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by Faiz Kermani in August, 2003
Gene therapy is considered to be one of the most exciting areas of medicine for the future. As it aims to correct the underlying genetic defects in human disease rather than just focusing on symptoms there is the potential for an actual cure. Following the completion of the draft of the human genome, there was considerable media coverage of gene therapy, but various safety concerns and technical problems have shown that many hurdles remain in this area.
Unfortunately, only slow progress was made over the next ten years, even though more than 400 clinical trials to test gene therapy for a range of different diseases were launched around the world (2). This caused considerable disappointment amongst patients suffering from the serious disease being investigated.
At present, the transfection vectors employed involve viral and non-viral mechanisms. Viral transfection vectors are considered more efficient than non-viral options, but because of their origins there are serious immunogenic concerns associated with their use (3). Although non-viral methods have been developed, such as liposomes, "targetibility" still remains a problem. For example, non-specific electrostatic interactions with cellular components can interfere with the delivery of therapeutic genes by these systems (3).
Another setback for gene therapy occurred in 2002 when it was reported that a child being treated in France for x-Severe Combined Immunodeficiency syndrome (x-SCID) showed signs of having developed leukaemia after undergoing treatment (6). This was extremely disappointing as initial work by the French group had been promising and earlier that year, a child in the UK had successfully been treated for the same condition using gene therapy (6, 7).
Pending further discussions, the authorities in France decided to halt the trials in this area as did officials in the US, where three similar trials were being carried out (6). Interestingly, advisors to the UK government decided against halting similar trials although they promised to closely monitor treatments (6).
In the US, gene therapy trials are regulated by the NIH and the FDA. The NIH has a special committee, the Recombinant DNA Advisory Committee (RAC), which focuses on this area of research (1). No trial can progress without full approval and sign off from these authorities. The FDA has made a considerable effort to reassure the public and healthcare professionals over safety concerns. For example, in March 2000, it launched random inspections of 70 clinical trials in more than two dozen gene therapy programs (2).
In the UK, the need for tight regulations has long been recognised and is managed through the Gene Therapy Advisory Committee (GTAC). In 1999, when the first death during a gene therapy trial occurred in the US, the GTAC had already been involved in a review of the serious adverse events and issues related to the monitoring of patients involved in gene therapy research (8). In 2000, more than 50% of European gene therapy clinical trials were taking place in the UK (9).
In 2001, the International Conference for Harmonisation (ICH) met in Japan to discuss issues affecting drug development in the US, Europe and Japan (10). At a Satellite Meeting on Biotechnological and Gene Therapy Products, the need to harmonise the scientific regulations for gene therapy in the three regions was officially recognised (10). The exchange of information was to be encouraged and further meetings focused on this area were planned. Although there is a long-term commitment to harmonise regulations in this areas, no such system yet exists for the three regions.
Despite this favourable situation, the Japanese authorities and the public have been as concerned as their international counterparts about the recent trial setbacks. Following the French case, the Japanese authorities placed all gene therapy trials on hold.
In March 2002, the Ministry of Health, Labor and Welfare (MHLW) and the Ministry of Education, Culture, Sports, Science and Technology strengthened the guidelines concerning gene therapy in Japan through the issuing of new regulations (12). For example, as part of the revisions, written consent of test subjects rather than oral consent would be required for such trials (12). Previously, it was possible in certain situations for oral consent to be acceptable (12).
Recently, the prospects for the resumption of gene therapy trials in Japan have brightened. In September 2002, Shinshu University submitted a gene therapy proposal to the MHLW's Health Sciences Council (13). The proposed three-year trial involves the injection of the beta interferon gene into the foci of malignant melanoma, in five patients (13).
One of the most active companies in gene therapy in Japan is AnGes. The company is currently involved in developing a product containing the gene coding for hepatocyte growth factor (HGF). Between 2001 and 2002, the company signed a deal with Daiichi Pharmaceutical company to distribute the HGF gene product in Japan, the USA and Europe. Clinical studies are underway in the USA and planned in Japan and Europe.
Mitsubishi Chemical Corporation has also become involved in gene therapy through the setting up an industry-academic collaboration with a spin out company from Imperial College, London. Called IC-Vec Ltd, the joint-venture company will focus on non-viral gene therapy.
As the UK's GTAC points out in its recent Ninth annual report, "the success achieved by the French Group in treating infants with X-SCID with gene therapy must not be overlooked. However, such trials must proceed with caution. Only by doing so can we ensure that gene therapy can make the difficult transition from being a laboratory experiment to being a clinical reality" (14).
This article is a contributed to BioJapan by Faiz Kermani, Ph.D. (Faiz.Kermani@chiltern.com) of Chiltern International, on August 18th, 2003.
Copyright remains with the author. For questions and comments, please do not hesitate contact him directly. |
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