Office of Technology Assessment at the German Bundestag

Joachim-J. Schmitt • Leonhard Hennen • Thomas Petermann

The status and prospects for scientific and medical solutions in developing gene therapy techniques

TAB report no. 025. Berlin 1994, 93 pages

Summary

No development of new forms of therapy is presently attracting greater hope of at last finding therapies for the most serious and agonising human diseases than gene therapy techniques. In gene therapy, genes are introduced into the patient's body. These can block malfunctioning of the patient's genes, replace them or supplement them by functional genetic products (therapy of genes). Gene therapy can also be used to combat symptoms by transferring the production of a therapeutically active substance to the patient's body (therapy with genes). Originally, attempts were made to use gene therapy techniques to cure inherited diseases caused by malfunction of a single gene (e.g. the inherited adenosin-desaminase defect, or ADA defect). Now, however, gene therapy trials are in process for complicated and widespread diseases such as cancer and AIDS. There is even discussion of gene therapy treatment of diseases which have not yet occurred but for which a genetic disposition can be identified. The treatment of genetic disposition is regarded by some researchers as the true field of application of gene therapy in the future.

In contrast to the gene therapy transformation of body cells (soma cells) described above which are not passed on to the patient's descendants, changes in human reproductive cells (germ track cells) would be inherited. As germ track therapies for humans (besides the ethical problems in experimenting with human embryos) open the door to human breeding and to attempts to improve the gene pool of entire populations (eugenics), germ track gene therapy in Germany was prohibited by the 1990 Embryo Protection Act. This decision was based on the results of the work of a series of commissions which had been looking at the possible impact of gene therapy and the need for statutory regulation since 1983. In contrast to the prohibition on development and use of germ track gene therapy, they saw no need for the most part for special statutory regulation of the development of gene therapy for somatic cells. They argued that the restriction of the therapy to the individual being treated meant that somatic gene therapy did not involve any new ethical problems. Somatic gene therapy could, in their view, be regarded as an extension of existing therapeutic options. Accordingly, the generally accepted principles and regulations for therapeutic trials were to be applied. Meanwhile, however, a debate has emerged over the need for specific statutory regulation for somatic gene therapy as well. As responsibility for the relevant statutory regulation in Germany is a matter for the Länder, the German Upper House - the Bundesrat - suggested in October 1992 a review of the adequacy of existing statutory regulations for covering gene therapy. To consider this issue the German Federal Government set up an inter-ministerial joint Federal-Länder Working Party under the aegis of the Federal Ministry of Health.

One decisive factor for the need for further statutory regulation is an assessment of the risks which could arise to patients and other humans from gene therapy and the techniques for transferring the therapeutically active genes to the cells and bodies of the patients. These questions are the focus of the present report. Ethical aspects and the debate over long-term possible social consequences of widespread use of gene therapy (e.g. changes in the cultural view of "disease") are only touched on.

Risks to the patients arise primarily from the fact that the transfer of genes to date has been relatively diffuse, and regulation of the genes in the patient's body is currently virtually impossible to influence. As current methods cannot ensure that the genes are not introduced into body tissue and cells where they are not meant to go (e.g. in the patient's reproductive cells) and do damage there, some scientists feel that is impossible to support the transfer of genes directly to the patient's body (in vivo) in the current state of science and technology. Some doctors avoid the problem by removing cells from the patient's body, inserting the new genes into these cells outside the patient's body (gene therapy ex vivo or in vitro) and then returning the cells to the patient. As this technique limits gene transfer to the target cells, and the cells can be examined before they are returned, this method is regarded as safer than gene therapy in vivo. Irrespective of in vivo and ex vivo methods, the problem remains that it is not possible with current methods to determine the exact site where the new gene is inserted in the cell's genetic material. The undirected integration of new genes can disrupt the structure of important genes in the cell and/or disrupt their regulation. In extreme cases the possibility cannot be excluded that genes will be "switched on" or substances overproduced which result in transforming cells into malignant cells.

If the gene taxis (vectors) used to insert the therapeutically effective genes into the patient's cells are derived from viruses, dangers to other human beings in the patient's environment might occur. It is true that viruses for use as vectors are genetically modified so that they cannot replicate. However, viruses have the capability to recombine DNA fragments, modify themselves continuously through mutation and adapt to new situations. It is accordingly feared that recombined viruses can spread and cause diseases in humans. The likelihood of such recombination and dissemination is a matter of dispute among experts. Some believe that science has now managed, through great effort, to destroy irreparably the ability of viruses used as vectors (specifically the much-used retroviruses) to replicate and recombine, so that the risk of transmission of a new virus by the patient undergoing gene therapy can be ruled out or at worst should be seen as extremely improbable. Other experts assume that growing use and dissemination of gene therapy will increase the likelihood that viruses will overcome the induced blocks to replication and recombination. The use of retrovirus fragments is regarded as particularly problematic here, as the human retroviruses include the pathogens causing some forms of cancer and AIDS. These experts argue that viral (and particularly retroviral) vectors should not be used, but replaced by other techniques of gene transfer (there are now many under development).

Risk-benefit analysis for gene therapy techniques is difficult, as the general efficacy of gene therapy has yet to be demonstrated. Despite over one hundred trials, there are still very few examples of positive effects of gene therapy. Improvements in the quality of life have been achieved in children with adenosin-desaminase deficiency, and one individual with hereditary hypercholesteremia. In some cancer patients treated with gene therapy the growth of metastases has been stopped or tumour size reduced. As no genuine cure of a disease has been achieved to date, it is still not possible to assess which gene therapy techniques are the most promising, and which can be dropped.

Based on the current assessment of hazards and risks of gene therapy techniques, four positions could be identified in Germany in 1994 on how future development of gene therapy should be moulded.

One group prefer the use of retroviral vectors, as gene transfer with these gene taxis offers the greatest prospect of success for rapid further development of gene therapy techniques. Unexpected side effects of the use of these vectors are regarded as unlikely.

A second group of scientists reject the use of viral and retroviral vectors in their initial clinical gene therapy trials. They are experimenting with nonviral methods of gene transfer in an attempt to avoid safety problems with the use of viruses.

A third group calls for efforts to influence effectively the regulation of the new gene in the patient's body before using gene therapy techniques in vivo. They also call for prior solution of the problems of limiting the insertion of genes to predetermined cells (tissue specificity) and specific insertion of the new genes at predetermined sites on the patient cell genetic material (the problem of insertion mutagenesis). Currently, they feel that, at most, ex vivo gene therapy trials can be supported.

The fourth group flatly rejects the use of viral and specifically retroviral vectors for safety reasons. They also argue (not least for reasons of social dangers) that development of gene therapy techniques should be permitted (if at all) only for a few diseases for which no alternative therapies are available.