Recent developments in gene transfer: risk and ethics
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《英国医生杂志》
1 Clinical Trials Research Group, Biomedical Ethics Unit, Faculty of Medicine, McGill University, 3647 Peel Street, Montreal, QC, Canada H3A 1X1 jonathan.kimmelman@mcgill.ca
Introduction
The risk associated with human gene transfer has five conceptual characteristics that, although not unique, arise more often with this type of therapy (see box). Firstly, active agents rather than chemicals are used to transfer genetic material. These vectors (usually retroviruses or adenoviruses) are therefore potentially capable of propagating themselves, recombining with other viruses, or carrying out complex programmes.6 Secondly, gene transfer functions on the basis of genetic information rather than on chemical structure. Thus, whereas chemical structures indirectly affect genetic functions, gene transfer directly participates in gene expression. Although this partly accounts for its therapeutic potential, it also underscores the possible potency of risks. Thirdly, many agents act simultaneously as delivery devices through their vector as well as pharmacological agents through their transgene. Not only does this complicate the assessment of risk but each component can cooperate to worsen risks. For instance, the leukaemia that occurred in the X linked severe combined immunodeficiency trial may be attributable to the combined toxicity of the vector (which integrated near an oncogene) and the transgene (which may have helped transform T cells).7 Fourthly, gene transfer agents that stably modify a person's tissues can involve risks with long latencies. Continuous, life long exposure to transgenes or vectors increases the probability of subtle toxic properties becoming manifest over the long term. Finally, much of the toxicity related to gene transfer is mediated through the immune system. Immune over reaction resulted in the death of a participant in a trial of an adenovirus vector in 1999.8 Induced immunity against standard treatments (for example, factor IX protein in participants in the haemophilia B trial) or autoimmunity are also concerns with human gene transfer.
Several methodological issues need consideration when testing the safety of gene transfer. Animal models, for example, present major problems because viruses that are pathogenic in humans often have different risk profiles in animals.9 A person's prior exposure to viruses similar to the vector can influence their response to gene transfer. This observation, combined with a non-linear dose-toxicity curve, led investigators in the 1999 adenovirus trial to conclude that the evaluation of vector safety was problematic in a traditional phase 1 trial design.8
Few of these features are unique to gene transfer. For example, trials of live vaccines involve active agents, conventional drugs can be immunotoxic, and animal models often fail to predict toxicity. What makes the risk with gene transfer distinctive is the frequency with which these hazards arise in trials, their co-occurrence in a trial, and our limited experience of assessing and managing such hazards.
Ethics of risk in clinical trials
Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB, McClelland A, et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet 2000;24: 257-61.
Hacein-Bey-Abina S, Le Deist F, Carlier F, Bouneaud C, Hue C, De Villartay JP, et al. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med 2002;346: 1185-93.
Aiuti A, Slavin S, Aker M, Ficara F, Deola S, Mortellaro A, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 2002;296: 2410-3.
Marshall E. Gene therapy. Viral vectors still pack surprises. Science 2001;294: 1640.
Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003;302: 415-9.
Williams D. Clarity and risk: the challenges of the new technologies. Med Device Technol 2001;12: 12-4.
Baum C, Dullmann J, Li Z, Fehse B, Meyer J, Williams DA, et al. Side effects of retroviral gene transfer into hematopoietic stem cells. Blood 2003;101: 2099-14.
Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 2003;80: 148-58.
Dettweiler U, Simon P. Points to consider for ethics committees in human gene therapy trials. Bioethics 2001;15: 491-500.
Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283: 2701-11.
Kimmelman J. Protection at the cutting edge: the case for central review of human gene transfer research. CMAJ 2003;169: 781-2.
Orkin SH, Motulsky AG. Report of the National Institutes of Health ad hoc committee. Report and recommendations of the panel to assess the NIH investment in research on gene therapy. Bethesda, MD: National Institutes of Health, 7 Dec 1995. Available at www4.od.nih.gov/oba/rac/panelrep.htm
King NMP. Defining and describing benefit appropriately in clinical trials. J Law Med Ethics 2000;28: 332-43.
Kohn DB, Sadelain M, Glorioso JC. The occurrence of leukemia following gene therapy. Nat Rev Cancer 2003;3: 477-88.
Welin S. Starting clinical trials of xenotransplantation—reflections on the ethics of the early phase. J Med Ethics 2000;26: 231-6.
Kohn DB, Sadelain M, Dunbar C, Bodine D, Kiem HP, Candotti F, et al. American Society of Gene Therapy (ASGT) ad hoc subcommittee on retroviral-mediated gene transfer to hematopoietic stem cells. Mol Ther 2003;8, 180-7.
Lidz CW, Appelbaum PS. The therapeutic misconception: problems and solutions. Med Care 2002;40: V55-63.
King NMP. Accident and desire: inadvertent germline effects in clinical research. Hastings Cent Rep 2003;33: 23-30.
Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions. JAMA 1999;281: 824-9.
Nevin NC, Spink J. Gene therapy advisory committee: long-term monitoring of patients participating in gene therapy: health departments of the United Kingdom. Hum Gene Ther 2000;11: 1253-5.(Jonathan Kimmelman, research associate1)
Introduction
The risk associated with human gene transfer has five conceptual characteristics that, although not unique, arise more often with this type of therapy (see box). Firstly, active agents rather than chemicals are used to transfer genetic material. These vectors (usually retroviruses or adenoviruses) are therefore potentially capable of propagating themselves, recombining with other viruses, or carrying out complex programmes.6 Secondly, gene transfer functions on the basis of genetic information rather than on chemical structure. Thus, whereas chemical structures indirectly affect genetic functions, gene transfer directly participates in gene expression. Although this partly accounts for its therapeutic potential, it also underscores the possible potency of risks. Thirdly, many agents act simultaneously as delivery devices through their vector as well as pharmacological agents through their transgene. Not only does this complicate the assessment of risk but each component can cooperate to worsen risks. For instance, the leukaemia that occurred in the X linked severe combined immunodeficiency trial may be attributable to the combined toxicity of the vector (which integrated near an oncogene) and the transgene (which may have helped transform T cells).7 Fourthly, gene transfer agents that stably modify a person's tissues can involve risks with long latencies. Continuous, life long exposure to transgenes or vectors increases the probability of subtle toxic properties becoming manifest over the long term. Finally, much of the toxicity related to gene transfer is mediated through the immune system. Immune over reaction resulted in the death of a participant in a trial of an adenovirus vector in 1999.8 Induced immunity against standard treatments (for example, factor IX protein in participants in the haemophilia B trial) or autoimmunity are also concerns with human gene transfer.
Several methodological issues need consideration when testing the safety of gene transfer. Animal models, for example, present major problems because viruses that are pathogenic in humans often have different risk profiles in animals.9 A person's prior exposure to viruses similar to the vector can influence their response to gene transfer. This observation, combined with a non-linear dose-toxicity curve, led investigators in the 1999 adenovirus trial to conclude that the evaluation of vector safety was problematic in a traditional phase 1 trial design.8
Few of these features are unique to gene transfer. For example, trials of live vaccines involve active agents, conventional drugs can be immunotoxic, and animal models often fail to predict toxicity. What makes the risk with gene transfer distinctive is the frequency with which these hazards arise in trials, their co-occurrence in a trial, and our limited experience of assessing and managing such hazards.
Ethics of risk in clinical trials
Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB, McClelland A, et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet 2000;24: 257-61.
Hacein-Bey-Abina S, Le Deist F, Carlier F, Bouneaud C, Hue C, De Villartay JP, et al. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med 2002;346: 1185-93.
Aiuti A, Slavin S, Aker M, Ficara F, Deola S, Mortellaro A, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 2002;296: 2410-3.
Marshall E. Gene therapy. Viral vectors still pack surprises. Science 2001;294: 1640.
Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003;302: 415-9.
Williams D. Clarity and risk: the challenges of the new technologies. Med Device Technol 2001;12: 12-4.
Baum C, Dullmann J, Li Z, Fehse B, Meyer J, Williams DA, et al. Side effects of retroviral gene transfer into hematopoietic stem cells. Blood 2003;101: 2099-14.
Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 2003;80: 148-58.
Dettweiler U, Simon P. Points to consider for ethics committees in human gene therapy trials. Bioethics 2001;15: 491-500.
Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283: 2701-11.
Kimmelman J. Protection at the cutting edge: the case for central review of human gene transfer research. CMAJ 2003;169: 781-2.
Orkin SH, Motulsky AG. Report of the National Institutes of Health ad hoc committee. Report and recommendations of the panel to assess the NIH investment in research on gene therapy. Bethesda, MD: National Institutes of Health, 7 Dec 1995. Available at www4.od.nih.gov/oba/rac/panelrep.htm
King NMP. Defining and describing benefit appropriately in clinical trials. J Law Med Ethics 2000;28: 332-43.
Kohn DB, Sadelain M, Glorioso JC. The occurrence of leukemia following gene therapy. Nat Rev Cancer 2003;3: 477-88.
Welin S. Starting clinical trials of xenotransplantation—reflections on the ethics of the early phase. J Med Ethics 2000;26: 231-6.
Kohn DB, Sadelain M, Dunbar C, Bodine D, Kiem HP, Candotti F, et al. American Society of Gene Therapy (ASGT) ad hoc subcommittee on retroviral-mediated gene transfer to hematopoietic stem cells. Mol Ther 2003;8, 180-7.
Lidz CW, Appelbaum PS. The therapeutic misconception: problems and solutions. Med Care 2002;40: V55-63.
King NMP. Accident and desire: inadvertent germline effects in clinical research. Hastings Cent Rep 2003;33: 23-30.
Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions. JAMA 1999;281: 824-9.
Nevin NC, Spink J. Gene therapy advisory committee: long-term monitoring of patients participating in gene therapy: health departments of the United Kingdom. Hum Gene Ther 2000;11: 1253-5.(Jonathan Kimmelman, research associate1)