Gene therapy. An ethical profile of a new medical territory

THE JOURNAL OF GENE MEDICINE C O M M E N T A R YJ Gene Med 2006; 8: 1358–1362.Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/jgm.979

Gene therapy. An ethical profile of a new medicalterritory

Michael Fuchs*

Institute of Science and Ethics(Institut fur Wissenschaft und Ethik),University of Bonn, Bonner Talweg57, 53113 Bonn, Germany

*Correspondence to: Michael Fuchs,Institute of Science and Ethics(Institut fur Wissenschaft undEthik), University of Bonn, BonnerTalweg 57, 53113 Bonn, Germany.E-mail: [email protected]

Accepted: 20 September 2006

AbstractFrom early on, the possibility of genetic intervention in humans has been thesubject of philosophical and ethical reflection in the scientific community. Itbecame the object of public debate and parliamentary decision-making underthe rule of law even before the first authorized trials on human subjects couldstart. This article explains why the debate on germ-line intervention andgenetic enhancement is still ongoing. The focus is on somatic gene therapy.There is a political and academic consensus that it represents an adequate toolfor a high-ranking end if some points are considered and taken into account.But where do we stand and what are the ethical conclusions we can drawfrom recent clinical experiences? Copyright 2006 John Wiley & Sons, Ltd.

Keywords somatic gene therapy; germ-line intervention; genetic enhancement;ethical principles; rejection of the instrumentalisation of individuals; inclusion ofpatients in trials

IntroductionFrom early on, the possibility of genetic intervention in humans has been thesubject of philosophical and ethical reflection in the scientific community. Itbecame the object of public debate and parliamentary decision-making underthe rule of law even before the first authorized trials on human subjects couldstart. When the first officially sanctioned clinical trial in somatic gene therapystarted in 1990 at the NIH, the ethical discussion had already been going onfor more than two decades and the principal investigators had been involvedin it for several years. They had to explain a concept of gene therapy bydistinguishing gene therapy from the concept of eugenics which had been stilldominant at the CIBA Foundation Symposium held in London in 1962 on thetheme ‘Man and His Future’ [1].

Ongoing debate on germ-line intervention andgenetic enhancementAt all levels of reflection the distinction between germ-line intervention andsomatic intervention on the one hand, and therapy and enhancement – anintervention which does not treat an illness, or which is not indicated med-ically speaking – on the other was seen to be relevant not only for definingpriorities of medical research, but also for evaluating their moral acceptabil-ity, even though it is often difficult to delineate one from the other and togive well-founded reasons. Both the Parliamentary Assembly of the Council ofEurope and the US President’s Commission on Ethical Problems in Medicineand Biomedical and Behavioral Research published reports in 1982 adopt-ing positions in favor of somatic-cell gene therapy [2,3]. The two reportswere followed by similar policy statements by various ad hoc committees

Copyright 2006 John Wiley & Sons, Ltd.

Commentary 1359

in several European countries [4,5], which were in favorof somatic-cell gene therapy and opposed to germ-linetherapy and genetic enhancement.

Although the arguments are quite similar, some proposea moratorium for germ-line therapy while others demanda formal prohibition of all attempts to deliberately modifythe genome of germinal cells and even of any gene therapyinvolving the risk of such a modification [4]. Moreover,the consensus is not complete and the debate on germ-line gene therapy continues all over the world. Butwhy should genetic enhancement be strictly prohibitedwhereas enhancement in the fields of plastic surgery, hairtransplantation or growth hormone injection is more orless accepted?

As far as germ-line therapy is concerned, some scientistsand ethicists argue that it is medically necessary toprevent certain classes of diseases and that it shouldnot only be allowed but even be advisable, since itfits with the duty to remove harm. On the one handthe European Society of Gene Therapy (ESGT) sharesthe ethical and social concerns against germ-line cellmodification and does not support it [6]. The AmericanAssociation for the Advancement of Science (AAAS) calledfor a moratorium on inheritable genetic modificationstechnology [7]. Nevertheless, an opinion poll showedthat a clear majority of responding scientists (64%) fromthe American Society of Human Genetics view germ-line intervention to prevent serious disease as ethicallyacceptable, if and when gene repair/replacement were tobecome a safe and validated technique [8].

Ethical acceptability of somatic genetherapy

Attempts to express a transgene in human somatic cellsfor therapeutic reasons generally have been regarded ahigh-ranking moral objective. Poll data provided by theLouis Harris organization in 1986 and 1992 showed theopenness of the American public to the use of genetictechnology in the war against disease [9]. The moreurgent the medical need, the more likely respondentswere to approve the use of gene therapy. The datareflected also a strong support of research in that area.Walters and Palmer [9] found 28 policy statements fromgovernmental authorities, groups of experts consultedby state authorities, churches and medical associationspublished from 1980 through 1993 on the topic. All 28agreed that somatic-cell gene therapy for the treatment ofserious diseases is ethically acceptable in principle. ‘‘Thereare few issues in all of biomedical ethics on which onewould be able to discover such unanimous agreement’’[9]. The main reason for that agreement is that both in thescientific community and in public perception ‘‘somatic-cell gene therapy has increasingly come to be viewed asa natural and logical extension of current techniques fortreating disease’’ [8].

In medical ethics the argument that a new technologyis morally acceptable because there is an analogy between

the new technique and an old one that is ethically non-problematic is always important. If such an analogy canbe found it only has to be asked if the old technology isreally without any difficulties and if there are no morallysignificant differences. The analogy which can be mostoften found in the literature is the one between somatic-cell gene therapy and organ or tissue transplantation[4–6]. Other comparisons have been proposed. Forinstance, one argument was that the new therapy closelyresembles medications or enzyme therapies currentlyused. Since some applications of gene therapy functionas vaccinations this has been regarded as anothersimilarity. All these analogies have been used in favorof the ‘gene-therapy-as-extension view’ [9]. However,given the gene-therapy-as-extension view the necessaryethical analyses of somatic-cell gene therapy do not seemto differ categorically from conventional experimentaltherapy. Thus it is subject to ethical criteria similar tothose applicable to any other step into new medicalterritory. Some researchers even argue that somatic-cellgene therapy is less invasive than the allotransplantationof a major organ or the allotransplantation of tissues likebone marrow since the probability that the cells will berejected by the immune system of the patient is muchlower.

Experiences from clinical trials

But where do we stand within this new territory? Whatis the situation from an ethical perspective? Clinicaltrials have been conducted over a long period of time,and although they did not cause any harm to the testsubjects, they also did not produce any demonstrablecurative successes during the first years of experience.On occasion these trials aroused hopes that today mustclearly be considered unfounded – on the grounds thatthey were premature. For some years now the potentialto cause harm has been readily apparent. In September1999, 18-year-old Jesse Gelsinger died after being injecteda few days earlier with a high dose of adenovirus inan experimental trial [10]. The virus carried a genewhich it is hoped may cure a severe deficiency thatimpairs the urea cycle and can cause death even in earlychildhood. Gelsinger participated voluntarily in the trial,which – as is standard practice in phase I trials – wasintended to determine toxicity. He himself suffered fromthe deficiency of the ornithine transcarbamylase (OTC)enzyme in the liver that impairs the urea cycle and whichsubsequent phases of the trial were intended to remedy.Although he was not entirely free of the symptomsof his condition, they were largely under control andwere not life-threatening. Jesse Gelsinger died of theimmune reaction to the injected adenoviruses. Sincethis was the first serious incident in a gene therapystudy, Gelsinger’s death gave rise to numerous criticalquestions about the planning of the trial, the selection ofthe participants and information provided to them, thecooperation between scientific and ethical supervisory

Copyright 2006 John Wiley & Sons, Ltd. J Gene Med 2006; 8: 1358–1362.DOI: 10.1002/jgm

1360 M. Fuchs

bodies, and the independence of the individuals servingon these bodies [11].

Shortly afterwards, however, the first curative successeswith gene therapy were reported. At the Necker Hospitalin Paris Alain Fischer had treated children suffering fromthe severe immune deficiency SCID-X1 – which is usuallyfatal in early childhood. He had removed haematopoieticstem cells from his patients and corrected the geneticdefect in these cells using gene transfer [12]. Trialshave since also been conducted in Milan and Londonthat also reveal the effectiveness of somatic-cell genetherapy for significant disorders of the immune systemon the basis of adult stem cells. Yet the hopes ofthe patients and their relatives, especially in the caseof SCID-X1, were soon dampened by the diagnosis ofunusual leukaemias that occurred in a small number ofthe French patients [13]. In January 2005, the Frenchhealth authorities announced indications of leukaemia ina third of the altogether eleven patients [14] – only a fewmonths after Fischer had reported the death of one of thetwo children in whom leukaemia had been diagnosed in2002. The diagnosis of the third case of leukaemia hassince been confirmed. In Milan, where patients sufferingfrom adenosine deaminase-deficient (ADA−) SCID weretreated, and London, where Adrian J Thrasher treatedcases of X-linked SCID in a study very similar to the onein Paris, no leukaemias occurred.

Based on the various cases, conclusions can be drawnregarding dangerous doses and perhaps particularly at-risk age groups. Yet the patients in question are notonly at risk from leukaemias caused by gene therapy, butalso – and in the first place – from their severe immunedeficiency. Without effective therapy the children treatedby Alain Fischer would probably no longer be alive.The ethical issue at stake in somatic-cell gene therapythus proves to be the question of when trials should becommenced, interrupted and restarted and with whichparticipants. Since Gelsinger’s death, safety research hasgathered new impetus and attracted fresh attention. Inview of the expectation of higher safety standards inthe future, when is it morally justifiable to commence aclinical trial?

Balancing of principles and values

It is against this backdrop that concrete steps to tackle theissue of when and under what conditions trials of genetherapy treatment may be legitimate or even morallynecessary have to be taken. The famous four principlesof biomedical ethics – namely autonomy, beneficence,nonmaleficence and justice [15] – may assist us in siftingthrough the ethical criteria of relevance to determinewhether experimental therapies using viral transductionof genetically modified hematopoietic stem cells withsubsequent transplantation into the patient could beindicated [16–18]. Self-determination can be built intothe working procedure through the requirement forinformed consent. In the case of minors, there is a need

both for the assent of the affected party and for theorientation of parental consent to the well-being of thechild. In accordance with the principle of beneficence itis necessary first and foremost to consider the specificbenefit for the patient, most notably in relation to thespontaneous course of the disorder and the results thatcan be expected with alternative therapies. The principleof nonmaleficence requires, above all, that we avoidcreating iatrogenic (lethal) injuries, strains or risks forthe patient. Last but not least, the principle of distributivejustice necessitates discussion of the distribution of harmsand benefits between various individuals. The questionto be addressed here is whether the gain in knowledgeand the associated prospect of future therapeutic usescan justify a not-so-favourable risk/benefit ratio for thepatient affected here and now.

It is readily apparent that the primary focus ofeach of the various principles will produce differentdecisions as to the timing for commencing a trial andthe criteria for inclusion of patients as test subjects. Ifthe principle of nonmaleficence is taken in isolation, onewill hesitate to adopt experimental approaches in favourof established therapies. If the emphasis is placed onindividual consent, there will be a temptation to holdback with the therapies until the patient is able to giveconsent. If one considers the benefit and the hoped-for effectiveness, very young patients will be especiallypreferable. As a possible solution to the normativestalemate between competing principles of equal merit, agroup of authors recently has turned its attention to therejection of the instrumentalisation of individuals [17].In the philosophical tradition and in the internationaldebate on human rights this constitutes a core elementof the respect for every individual and their dignity. Itis by no means possible to derive from this principleevery detail for the formulation of criteria for inclusionand exclusion. Nevertheless, it has a relevant function ofnormative orientation for the question of target diseasesin gene therapy and inclusion of patients: in view of thehigh level of risk, human trials that are concerned solelywith toxicity would not appear to be justified [18]. Onlythe prospect of a cure and the absence of therapeuticalternatives can justify the inclusion of a patient in a genetherapy trial.

Where an alternative treatment is available trials shouldonly involve patients for whom no treatment is available,as for instance Wiskott Aldrich syndrome (WAS) orX-linked SCID patients who have no matching bonemarrow donor. Only with the progress of gene therapytechniques, risk assessment strategies and evidence oftherapeutic success does the question arise when therequirement that there has to be no effective alternativecan be or needs to be relaxed.

After further safety studies in mice we have some ideashow to prevent the risks but we are still in a situationof uncertainty. Is it ethical to start trials now only as acompassionate response to requests of dying patients ortheir parents following the principle of rescue? Is thereany evidence that the term ‘hopelessly incurable’ is used


Commentary 1361

to justify dangerous experimentation, as Henry Beecher[19] feared at the very outset of gene therapy? Would itbe better to wait for further results from safety researchseen from the point of view of the patients? One mightargue that new vectors will provide a higher degree ofsafety in the near future. Is it ethical to wait?

Inclusion in a trial thus becomes an individual decisionin which the therapeutic intent and the individualprognosis are crucial. The advance in medical knowledgefrom which many future patients may perhaps profit canonly be of subordinate importance in view of the fact thatthe risks cannot be definitively controlled. This applies forinstance to the scenario of gene therapy for WAS. WASis a primary immune deficiency syndrome that occursonly in boys; with an incidence of one to four casesper million births it is an extremely rare disorder. It ischaracterised by the clinical triad of thrombocytopenia,eczema and recurrent pyogenic infections. There arevarious manifestations, including a form with isolated,relatively mild symptoms, a rather minor deficiency ofthe immune system in which life expectancy is notsignificantly impaired. This contrasts with the classicsyndrome, in which the accumulation of infections andcomplications leads to death in the patient’s childhood orearly adolescence.

Symptomatic therapies based on the substitution ofimmunoglobulins and administering of antibiotics arecurrently available, although in many cases they cannotprevent an early death. A curative therapy, on the otherhand, involves transplantation of allogenic hematopoieticstem cells from the bone marrow. The results of allogenicstem cell transplantation are unsatisfactory in thosecases where no HLA-identical donor is available. Invery general terms, allogenic stem cell transplantation isassociated with a considerable rate of infections, toxicside effects and damage to organs as well as graft-versus-host reactions. This unsatisfactory situation turnsour eyes to gene therapy. In classical terminology, suchtherapies that break new medical ground are not anexperiment, but rather a curative attempt [17]. This hassignificant implications for the procedure to be adoptedwhen recruiting patients. The therapeutic goal gearedto the individual patient must always be primary andsuperordinate to the interest in the advancement ofknowledge and the associated methodology. At the sametime it is essential that we strive to apply to such curativeattempts the safety standards associated with clinicaltrials.

Final remarks

The consensus about the gene-therapy-as-extension viewmentioned above left the question open as to what couldbe defined as the exact starting point of the extensionand in which direction the extension goes. Looking backon the theoretical debate and the history of clinical trialsdifferent answers are possible. Regarding the ideal ofgene repair as a concept of causal therapy the deviation

from classical therapies is remarkable. Following this lineof thought, we have to be aware that germ-line therapycould be seen as the logical next step. Regarding differentconceptions of gene addition there are similarities tocommon types of therapy. The best analogy is not easyto define. The use of stem cells, bone marrow and othertissues makes some studies on gene therapy comparable toclassical tissue transplantation. It is a question of the stateof the art in safety research if the remaining differencesjustify a specific regulation procedure for gene therapytrials. Other therapies are seen in analogy to medications.Finally, the analogy of vaccines is important for somekinds of studies. The specific ethical question here is thedistinction between prevention and enhancement. Whentalking about an adequate regulation system and theremaining ethical questions we should keep in mind thesedifferent approaches.

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Gene therapy. An ethical profile of a new medical territory

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