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Gene Therapy: Medicine of the Future?

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.

Initial success

In general, the US has been at the forefront of efforts to develop this form of disease treatment. In 1990, the first successful human gene therapy was carried out at the National Institutes of Health (NIH) in the US (1). A young patient was treated for adenosine deaminase (ADA) deficiency, a genetic condition that results in a immune deficiency disorder called severe combined immunodeficiency disease, which leaves patients prone to repeated serious infections.

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.

Technical and safety problems

A large part of the problem has been in determining how to deliver sufficient quantities of therapeutic genes in a safe manner. As systemic and biological barriers tend to interfere with the delivery of therapeutic genes, researchers have had to employ transfection vectors in order to deliver the genetic material into cells (3).

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).


In 1999, there was a major setback to international gene therapy research when an 18-year old participant in a US trial died (4). The US Food and Drug Administration (FDA) acted swiftly and suspended all gene therapy clinical trials at the centre (5). The authorities recommended numerous changes in order to increase the safety of using adenovirus vectors (4). This situation also shifted the emphasis of many gene therapy researchers to non-viral vectors.

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).

Stricter regulation

The continuing worry over safety issues has led to a necessary tightening of the regulations surrounding gene therapy trials around the world.

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.

Gene therapy in Japan

There is a considerable amount of genetic research occurring in Japan and in general, public acceptance for the concept of gene therapy is considered positive. This was highlighted in a survey carried out by the Institute of Biological Sciences, at the University of Tsukuba, which examined public attitudes internationally to gene therapy (11). Respondents were asked about whether they would consider gene therapy as an option for personal treatment and for the treatment of their children (11). In Japan, between 1991 and 1993, support for gene therapy as an option at a personal level increased from 53% to 66%. Over the same period those willing to consider gene therapy as a treatment option for children increased from 66% to 74%. However, respondents only favoured gene therapy in cases where it was to save life or increase quality of life (11).

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.


The recent setbacks in gene therapy have tended dampen media coverage of work in this area. Yet it is worth pointing out that although the rate might be slower than initially expected progress is being made. Furthermore, many academic groups and biotech and pharmaceutical companies are active in this area.

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).


  1. Gene Therapy Basics. American Society of Gene Therapy. http://www.asgt.org/
  2. Thompson L. (2000). Human Gene Therapy Harsh Lessons, High Hopes. FDA Consumer magazine September-October 2000. http://www.fda.gov/fdac/features/2000/500_gene.html
  3. Chaudhuri A. (2003). Cationic Liposomes - Promising gene carriers in non-viral gene therapy. http://www.wmrc.com/businessbriefing/pdf/pharmatech_2003
  4. Hollon T. (2000). Researchers and regulators reflect on first gene therapy death. Nature Medicine. Volume 6 Number 1 p 6.
  5. FDA suspends trials at gene-therapy lab. CNN.com. January 22, 2000. http://www.cnn.com/2000/HEALTH/01/22/gene.therapy/
  6. Gene therapy trials halted. BBC News. 3 October, 2002. http://news.bbc.co.uk/1/hi/health/2295707.stm
  7. "Bubble boy" cured in British gene therapy first. Japan Today. September 3, 2001. http://www.japantoday.com/gidx/news209693.html
  8. Sixth Annual Report (2000). Gene Therapy Advisory Committee. Health Departments of the United Kingdom. http://www.doh.gov.uk/GENETICS/gtac/sixth.htm
  9. Seventh Annual Report (2000). Gene Therapy Advisory Committee. Health Departments of the United Kingdom. http://www.doh.gov.uk/genetics/gtac/index.htm
  10. Paving the Way for a Smooth Implementation of the Common Technical Document. May 21- 24, 2001. International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use. http://www.ich.org/pdfifpma/ICHPRtokyo2001.pdf
  11. Macer D. (1993). High Acceptance of Genetic Screening and Gene Therapy in Japan and Australasia. http://www.biol.tsukuba.ac.jp/~macer/EEIN/EEIN3O.html
  12. Revision of the "Guidelines on Clinical Research of Genetic Therapy." Japan Bioindustry Letters. Vol.18 No. 4-3
  13. Shinshu University submits gene therapy plan to MHLW. Bio Journal - November 2002. http://www5d.biglobe.ne.jp/~cbic/english/2002/
  14. Ninth Annual Report (2002). Gene Therapy Advisory Committee. Health Departments of the United Kingdom. http://www.doh.gov.uk/genetics/gtac/index.htm

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.
BioJapan.de is grateful for this timely contribution.

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