, C., Byrne, B. J., Wilson, J. M., and Flotte, T. R. (2009) Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy, Proc Natl Acad Sci U S A 106, 16363–16368.PubMedCrossRefGoogle Scholar
  46. 46.
    Hudig, D., Haverty, T., Fulcher, C., Redelman, D., and Mendelsohn, J. (1981) Inhibition of human natural cytotoxicity by macromolecular antiproteases, J Immunol 126, 1569–1574.PubMedGoogle Scholar
  47. 47.
    Gene Transfer for Subjects with Hemophilia B Factor IX Deficiency. In: Available at: Accessed on: 1/23/2011.
  48. 48.
    Janetzki, S., Panageas, K. S., Ben-Porat, L., Boyer, J., Britten, C. M., Clay, T. M., Kalos, M., Maecker, H. T., Romero, P., Yuan, J., Kast, W. M., and Hoos, A. (2008) Results and harmonization guidelines from two large-scale international Elispot proficiency panels conducted by the Cancer Vaccine Consortium (CVC/SVI), Cancer Immunol Immunother 57, 303–315.PubMedCrossRefGoogle Scholar
  49. 49.
    Brantly, M. L., Spencer, L. T., Humphries, M., Conlon, T. J., Spencer, C. T., Poirier, A., Garlington, W., Baker, D., Song, S., Berns, K. I., Muzyczka, N., Snyder, R. O., Byrne, B. J., and Flotte, T. R. (2006) Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 alphal-antitrypsin (AAT) vector in AAT-deficient adults, Hum Gene Ther 17, 1177–1186.PubMedCrossRefGoogle Scholar
  50. 50.
    Tuszynski, M. H., Thal, L., Pay, M., Salmon, D. P., U, H. S., Bakay, R., Patel, P., Blesch, A., Vahlsing, H. L., Ho, G., Tong, G., Potkin, S. G., Fallon, J., Hansen, L., Mufson, E. J., Kordower, J. H., Gall, C., and Conner, J. (2005) A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease, Nat Med 11, 551–555.Google Scholar
  51. 51.
    Mease, P. J., Wei, N., Fudman, E. J., Kivitz, A. J., Schechtman, J., Trapp, R. G., Hobbs, K. F., Greenwald, M., Hou, A., Bookbinder, S. A., Graham, G. E., Wiesenhutter, C. W., Willis, L., Ruderman, E. M., Forstot, J. Z., Maricic, M. J., Dao, K. H., Pritchard, C. H., Fiske, D. N., Burch, F. X., Prupas, H. M., Anklesaria, P., and Heald, A. E. (2009) Safety, Tolerability, and Clinical Outcomes after Intraarticular Injection of a Recombinant Adeno-associated Vector Containing a Tumor Necrosis Factor Antagonist Gene: Results of a Phase 1/2 Study, J Rheumatol, Epub 2009/2012/2025.Google Scholar
  52. 52.
    Frank, M. B., Wang, S., Aggarwal, A., Knowlton, N., Jiang, K., Chen, Y., McKee, R., Chaser, B., McGhee, T., Osban, J., and Jarvis, J. N. (2009) Disease-associated pathophysiologic structures in pediatric rheumatic diseases show characteristics of scale-free networks seen in physiologic systems: implications for pathogenesis and treatment, BMC Med Genomics 2, 9.PubMedCrossRefGoogle Scholar
  53. 53.
    Worgall, S., Sondhi, D., Hackett, N. R., Kosofsky, B., Kekatpure, M. V., Neyzi, N., Dyke, J. P., Ballon, D., Heier, L., Greenwald, B. M., Christos, P., Mazumdar, M., Souweidane, M. M., Kaplitt, M. G., and Crystal, R. G. (2008) Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA, Hum Gene Ther 19, 463–474.PubMedCrossRefGoogle Scholar
  54. 54.
    Moss, R. B., Milla, C., Colombo, J., Accurso, F., Zeitlin, P. L., Clancy, J. P., Spencer, L. T., Pilewski, J., Waltz, D. A., Dorkin, H. L., Ferkol, T., Pian, M., Ramsey, B., Carter, B. J., Martin, D. B., and Heald, A. E. (2007) Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial, Hum Gene Ther 18, 726–732.PubMedCrossRefGoogle Scholar
  55. 55.
    Jaski, B. E., Jessup, M. L., Mancini, D. M., Cappola, T. P., Pauly, D. F., Greenberg, B., Borow, K., Dittrich, H., Zsebo, K. M., and Hajjar, R. J. (2009) Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial, J Card Fail 15, 171–181.PubMedCrossRefGoogle Scholar
  56. 56.
    Manno, C. S., Chew, A. J., Hutchison, S., Larson, P. J., Herzog, R. W., Arruda, V. R., Tai, S. J., Ragni, M. V., Thompson, A., Ozelo, M., Couto, L. B., Leonard, D. G., Johnson, F. A., McClelland, A., Scallan, C., Skarsgard, E., Flake, A. W., Kay, M. A., High, K. A., and Glader, B. (2003) AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B, Blood 101, 2963–2972.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Howard Hughes Medical InstitutePhiladelphiaUSA
  2. 2.The Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  3. 3.UMR Inserm U745, Faculty of Pharmaceutical and Biological SciencesUniversity Paris Descartes-Sorbonne-Paris CitéParisFrance

Personalised recommendations