Gene Therapy Studies Show First Successes

Within the third international conference of the "Euregenethy" held at the Paul-Ehrlich-Institut in Langen near Frankfurt on Thursday, 15th April, and Friday, 16th April 2004, international experts reported on success and side effects of clinical gene therapy. Euregenethy, coordinated by Odile Cohen-Haguenauer from the "Ecole Normale Supérieure de Chachan"near Paris, is a network of scientists and medical experts aiming at the international standardisation of gene therapy regulations and encouraging discussions on ethical issues of gene therapy. Euregenthy is supported by the Eurpean Commission (DG-Board). With its conferences, "Euregenethy" offers to scientists from academic institutions, regulatory authorities and industry as well as members of ethics committees opportunities for joint discussions at regular intervals.

Following a few setbacks, first successful treatments have been reported from clinical gene therapy studies. As an example, Alessandro Auiti from the San Raffaele Telethon Institute for Gene Therapy in Milano, Italy, reported that in patients suffering from the congenital immunodeficiency disease ADA-SCID (adenosine deaminase (ADA)-deficient severe combined immunodeficiency disease (SCID)) a largely normal immune system has been restored by using genetically modified blood stem cells. In some cases restoration lasted over a period of several years. Using so-called retroviral vectors, a functional gene is transferred into stem cells from the patient's bone marrow as a replacement for the defective gene. The modified blood stem cells differentiate within the patient's body into normal blood cells thus improving immune functions.

"It is foreseeable that gene therapy will offer improved or novel therapies", commented Klaus Cichutek, Vice President of the Paul-Ehrlich-Institut at the end of the conference. "However, with increasing efficacy, we are also facing side effects. We have to learn how to balance these risks against the benefits for the patients and how to manage such risks", said Cichutek. "To minimise risks as much as possible, a benefit/risk analysis was required in all cases, based on the exact knowledge of the individual gene therapy approach", Cichutek said. An example for this was the successful treatment of the life-threatening immune deficiency disease SCID-X1. With this method, two out of ten successfully treated patients had developed leukaemia as an adverse reaction. The patients have received appropriate treatment and are alive. According to current knowledge, however, the overall risk of this gene therapy is still lower than that of the available conventional therapy.

The leukaemia cases which occurred in Paris during SCID-X1 gene therapy were observed only in this special type of gene therapy. They were previously known only as a theoretical adverse reaction of retroviral vector use. Christof von Kalle at the University of Freiburg, Germany, is testing a special method for the early diagnosis of this adverse reaction. "Adverse reactions must be communicated rapidly at an international level and must be evaluated by the scientific community of experts familiar with gene therapy", demands Odile Cohen-Haguenauer. According to Euregenethy, the principal investigator of the SCID-X1 gene therapy study in Paris,Alain Fischer, had shown an excellent conduct when communicating internationally the clinical hold of his study and the subsequent investigations of the causes of the leukaemias observed.

Other highlights of the conference included reports on the clinical development of the gene therapy of rheumatoid arthritis by Barrie Carter, Targeted Genetics Corporation, Seattle, and reports by other scientists on gene therapy of cardio-vascular disease and cancer as well as first trials of preventive vectored vaccines. Another subject of discussion was the experience gained from the use of HIV-derived replication-incompetent gene transfer vectors. Inder Verma from The Salk Institute, La Jolla, CA, reported on further development of lentiviral vectors. These vectors are replication-incompetent particles derived from the Human Immunodeficiency Virus or other related lentiviruses. The first study, reported by Boro Dropulic, VirXsys, during the conference is currently underway in the USA using lentiviral vectors transferring HIV-inhibitory genes for the treatment of HIV-infected patients. The fist three patients could be treated without showing any adverse reactions. Lentiviral vectors are expected to improve gene transfer efficiency, thus improving ways of treating other severe diseases, e.g. cancer. Here, e.g. so-called tumour suppressor genes could be used which suppress the replication of malignant cells. Inder Verma's arguments at the conference were that such vectors would bring about tremendous progress since they could also be used to modify resting cells which occur frequently in the body.

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