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  Gene therapy
A Genetic Interest Group Policy Paper

This spring researchers at Stanford University announced that they had started a trial of gene therapy delivered by aerosol to the lungs of patients with cystic fibrosis. The treatment consists of using a nebuliser to blow a mist of viral particles containing working copies of the CFTR gene into the patient's mouth. The team conducting the trial are excited because the procedure is showing signs of working—they were able to identify the gene in sinus tissue, showing that gene transfer had been accomplished. The lead researcher reports that they have also detected clinical effects: "we saw a significant reduction in inflammation in patients treated", he said.

Cystic fibrosis is a relatively common life-threatening genetic disease. In the United Kingdom alone there are estimated to be 7000 cases. When an individual inherits two defective copies of the CFTR gene a channel which allows water and electrically charged ions to flow in and out of cells fails to function properly. Among other symptoms, inflammation, clogging mucus, and infections affect the patient's lungs and sinuses. At present, drugs and physiotherapy can mitigate symptoms, but there is no cure. In this regard, cystic fibrosis is typical of the estimated 4000-5000 single gene disorders that collectively constitute a significant cause of ill health, disability and reduced life expectancy.

As the work cited above indicates, progress in gene therapy research has been made. Unfortunately it is limited. The gene for cystic fibrosis was isolated ten years ago, but gene therapy for the condition, or for any other condition, has not yet progressed beyond Phase II clinical trials, in which treatments are tested on small groups of people with the condition to test for clinical effect. Nevertheless, it continues to offer one of the best hopes for tackling conditions for which there is currently little or no effective treatment. This paper outlines some of the history of gene therapy and the barriers to further progress.

Today, most people accept the principle of gene therapy as a treatment for individuals with a genetic or acquired disorder. But there are also concerns about potential risks associated with the procedure to the patient, and perhaps to others if changes are made inadvertently that affect the reproductive cells—that is, germ-line changes. There are also concerns about a 'slippery slope' towards deliberate tampering with the germ-line or gene therapy for enhancement of normal traits. This paper also provides a response to these concerns, in part by outlining the regulatory framework that governs the field today, and in part by examining whether the more radical procedures might offer some benefits in the future.

A Brief Overview

Gene therapy as a treatment for single gene disorders is in fact but one aspect of a procedure that has many possible applications. In his overview, Gene therapy—where are we?, Alan E Smith provides a useful summary of the technique, its applications and its methods:

'Gene therapy is the use of nucleic acids as therapeutically useful molecules. The approach has many potential applications; the most obvious of which is to correct the defects in monogenic inherited diseases such as cystic fibrosis (CF). However, many other applications are possible and these include gene transfer to stimulate a specific immune response, to mediate specific cell killing, to activate a pro-drug, or to produce a molecular decoy required for the replication of a virus.

A vector is the vehicle used to introduce the gene into the target cell. Disabled viruses are commonly used because they can perform many of the tasks necessary to achieve successful gene transfer, such as bind to a target cell and deliver the viral genome to the nucleus for transcription. Non-viral vectors, based on plasmid DNA produced in bacteria and often complexed with lipids, are also being used since they lack foreign proteins and therefore may avoid immunological pitfalls common to engineered viral vectors—albeit at the cost of lower efficiency.'

As Smith points out, there are applications to acquired as well as monogenic inherited disorders. Indeed, whereas during the second half of the 1980s the majority of research was on single-gene disorders, from 1990 onwards attention has shifted towards acquired disorders such as cancer and HIV. Globally, as of 1 June 1999, 380 trials had been performed involving a total of 3173 patients. Of these 240 were cancer therapies involving 2166 patients and 53 were on monogenic diseases involving 296 patients. It seems likely that this trend will continue. Naturally, GIG's primary concern is the monogenic disorders. But equally we welcome advances that offer therapeutic solutions to other intractable conditions. Furthermore, it is to be hoped that advances in other areas will assist in the development of techniques for the monogenic diseases, as well as providing specific treatment options for some of the symptoms of the patients represented by GIG.

Put simply, somatic gene therapy for monogenic disorders involves supplementing or replacing faulty variations of genes with normally functioning ones in bodily cells. The changes made are not passed on to the next generation. Monogenic disorders for which gene therapy has been attempted include cystic fibrosis, familial hypercholesterolaemia, mucopolysaccharidosis types I and II, alpha-1-antitrypsin deficiency, severe combined immunodeficiency and Gaucher's disease.

The simplest way of performing gene therapy in monogenic disorders is to treat the patient repeatedly with the normally functioning gene. For this approach to work, integration and extended replication of the gene is not necessary; it must merely express itself long enough to produce an effect. This is the approach being taken by researchers working on cystic fibrosis. True gene therapy involves the permanent replacement of damaged genes, perhaps in stem cells, or the introduction of normally functioning genes, perhaps in artificial chromosomes, alongside the abnormal ones. At present, this approach has not made it beyond basic research into clinical trials. To appreciate the obstacles to success faced by researchers today, it is useful first to summarise the history of the subject.

The promises and dangers of gene transfer were first discussed in the late 1960s. During the 1970s, some of the basic techniques were developed and widely discussed within the scientific community. Basic research was taken further in the 1980s. And then, to much fanfare, the first ever human gene therapy trial was attempted in the United States in 1990. A young girl called Ashanthi DeSilva received gene therapy for a form of immunodeficiency. She had been born with a defective version of the gene that normally makes the essential enzyme adenosine deaminase (ADA). The therapy seemed to work. When she appeared before the House Science Committee four years later, the then chair George Brown was moved to declare that she was "living proof that a miracle has occurred." And yet, just one year later, in 1995, the gene therapy community had to face up to the fact that for all the early enthusiasm, and media hype, there was no evidence that gene therapy was actually working. Indeed, even the data from the pioneering ADA trials were inconclusive: Ashanthi and others treated with gene therapy were also being given the conventional treatment for the disorder—injections of synthetic ADA—which might have been responsible for their good health.

This prompted a call, led by the National Institutes of Health, for less hype and more research. Looking back on this period from the vantagepoint of today, Elizabeth Nabel outlines both the positive effect of the correction to expectations and the issues research is now addressing:

'The field had gone through at least five years of highly visible and publicised clinical studies but the hype and the hope clearly exceeded the accomplishments. Responding to concerns of investigators and the public alike, NIH director Harold Varmus established an advisory committee; their report (http://www.nih.gov/news/panelrep.phpl) had a remarkably positive effect on the field. Renewed efforts were made to understand the basic biology of gene transfer, the molecular biology of vectors and the cellular mechanisms of vector uptake and gene expression. The stampede to clinical trials abated. The field had undergone a "market correction".'

Of the three problems highlighted, many researchers would isolate gene delivery as the most important at the moment. And to Nabel's three issues, we should also add the related issue of dealing with the host's immune response if viruses are used to transfer the normally functioning genes. Work on all these areas over the last four years has generated new insights and a steady return of confidence to the field. In the UK, the Gene Therapy Advisory Committee reports that during 1997 new approaches and renewed financial support for the field indicates that 'gene therapy is moving into an expansive phase'. In 1998, the European Working Group on Human Gene Transfer and Therapy was rechristened the European Society for Gene Therapy to reflect the move "from working hypotheses into clinical studies", in the words of its president Oliver Danos. And in his 1999 Presidential Address to the American Society of Gene Therapy, James Wilson outlined innovative approaches to clinical trials that might yield data faster and accelerate the process of commercialisation.

Patient groups play an active part in raising money for and in securing patient participation in trials, and GIG and sister organisations in other countries lobby at the political level to secure market incentives to speed up the process of commercialisation that James Wilson spoke of. We all look forward to the fillip gene therapy will receive from the completion of a detailed and highly accurate map of the human genome, which should be in hand within four years. By then, further advances in some of the techniques already discussed should create the platform for an intensive period of research on all fronts.

Clearly there is a long way to go before treatments become a reality. Equally clearly much progress has been made. For some, both sides of this equation are a cause for concern. They worry that the lack of progress indicates that we don't know enough about the risks of the procedures we are currently trying, and they worry that enthusiasm for the progress that has been made and the further progress that will be made in the future means that we might use the power of gene therapy to begin 'genetic engineering' on humans. GIG does not share these concerns.

Risks in Context

Gene therapy, in the UK and elsewhere, is highly regulated. It is worth quoting from the House of Commons Science and Technology Committee's 1995 report Human Genetics: The Science and its Consequences at some length on this:

'There is no evidence of any possibility of a Frankenstein emerging from a test tube, by genetic manipulation. The effects of modest genetic changes even limited to a single individual in his lifetime, need, and get, scrupulous consideration. The Committee on the Ethics of Gene Therapy under the Chairmanship of Sir Cecil Clothier (the Clothier Committee) considered gene therapy in 1991… The Committee's recommendations formed the terms of reference for the Gene Therapy Advisory Committee (GTAC), which was established in November 1993. GTAC reviews all proposals for gene therapy studies in the United Kingdom. In addition, such proposals must also be considered by the Local Research Ethics Committees of the authorities in which the research will take place.'

GTAC applies six principles when considering gene therapy for adults and children. They ensure that therapies currently in trial are tightly regulated and limited to certain classes. They also aim to balance the risks and benefits for the individual undergoing what is still an experimental procedure rather than a course of treatment. The principles are:

(a) gene therapy is research and not innovative treatment;

(b) only somatic therapy should be considered;

(c) in view of safety and ethical difficulties germ line interventions are off limits at present;

(d) gene therapy should be restricted to life threatening disorders where no current alternative effective treatments are available;

(e) patients should take part in gene therapy research trials only after a full explanation of the procedures, risks and benefits and after they have given their informed consent, if they are capable of doing so; and

(f) recognising that some people, including young children, may not be able to give such consent, therapeutic research involving such patients must not put them at disproportionate risk.

Similar controls exist in other countries. GTAC and other regulatory bodies have also performed risk assessments on the possibility of inadvertent germ-line modification during somatic gene therapy, on both fetuses and people, as well as other possible side effects of current trials. But what of the future: are we in danger of allowing a technology to develop that will one day slip beyond our control?

There are two parts to the answer to this question. In the first place, GIG does not believe that real benefits should be discarded simply because the same technology may be used in untoward ways at some point in the future. Secondly, we should be careful not to rule out forever novel applications of gene therapy that may become possible, and safe, given further scientific development. Such applications may not be untoward at all.

In 1982, gene therapy pioneer French Anderson introduced the four well-known categories of human gene therapy into the scientific literature. This is Maurice A. M. De Wachter's summary:

1) somatic cell gene therapy: here a genetic defect in the somatic, or body, cells of a patient are being corrected;

2) germ-line gene therapy: here a genetic defect in the germ, or reproductive cells of a patient are being corrected so that offspring of the patient would also be corrected;

3) enhancement genetic engineering: here a gene is being inserted in order to try to enhance or improve a specific characteristic, for example adding an additional growth hormone to increase height;

4) eugenic genetic engineering: here genes are being inserted in order to try to alter or improve complex human traits that depend on a large number of genes as well as on extensive interactions with the environment, for example intelligence, personality, character.

Some might prefer to subsume the fourth category within the third. Some might also choose to label the second and third eugenic as well. At its simplest, the division highlights that beyond somatic therapy we can imagine germ-line alterations and enhancement therapy. Should these be rejected in principle and forever? GIG does not believe so.

In a discussion of germ-line modification six years ago, Nelson Wivel and LeRoy Walters pointed out that many of the techniques of germ-line modification are being developed in animal models. The starting point of this work is the fact that 'in 1980, it was demonstrated that direct injection of foreign genes into the pronucleus of the fertilized mouse egg, followed by oviductal implantation of the surviving zygotes, resulted in the integration and apparent retention of exogenous genes in all cells of the newborn animal; the foreign genes were transmitted to the offspring.'

Currently, germ-line gene therapy is not being actively researched in anything other than animals, but there is a lot of discussion about its value and desirability within the scientific community and elsewhere. James Watson believes that the procedure will become a reality in humans within 20 years, and a good thing too. He is reported as saying that any international attempt to prevent germ-line engineering would be "a complete disaster". Others however question the need for germ-line gene therapy. In a response to Watson, the UK's Anne McLaren argued that 'the simpler and safer technique of preimplantation genetic diagnosis, already in clinical use, renders germline gene therapy for genetic disease virtually pointless.' Some go further, questioning its desirability as well as its value. Billings, Hubbard and Newman mount an absolute objection: 'Human germline interventions would necessarily alter the lives of individuals who are yet to be born. Informed consent by the affected individuals is not yet possible. Extension of the parental right to consent for minors would be required. Such legal permission to specifically alter the lives of generations of unborn individuals would be unprecedented and unjustified.' In the popular and sociological literature phrases such as 'playing God', or 'colonising the future' are widely used to express this and related absolute objections to germ-line therapy.

The Clothier Report, which as we have already seen established the regulatory framework for human gene therapy in the UK, makes a firm distinction between somatic and germ-line gene therapy. It proposed firm regulation of the former, but it did not regard it as fundamentally novel. It does not, they argued, 'represent a major departure from established medical practice; nor does it …pose new ethical challenges.' They took a different view on germ-line gene therapy. However, and significantly, while they recommended that the procedure be ruled out, they did not say that this prohibition should be an indefinite one, and nor did they mount absolute objections to it. Indeed, they rejected arguments similar to those mounted by Billings et al by pointing out that selective termination of an affected pregnancy followed by the birth of an unaffected child has the same effect on future generations as germ-line gene therapy.

GIG agrees with the approach taken in the Clothier Report on this subject. Everything we do affects future generations. Germ-line changes or the consequences of selective termination or pre-implantation diagnosis will be felt by generations to come. But so will the consequences of not interfering in the genetic lottery of life—diseases as well as genetic modifications run in families. At present, germ-line gene therapy should be ruled out on grounds of safety. But if a number of scientific issues can be addressed—including achievement of precise insertion and deletion of genetic changes—the possibility of germ-line therapy for some conditions should be considered. One possible advantage of the procedure for the individual and the family is that it could allow them to reproduce freely without the worry of passing on the condition to future generations. According to many scientists the procedure might also be easier to perform than somatic therapy—and more complete in that the changes would integrate into all the bodily cells. Some experimental procedures currently being considered, such as in-utero gene therapy, have been criticised on the grounds that they run an increased risk of inadvertently causing germ-line changes with unpredictable and potentially hazardous consequences. Perhaps in the future, deliberate germ-line modification at this stage might be considered the best way to realise the benefits of early therapy while controlling for the risks.

But what about Anne McLaren's more practical objection?—that 'the simpler and safer technique of preimplantation genetic diagnosis, already in clinical use, renders germline gene therapy for genetic disease virtually pointless.' Her view is that, this being the case, interest in germ-line modification must be about something other than extending somatic therapies for disease. She went on 'or is it germline engineering for enhancement towards which he wishes to proceed unhindered? If it is the latter, he should say so. How about it Jim?'

We have already outlined why we believe that there are some specific reasons to keep an open mind on germ-line therapy for the treatment of disease. And conceptually, as well as practically, it is possible to maintain a distinction between therapy and enhancement. But Anne McLaren is also surely right that a lot of the interest in the field is due to the possibility of enhancement at some point in the future. Leaving aside the thorny issue of character and behavioural traits outlined in French Anderson's fourth category, gene therapy, including germ-line gene therapy, as a tool to enhance resistance to acquired diseases, including the cancers, is a distinct possibility. In GIG's view, research relating to these matters should be allowed. It should then be left up to future generations to decide whether such options amount to an extension of the humanist goals of medicine or a eugenic policy of social control, and accordingly whether they should be used.


Smith, A. E. (1999), 'Gene therapy—where are we?, Supplement to the Lancet: Molecular medicine, 354: SI1. http://www.wiley.co.uk/genetherapy/clinical/diseases.phpl.

Cited in Marshall, E. (1995), 'Gene Therapy's Growing Pains', Science, 269: 1050-1055.

Nabel, E. G. (1999), 'The Development of Human Gene Therapy', Nature Medicine, 5 (7): 728.

House of Commons Science and Technology Committee, Third Report: Human Genetics: The Science and its Consequences, 1, London, HMSO, 1995: xlvi.

De Wachter, M. A. M. (1993), 'Ethical Aspects of Human Germ-Line Gene Therapy', Bioethics, 7 (2/3): 166-177.

Wivel, N. A. and Walters, L. (1993), 'Germ-Line Gene Modification and Disease Prevention: Some Medical and Ethical Perspectives', Science, 262: 533-538.

McLaren, A. (1998), 'Problems of germline therapy', Nature, 392: 645.

Billings, P. R., Hubbard, R., and Newman, S. A. (1999), 'Human germline gene modification: a dissent', The Lancet, 353: 1873-1874.
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