The ethics of gene therapy: Balancing the risks

Current Opinion in Molecular Therapeutics

Volumn 12, Issue 5, 2010, Pages 578-585

  Deakin, Claire T ^a,b,c   Alexander, Ian E ^b,c   Kerridge, Ian ^b,d  

^a CHILDREN'S MEDICAL RESEARCH INSTITUTE   (Australia)

^b UNIVERSITY OF SYDNEY   (Australia)

^c University of Sydney   (Australia)

^d WESTMEAD HOSPITAL   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

ORNITHINE CARBAMOYLTRANSFERASE;

CROHN DISEASE; DISEASE COURSE; ENZYME ACTIVITY; ENZYME DEFICIENCY; GENE THERAPY; GLYCOGEN STORAGE DISEASE TYPE 2; HUMAN; HYPERAMMONEMIA; INTERPERSONAL COMMUNICATION; MEDICAL DECISION MAKING; MEDICAL ETHICS; MULTIPLE SCLEROSIS; MUTAGENESIS; NONHUMAN; PATIENT SELECTION; PREDICTION; PROGNOSIS; REVIEW; RHEUMATOID ARTHRITIS; RISK ASSESSMENT; RISK BENEFIT ANALYSIS; RISK MANAGEMENT; SICKLE CELL ANEMIA; SOCIAL WELFARE; UNCERTAINTY; WISKOTT ALDRICH SYNDROME;

DECISION MAKING; GENE THERAPY; HUMANS; RISK ASSESSMENT;

EID: 77957729783     PISSN: 14648431     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (56)

1. World Medical Association Declaration of Helsinki: 59th World Medical Association General Assembly, Seoul, South Korea (2008). www.wma.net/en/ 30publications/10policies/b3/17c.pdf
2. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, US Department of Health, Education and Welfare, National Institute of Health, Washington DC, USA (1979). ohsr.od.nih.gov/guidelines/belmont.html
3. National statement on ethical conduct in human research: National Health and Medical Research Council, Australian Research Council, Australian Government, Canberra, Australia (2007). www.nhmrc.gov. au/-files-nhmrc/file/ publications/synopses/e72-jul09.pdf
4. King NM, Cohen-Haguenauer O: En route to ethical recommendations for gene transfer clinical trials. Mol Ther (2008) 16 (3):432-438. • Presents an analysis of and proposes a stratification model for risk assessment in gene therapy trials.
5. Kimmelman J: Gene transfer and the ethics of first-in-human research: Lost in translation. Cambridge University Press, Cambridge, UK; New York, NY, USA (2010). • A recent, comprehensive and well-researched analysis of the ethical issues surrounding the translation of gene therapy research.
6. Deakin CT, Alexander IE, Kerridge I: Accepting risk in clinical research: Is the gene therapy field becoming too risk-averse? Mol Ther (2009) 17 (11):1842-1848.
7. Walters L, Palmer JG: The Ethics of Human Gene Therapy. Oxford University Press, New York, NY, USA (1997).
8. Anderson WF: Human gene therapy: Scientific and ethical considerations. J Med Philos (1985) 10 (3):275-291.
9. Beyond therapy: Biotechnology and the pursuit of happiness: US President's Council on Bioethics, Washington, DC, USA (2003). biotech.law.lsu.edu/research/pbc/reports/beyondtherapy/beyond-therapy-final- report-pcbe.pdf
10. Hacein-Bey-Abina S, Garrigue A, Wang GP, Soulier J, Lim A, Morillon E, Clappier E, Caccavelli L, Delabesse E, Beldjord K, Asnafi V et al: Insertional oncogenesis in 4 patients after retrovirusmediated gene therapy of SCID-X1. J Clin Invest (2008) 118 (9):3132-3142.
11. Howe SJ, Mansour MR, Schwarzwaelder K, Bartholomae C, Hubank M, Kempski H, Brugman MH, Pike-Overzet K, Chatters SJ, de Ridder D, Gilmour KC et al: Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest (2008) 118 (9):3143-3150.
12. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, Ozelo MC, Hoots K, Blatt P, Konkle B, Dake M et al: Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med (2006) 12 (3):342-347.
13. Mingozzi F, Meulenberg J, Hui D, Basner-Tschkarajan E, Hasbrouck N, Edmonson S, Hutnick N, Betts M, Kastelein J, Stroes E, High K: AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells. Blood (2009) 114 (10):2077-2086.
14. Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, Wilson JM, Batshaw ML: Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab (2003) 80 (1-2): 148-158.
15. Stein S, Ott MG, Schultze-Strasser S, Jauch A, Burwinkel B, Kinner A, Schmidt M, Krämer A, Schwäble J, Glimm H, Koehl U et al: Genomic instability and myelodysplasia with monosomy 7 consequent to Evi1 activation after gene therapy for chronic granulomatous disease. Nat Med (2010) 16 (2):198-204.
16. Fischhoff B, Lichtenstein S, Slovic P, Derby SL, Keeney RL: Acceptable Risk. Cambridge University Press, Cambridge, MA, USA (1981). • Provides a useful exploration of acceptable-risk problems and decisionmaking processes. This book is pragmatic and relevant to decision-making about risk in gene therapy research, despite its early publication date.
17. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R et al: LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science (2003) 302 (5644):415-419.
18. Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, Scaramuzza S, Andolfi G, Mirolo M, Brigida I, Tabucchi A et al: Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med (2009) 360 (5):447-458.
19. ash mouse: A missense mutation in the ornithine transcarbamylase gene also causes aberrant mRNA splicing. Proc Natl Acad Sci USA (1989) 86 (11):4142-4146.
20. van Til NP, Stok M, Aerts Kaya FS, de Waard MC, Farahbakhshian E, Visser TP, Kroos MA, Jacobs EH, Willart MA, van der Wegen P, Scholte BJ et al: Lentiviral gene therapy of murine hematopoietic stem cells ameliorates the Pompe disease phenotype. Blood (2010) 115 (26):5329-5337.
21. Mostoslavsky G, Fabian AJ, Rooney S, Alt FW, Mulligan RC: Complete correction of murine Artemis immunodeficiency by lentiviral vector-mediated gene transfer. Proc Natl Acad Sci USA (2006) 103 (44):16406-16411.
22. Klein C, Nguyen D, Liu CH, Mizoguchi A, Bhan AK, Miki H, Takenawa T, Rosen FS, Alt FW, Mulligan RC, Snapper SB: Gene therapy for Wiskott-Aldrich syndrome: Rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice. Blood (2003) 101 (6):2159-2166.
23. Ginn SL, Liao SH, Dane AP, Hu M, Hyman J, Finnie JW, Zheng M, Cavazzana-Calvo M, Alexander SI, Thrasher AJ, Alexander IE: Lymphomagenesis in SCID-X1 mice following lentivirusmediated phenotype correction independent of insertional mutagenesis and γc overexpression. Mol Ther (2010) 18 (5):965-976.
24. Shou Y, Ma Z, Lu T, Sorrentino BP: Unique risk factors for insertional mutagenesis in a mouse model of XSCID gene therapy. Proc Natl Acad Sci USA (2006) 103 (31):11730-11735.
25. Montini E, Cesana D, Schmidt M, Sanvito F, Bartholomae CC, Ranzani M, Benedicenti F, Sergi LS, Ambrosi A, Ponzoni M, Doglioni C et al: The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy. J Clin Invest (2009) 119 (4):964-975.
26. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, Selz F, Hue C, Certain S, Casanova JL, Bousso P et al: Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science (2000) 288 (5466):669-672. (Pubitemid 30241569)
27. Aiuti A, Slavin S, Aker M, Ficara F, Deola S, Mortellaro A, Morecki S, Andolfi G, Tabucchi A, Carlucci F, Marinello E et al: Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science (2002) 296 (5577):2410-2413.
28. O tt MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, Kühlcke K, Schilz A, Kunkel H, Naundorf S et al: Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med (2006) 12 (4):401-409.
29. Veldman A, Santamaria-Araujo JA, Sollazzo S, Pitt J, Gianello R, Yaplito-Lee J, Wong F, Ramsden CA, Reiss J, Cook I, Fairweather J et al: Successful treatment of molybdenum cofactor deficiency type A with cPMP. Pediatrics (2010) 125 (5):1249-1254.
30. Patel NC, Chinen J, Rosenblatt HM, Hanson IC, Brown BS, Paul ME, Abramson SL, Ritz J, Shearer WT: Long-term outcomes of nonconditioned patients with severe combined immunodeficiency transplanted with HLA-identical or haploidentical bone marrow depleted of T cells with anti-CD6 mAb. J Allergy Clin Immunol (2008) 122 (6):1185-1193.
31. Railey MD, Lokhnygina Y, Buckley RH: Long-term clinical outcome of patients with severe combined immunodeficiency who received related donor bone marrow transplants without pretransplant chemotherapy or post-transplant GvHD prophylaxis. J Pediatr (2009) 155 (6):834-840.
32. Hacein-Bey-Abina S, Hauer J, Lim A, Picard C, Wang GP, Berry CC, Martinache C, Rieux-Laucat F, Latour S, Belohradsky BH, Leiva L et al: Efficacy of gene therapy for X-linked severe combined immunodeficiency. N Engl J Med (2010) 363 (4):355-364.
33. Johnson FR, Ozdemir S, Mansfield C, Hass S, Miller DW, Siegel CA, Sands BE: Crohn's disease patients' risk-benefit preferences: Serious adverse event risks versus treatment efficacy. Gastroenterology (2007) 133 (3):769-779.
34. Johnson FR, Van Houtven G, Ozdemir S, Hass S, White J, Francis G, Miller D W, Phillips JT: Multiple sclerosis patients' benefit-risk preferences: Serious adverse event risks versus treatment efficacy. J Neurol (2009) 256 (4):554-562.
35. O'Brien BJ, Elswood J, Calin A: Willingness to accept risk in the treatment of rheumatic disease. J Epidemiol Community Health (1990) 44 (3):249-252.
36. van Besien K, Koshy M, Anderson-Shaw L, Talishy N, Dorn L, Devine S, Yassine M, Kodish E: Allogeneic stem cell transplantation for sickle cell disease. A study of patients' decisions. Bone Marrow Transplant (2001) 28 (6):545-549.
37. Madsen SM, Holm S, Davidsen B, Munkholm P, Schlichting P, Riis P: Ethical aspects of clinical trials: The attitudes of participants in two non-cancer trials. J Intern Med (2000) 248 (6):463-474.
38. Nurgat ZA, Craig W, Campbell NC, Bissett JD, Cassidy J, Nicolson MC: Patient motivations surrounding participation in phase I and phase II clinical trials of cancer chemotherapy. Br J Cancer (2005) 92 (6):1001-1005.
39. Madsen SM, Mirza MR, Holm S, Hilsted KL, Kampmann K, Riis P: Attitudes towards clinical research amongst participants and nonparticipants. J Intern Med (2002) 251 (2):156-168.
40. King NM: RAC oversight of gene transfer research: A model worth extending? J Law Med Ethics (2002) 30 (3):381-389.
41. Paling J: Strategies to help patients understand risks. Br Med J (2003) 327 (7417):745-748. • Briefly outlines practical measures for improving the communication of risk information.
42. Epstein RM, Alper BS, Quill TE: Communicating evidence for participatory decision making. JAMA (2004) 291 (19):2359-2366. • Reviews the literature on risk communication in clinical settings, and includes clinician-directed recommendations for improving communication.
43. Visschers VH, Meertens RM, Passchier WW, de Vries NN: Probability information in risk communication: A review of the research literature. Risk Anal (2009) 29 (2):267-287.
44. Schapira MM, Nattinger AB, McHorney CA: Frequency or probability? A qualitative study of risk communication formats used in health care. Med Decis Making (2001) 21 (6):459-467.
45. Knapp P, Raynor DK, Berry DC: Comparison of two methods of presenting risk information to patients about the side effects of medicines. Qual Saf Health Care (2004) 13 (3):176-180.
46. Young S, Oppenheimer DM: Effect of communication strategy on personal risk perception and treatment adherence intentions. Psychol Health Med (2009) 14 (4):430-442.
47. Young SD, Oppenheimer DM: Different methods of presenting risk information and their influence on medication compliance intentions: Results of three studies. Clin Ther (2006) 28 (1):129-139.
48. Zikmund-Fisher BJ, Ubel PA, Smith DM, Derry HA, McClure JB, Stark A, Pitsch RK, Fagerlin A: Communicating side effect risks in a tamoxifen prophylaxis decision aid: The debiasing influence of pictographs. Patient Educ Couns (2008) 73 (2):209-214.
49. Kurz-Milcke E, Gigerenzer G, Martignon L: Transparency in risk communication: Graphical and analog tools. Ann NY Acad Sci (2008) 1128:18-28.
50. Brehaut JC, Fergusson DA, Kimmelman J, Shojania KG, Saginur R, Elwyn G: Using decision aids may improve informed consent for research. Contemp Clin Trials (2010) 31 (3):218-220.
51. Hazen RA, Eder M, Drotar D, Zyzanski S, Reynolds AE, Reynolds CP, Kodish E, Noll RB, Multi-Site Intervention Study to Improve Consent Research Team: A feasibility trial of a video intervention to improve informed consent for parents of children with leukemia. Pediatr Blood Cancer (2010) 55 (1):113-118.
52. Trevena LJ, Davey HM, Barratt A, Butow P, Caldwell P: A systematic review on communicating with patients about evidence. J Eval Clin Pract (2006) 12 (1):13-23.
53. Appelbaum PS, Roth LH, Lidz CW, Benson P, Winslade W: False hopes and best data: Consent to research and the therapeutic misconception. Hastings Cent Rep (1987) 17 (2):20-24.
54. Henderson GE, Easter, MM, Zimmer CR, King NM, Davis AM, Bluestone Rothschild B, Churchill LR, Wilfond BS, Nelson DK: Therapeutic misconception in early phase gene transfer trials. Soc Sci Med (2006) 62 (1):239-253.
55. Wendler D: The assent requirement in pediatric research. In: The Oxford Textbook of Clinical Research Ethics. Emanuel E, Grady C, Lie R, Miller F, Wendler D (Eds), Oxford University Press, New York, NY, USA (2008):661-669.
56. Kunin H: Ethical issues in pediatric life-threatening illness: Dilemmas of consent, assent, and communication. Ethics Behav (1997) 7 (1):43-57.