Gene Therapy

Advisory report | 04-06-1997

Recent decades have seen an impressive increase in knowledge and insight in the field of molecular biology. Research in this area is centered around molecular genetics: the study of the structure and function of genetic material. This discipline offers many possibilities for practical application and gene therapy is one of these.
 This report is primarily concerned with somatic gene therapy, which can be defined as the introduction of specific alterations in the genetic material of human body cells for the purposes of medical treatment, diagnosis or disease prevention. The issue of germ-line gene therapy is also addressed by the Committee but only in general terms. From a technical viewpoint, the two are comparable but there is one essential difference: genetic alterations in somatic cells are limited to the individual undergoing the intervention, whereas genetic alterations in germ-line cells are transmitted to offspring. Throughout this report, the term ‘gene therapy’ without any further specification is used to refer to somatic gene therapy.

Background and prospects

Many diseases can ultimately be traced back to cells which do not function appropriately at molecular level. It is theoretically possible to develop gene therapy for use in combatting a wide range of illnesses.
 The genetic alterations being pursued in gene therapy are referred to within the profession as genetic modifications and comprise the addition of genetic material to cells or alterations in the cells’ genetic material. In carrying out this process, known as gene transfer, use is made of vectors, which can be regarded as a means of transporting genetic material to cells. The term gene delivery system is used to refer to the combination of the vector and the gene(s) to be transferred.
 Viruses have a number of inherent properties which make them suitable for use as vectors. Characteristically they replicate within host cells. Viral gene transfer systems consist of genetically altered non-replicating or replication-deficient viruses to which the genes to be transferred are added. Non-viral methods of gene transfer also exist and these include the use of artificial membranes called liposomes, which spontaneously enclose DNA and surrender their contents to the cytoplasm of the cell.
 Depending on the route of administration, a distinction can be made between two methods of gene therapy. In vivo gene therapy means that the gene delivery system is introduced directly to the cells within an individual patient. In this method, it is important that the desired effect is only brought about in the target cells and that other cells remain unaffected. In the case of ex vivo treatment, selected cells are removed from the patient’s body and genetically modified in a laboratory and then reintroduced into the patient. Stem cells from bone marrow or blood are especially well-suited to this technique.

The current state of knowledge

Throughout the world, approximately 250 gene therapy clinical trials are being planned or are currently under way. About 150 of these trials are carried out in the United States and over 50 in Europe. More than 70 per cent are focused on cancer, while just under 10 per cent are AIDS-related. In addition to these areas, gene therapy is also being tested in relation to a host of other diseases, including hereditary disorders, cardiovascular diseases, neurological disorders and rheumatism. At the end of 1996, over 2,000 patients had been involved in gene therapy trials; in the Netherlands, this amounted 96 patients in 5 centres by 1 April 1997 (annex D).
 To date, no human disease has been cured by gene therapy, but a branch of research that is still in its infancy can hardly be expected to provide cures, particularly when its primary purpose is to establish the feasibility and safety of gene therapy. The effectiveness of this therapeutic strategy is, of course, also under examination, but the organization and scope of the studies do not permit definitive conclusions with regard to efficacy. The (provisional) findings of a few studies are now available. These include both promising and disappointing results, which can be summarized as follows.
 The feasibility of gene transfer in humans has been established. While it is true that no therapeutic effects have been observed, measurable biological responses have been recorded which could prove to be of therapeutic relevance. In addition to these findings, use of gene therapy as a marking instrument provides the opportunity to track the fate of genetically marked cells in vivo. The results of these studies have important implications for bone marrow transplants in leukaemia patients. The side effects of gene therapy are few. In some cases, however, viral vectors can evoke immune responses in the recipient and this phenomenon deserves serious attention. Optimal reproducibility and efficiency in gene transfer and gene expression have not yet been achieved and difficulties remain with regard to the efficient production of vectors and gene delivery systems on a large scale. In the studies carried out so far, the undesirable spread of viral vectors has not yet been observed.
 The Committee notes that, while the concept of somatic gene therapy has gained recognition in the medical world within a short period of time, there are still a number of obstacles to be negotiated before gene therapy becomes a reality. To that end further development of animal models of disease is indispensible.
 In itself, the ethical acceptability of somatic gene therapy is not at issue. Interest of the general public in this subject is considerable, however, and the Committee stresses the importance of prudence, openness and realism in reporting the advances made in gene therapy research.
 Vast amounts of money are involved in the development of gene therapy. Without investment from industry difficulties are anticipated in establishing gene therapy as a therapeutic strategy. A negative aspect of industrial involvement is that economic considerations determine the direction of research. It is already clear that research focusing on cancer and cardiovascular diseases is more attractive than studies focused on rare hereditary disorders. If these matters are left exclusively to market forces, it is doubtful whether patients with rare disorders will benefit from gene therapy.

Legislation

Experience in this relatively new field of medicine is still extremely limited and gene therapy is presently at a stage that it cannot be excluded that genetic modification produces unpredictable negative effects. The public has to feel confident that measures have been taken to ensure the safety of experiments and that patients taking part in such experiments enjoy sufficient legal protection. The Committee has conducted a review of the wide range of legislation relevant to gene therapy research. Most aspects of gene therapy research are covered in one way or another, either by proposed legislation or by laws which are already in force. However, the results to emerge from the Committee’s analysis do not present the simplest and most transparent of pictures. The Committee has also observed occasional gaps in legislation which are not specific to gene therapy but which apply to the medical application of cells, tissues and biologicals.
 The Committee recognizes the need for a separate review of the biosafety on one hand and the medical-ethical and legal aspects on the other. National evaluation of gene therapy protocols is currently taking place under the auspices of two ministries: the Ministry of Housing, Spatial Planning and the Environment and the Ministry of Health, Welfare and Sport. There is a danger that by operating independently, the ministries will compromise the efficiency of their activities and that communication problems will arise between government bodies and researchers. The Committee makes a number of recommendations aimed at overcoming these obstacles.

Recommendations

With regard to scientific research, the Committee recommends:

◾- increasing emphasis on research dealing with:
◾- the basic principles of gene transfer and gene expression
 - the mechanisms of disease pathogenesis
 - the development of effective animal models of disease

- conducting a feasibility study in the short term to set up an accessible national or European central facility for the production, quality control and possibly also the development of clinical grade materials for gene therapy research. The Committee advocates involving the Ministry of Health, Welfare and Sport, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science and the Ministry of Housing, Spatial Planning and the Environment in this process.
 The Committee issues the following advice at clinical researchers in particular:
 - adherence to high standards of excellence in clinical protocols
 - working practices based exclusively on the principles of Good Clinical Practice (GCP), Good Laboratory Practice (GLP) and Good Manufacturing Practice (GMP)
 - contractually established responsibilities and liabilities for each step of the research process
 - timely consultation with insurance experts for the purpose of securing the necessary insurance arrangements
 - optimal protocol and documentation for each step of the research
 - extensive follow-up studies of patients treated.

With regard to the use of genetically modified organisms (GMOs) the Committee recommends:

◾- the swift preparation of specific laws governing human gene modification, such as to avoid overlap with other legislation, including the Bill on Medical Research with Human Beings
 - requesting the Working Group for the Prevention of Infection to draw up national protocols for treatment and care of gene therapy patients, with the aim of preventing the unwanted distribution of GMOs via hospitals.

With regard to the safety of products and procedures the Committee recommends:

◾- supporting initiatives for the introduction of a new category of ‘products’ containing material of human, animal or viral origin and which could be called biological products for medical use or simply referred to as biologicals
 - stimulating the development of specific quality standards for biologicals
 - working, in the long term, towards a single quality system, based on the principles of GLP and GMP, for the donation, treatment and transplantation of cells, blood, organs and tissues of human or animal origin (xenotransplantation), regardless of whether the transplants involved are autologous, allogenic or xenogenic.
 In the period prior to the realization of such measures, the Committee recommends:
 - the (provisional) expansion of the Medicines Act by the addition of a decree on biologicals
 - demanding that quality assurance systems based on the principles of GLP and GMP are applied to the genetic modification of cells to be administered to humans within the framework of ex vivo gene therapy
 - designating selected individuals, the most likely candidates being hospital pharmacists, with the authority to issue modified cell preparations for administration to humans; these individuals should be fully informed of their duties and responsibilities in respect of gene therapy.

With regard to the development of treatments for patients suffering from rare diseases, the Committee considers it desirable:

◾- to advocate the realization of European legislation on orphan drugs and to make resources available for the development of such medicines.

With regard to the central evaluation of gene therapy protocols within the framework of the Bill on Medical Research with Human Beings, the Committee argues for the following in the interests of an efficacious and clear policy:

◾- the establishment of a clear and unambiguous relationship between the Central Committee on medical ethics and the local ethical committees
 - learning from the experiences of institutions in other parts of the world, especially the Gene Therapy Advisory Committee in the United Kingdom
 - emphasizing the technological and scientific evaluation of usefulness and feasibility and the related issue of estimating the extent and the nature of the risks for individual patients
 - involving experts from the field of gene therapy in the technological and scientific evaluation, where necessary from outside the Netherlands
 - incorporating periods of evaluation in the relevant Order in Council of the Bill on Medical Research with Human Beings to establish at an early stage when and for which categories central evaluation is no longer needed.

With regard to coordination and communication between government bodies and the field itself, the Committee considers it vital that:

◾- the example of the Gene Therapy Advisory Committee is followed in coordinating national evaluation via a single, clearly identified point of contact located at the Ministry of Health, Welfare and Sport
 - the policy lines and the current regulations relating to human gene therapy research are set out in a brochure for the information of those working in this field and for the improvement of coordination within and between the ministries involved.

With regard to the institutions in which gene therapy research on human subjects is permitted, the Committee recommends:

◾- refraining from general licensing for gene therapy
 - linking licenses to specific protocols
 - determining per protocol whether the applicant institution possesses the required expertise and infrastructure for the protocol in question.

Finally, with regard to developments which call for government scrutiny in the future, the Committee mentions:

◾- germ-line gene therapy in connection with research on human embryos: a Health Council report on this subject seems advisable
 - foetal gene therapy: development of ideas on its ethical acceptability and on determining the limits of acceptability prior to the development of relevant protocols.