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Bioethic information and analysis newsletter

Following Letter

N°34 - October 2002

Interrupted tests : What future for genic therapy ? 

On 4th October, the press announced that the genic therapy testing being performed in France on "balloon children" suffering from severe immunity deficiency has been suspended. Does this mean therefore, that genic therapy has no future ?

How does it work ?
For more than ten years now, a great deal of hope has been put in genic therapy. Its principle is simple in theory : for diseases associated with a modified gene for example, the idea is to replace a modified gene with a normal gene, if its sequence and method of regulation, which are sometimes very complex, are known. One could also envisage the introduction of genes producing substances which are toxic for cancerous cells, or which trigger an apoptosis programme (self-destruction). 

The difficulties encountered
Various technical problems then appeared which made the use of this therapy difficult or even impossible in certain diseases. The first condition, already mentioned, is a knowledge of the gene and its means of regulation ; if this is too complex, or too specific, there is some risk of not being able to sufficiently control the expression of the gene introduced. The accessibility of the target cells is also involved in the technical feasibility : with blood cells, for example, access is easy, since one can simply extract hæmatopoietic stem cells from bone marrow to « cure » them, and then re-inject them back into the patient (ex vivo tests). With muscular pathologies, or other cells which cannot be cultivated, a carrier must be found to transport the gene to the right place (in vivo tests). The recombining adenovirus can be used : by removing certain parts from its sequence (thus preventing it from producing a new virus), to insert the normal gene, or at least the parts which are absolutely vital for the operation of the gene, in the right place : this is the case for dystrophine, which is a very large gene, which must be « shrunk » in order to allow it to « enter » into the virus. Another difficulty concerns the duration of the expression of the gene, once it is inserted in the right cells : even in cells which do not divide, such as hepatocytes, the expression of the gene decays over a period of time. Finally, if the carrier is a retrovirus, it may, by inserting itself at random in the genome, modify a gene or « awaken » a cell multiplication gene ; this is what appears to have happened, with the test which so far was proving very positive, of genic therapy for balloon babies suffering from a severe combined immune deficiency linked to the X (SCID-X) ; this risk was considered as theoretical, but which may have occurred in the child exhibiting a proliferation of white blood cells. However, it remains to be proved that this is in fact the mechanism operating, and that it is not some other phenomenon. The genic therapy tests which were suspended in the USA following this announcement, have since resumed.

The results
The technical problems mentioned above explain the low success rate, despite the large number of tests in progress : since 1989, more than 500 tests have been launched : 2/3 for cancers, 14% for hereditary diseases and 9% for infectious diseases. The technical difficulties encountered, such as certain serious undesirable effects, have dampened the initial enthusiasm. However, even if genic therapy is not the panacea hoped for, it certainly remains a therapeutic route worth pursuing, at least for certain specific diseases, in view of the technical criteria mentioned. Moreover, it can also be used in conjunction with other techniques such as cellular therapy, for example in the treatment of hereditary skin diseases.
(cf. : February 2001).

Research on the human embryo : debates at the European Parliament ! 

2002-2006 Programme
Last April, the European Parliament adopted the 6th Master Research and Development Programme (VI° PCRD), for the period 2002-2006 and for a sum of 17.5 million euros, representing the third largest budget in the European Union.
After a debate by the Industry and Research committee, and the vote for the first and second readings at the plenary session, the exchanges were extremely lively on the part dealing with « Biotechnology and the Science of Life ». Supporters of research on the human embryo refused to reopen the debate which took place during the human genetics temporary committee on the « economic, legal and ethical stakes of modern medicine », for the whole of 2001. That committee had adopted a perfectly clear resolution by refusing to fund research on human embryos, and therapeutic or reproductive cloning and had thus reaffirmed the constant position of the European Institutions regarding respect for human dignity and life. However, in the plenary session, the resolution, which was made incomprehensible and contradictory by the effect of amendments, was finally rejected, in the absence of any majority one way or the other, which is a clear indication that no compromise is possible on such a sensitive subject.
In April, therefore, the VI° PCRD was adopted under a joint decision procedure between the Council (Heads of State and of Governments) and the European Parliament. The specific programmes (such as biotechnology and science of life) have been adopted by the Council by qualified majority.

Against funding 
The Danish Presidency, (Denmark is presiding over the European Union from 1st July till 31st December 2002) on the initiative of an ex-European MP, Rocco Butiglione, who is currently the Italian Minister of Foreign Affairs, and according to the procedure, proposed on 30th July to freeze all research funding for research on human embryos. This compromise was sought after observing that the opinion of our societies is not yet ready to accept, for ethical reasons, research on human embryos (still considered in the debates as human beings). This proposal was supported by Austria, Portugal, Ireland and Italy, Germany abstaining.

For funding
But before the final adoption of specific programmes, which is the last stage before releasing European funds for Research, several meetings took place between the Reporter, the French Gérard Caudron, the European committee and the Council of Research Ministers, in search of a common position regarding respect for human dignity, a rather vague term which may open the door to the use of human embryos for treating incurable diseases. The French Reporter and a few MPs in the Industrial Committee declared that this common position should be considered as an agreement justifying funding of embryonic research and motivating their refusal to support the Danish Minister's compromise.

What about the procedure ?
During a press conference on 26th September, another group of MPs supportive of respect for human beings, at whatever stage of development : the German Hiltrud Breyer, Irish Dana Scallon, French Elizabeth Montfort, Italian Mario Mauro and Portuguese José Ribeiro e Castro, challenged the legitimacy of the « agreement » concluded between the French Reporter and a few MPs in the Industrial Committee for the reason that the specific programmes are subject to decision by the Council, and not to joint decision with the European Parliament, and that the procedure had therefore not been followed. They additionally stated that this procedural battle was hiding a more fundamental question « Can human beings be considered as material to be used for treating other human beings suffering from incurable diseases ? »

Research on the human embryo : the decision of the European Council 

It is in the context of this controversy, that the European Council of Research Ministers adopted on 30th September last, their final decision which stipulates in article 3, Application of ethic principles :
« The Council and the Committee are agreed that the arrangements concerning research activities involving the use of human embryos and human embryonic stem cells which may be funded under the 6th Master Programme will be defined by 31st December 2003. The Committee declares that, in the interim and pending the definition of the specific application measures, it will not propose funding such research activities, apart from the study of human embryonic stem cells stored in banks or isolated during culture. The Committee will monitor progress and the needs of science...taking into account the advice of the European Ethics Group and the European Group of Counsellors for the Ethics of Biotechnology » (Document issued by the European Union Council. 12374/02 ADD1)

A report is to be presented to the European Parliament for comment during the first semester of 2003.
One is astounded by the content of such a decision : it is not research on the embryos which is in question, since it is possible to fund studies on embryonic stem cells which are already available, but the means of making this accepted by the opinion of our societies. This is a far cry from the common position adopted by the Committee on 28th January 2002. One should add that France, as represented by the Minister for European Affairs, Noëlle Lenoir, ex-President of the European Ethics Group, well-known for her support for this type of research, rejected the Danish compromise despite its being in accordance with the French legislation applicable today : since the revision to the bioethical laws is not yet complete, it is the 1994 law which applies, which does not authorise any research on human embryos.
Moreover, according to this decision, certain member States (France, Portugal, Ireland, Austria, Germany, Italy and Spain) will have to fund research on the available embryonic stem cells, through their contribution to the community budget, whereas they prohibit such research on their own territory…