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Gene therapy medicinal products: the first gene therapy product has been approved – where does the future lie?

Is gene therapy close to broad clinical application? Following negative headlines at the end of the 1990s, gene therapy had almost disappeared from the public radar to become an issue almost exclusively dealt with by research laboratories. Gene therapy has now reappeared in the public domain since the European Medicines Agency EMA gave the Dutch biotech company uniQure the go-ahead for the application of somatic gene therapy for the treatment of a very rare metabolic disorder. This is the first gene therapy product to be approved by the European Commission. Gene therapy has been practised in China since 2003, but details of the therapy methods have not been published in international journals. Are further gene therapies likely to be approved? The first gene therapy trial was carried out in the USA in 1989. Will gene therapy now achieve resounding success as many publications suggest or is it heading for a phase of consolidation?

Clinical trials over the last ten years have achieved impressive successes, in particular in children with severe inherited immunodeficiency disorders (e.g. Anlinker et al., 2012). Proof-of-concept was achieved for a number of monocausal, genetic diseases. With regard to the clinical trials carried out in Europe, in particular with paediatric patients, the BBAW report (p. 50ff) reached a positive (intermediary) result: 39 out of 42 children benefited from the treatment at least for a certain period of time; follow-up examinations of 32 patients showed that 27 children continued to benefit from the treatment after five years and some of them even after ten years. However, six of the patients treated were diagnosed with leukaemia, a further two with myelodysplastic syndrome and two died.

Scientific and medical progress in the field of gene therapy is often rather ambivalent. People are well advised to read the “Gene Therapy in Germany” report compiled by the interdisciplinary ‘Gene Technology Report’ study group of the Berlin-Brandenburg Academy of Sciences (BBAW) in order to avoid coming to hasty conclusions. The second amended edition of the report presents the state of gene therapy research in Germany and highlights the potentials as well as limitations of the method.

The experts concluded – at least for one of several areas where gene therapy can be applied: “If we manage to minimise the risk of insertional mutagenesis by developing safe and optimised vectors and gene transfer methods, we can safely assume that gene therapy will be the therapy of choice for some severe immune defects within a couple of years.” There are numerous issues that make the use of viral vectors difficult: an intact therapeutic gene that is introduced into a genome with a retroviral gene shuttle (vector) might potentially activate or switch off one or more important genes at the site of integration or in close vicinity to it and could possibly cause harmful mutations to the DNA or even cancer. Vectors used to transfer new genes into the body can enter every cell, and hence accidentally enter cells that are not affected by disease.

Vectors have to become safer

Florian Kreppel from the Division of Gene Therapy at the University of Ulm believes that the use of viral vectors shows much promise but that it is necessary to fix any potential problems and optimise the vectors used to transfer new genes. Kreppel is currently working on gene transfer vectors that are able to efficiently deliver a new gene to the target cells. 

The two gene therapy approaches, the in-vivo and the ex-vivo approaches, are associated with different problems. © Berlin-Brandenburg Academy of Sciences

The in-vivo approach (see diagram), which delivers the genetic material inside the living body, struggles with immune responses and the neutralisation of the vector particles. The ex-vivo method, which delivers genetic material outside the living body, is not specific enough, which increases the risk of insertion mutagenesis. “These problems have not yet been completely resolved,” said Kreppel. In addition, ex-vivo approaches that involve viral gene shuttles also struggle with immune responses of patients who have been in contact with the wild-type virus before.

Although non-viral vectors do not struggle with the immune response, they nevertheless have the disadvantage of an extremely low level of efficiency. For Kreppel, this is fairly evident as viruses have had millions of years to optimise their gene transfer processes. And synthetic non-viral gene shuttles have not yet been able to catch up. “It is currently impossible to achieve the efficiency of viral gene transfer with synthetic vectors,” said Florian Kreppel.

Each disease requires its own vector

Dr. Florian Kreppe – biochemist and gene therapy expert from Ulm. © Uni Ulm

uniQure’s adeno-associated vector (AAV) has the advantage that it is not pathogenic for humans. And this makes the virus relatively safe. However, Kreppel believes that the first approval does not signal a breakthrough for gene therapy; it is just one vector for one specific disease, and it cannot be transferred to other diseases and forms of treatment. Nevertheless, Kreppel regards the first approval of a gene therapy as a major success as well as evidence that gene transfer can treat diseases causally.

The Journal of Gene Medicine provides an overview over gene therapy trials worldwide (www.abedia.com/wiley/vectors.php). The list clearly shows that the approval of uniQure’s product is far from being representative but that nevertheless gene therapy is making huge progress: 166 gene therapy clinical trials were carried out between 1990 and 1995, 413 clinical trials by 2000 and as many as 1700 by 2011. By 3rd December 2012, the number of gene therapy clinical trials had reached 1843. 63.7 percent of all clinical trials have been carried out in the USA; 11 percent in Great Britain, 4.4 percent (81 trials) in Germany and 2.9 percent in France.

The distribution of indications for which gene therapy trials have been carried out gives a similar picture. The majority of clinical trials (64 percent) focus on tumour diseases, 8.7 per cent focus on monogenic diseases, 8.4 percent on cardiovascular diseases and 8 percent on infectious diseases. The majority of trials focus on the transfer of antigens (20.5), followed by cytokines (18.4 percent) and tumour suppressor genes (8.3 percent), suicide genes (8.1 percent) and lacking genes (8 percent). The online database lists 42 different vectors; adenoviruses (23 percent) are the most frequently used vectors, followed by retroviruses (20 percent), naked DNA (18 percent), cowpox (8 percent), liposome transfection (6 percent), poxviruses (5 percent) and adeno-associated viruses (5 percent).

Approval was almost a foregone conclusion

Boris Fehse was relatively sure that the first gene therapy approval was not far off. Fehse is a biomedical specialist and co-author of the BBAW report and knows the field of gene therapy inside out. He is the head of the Cell and Gene Therapy research department in the Stem Cell Transplantation Clinic at the Hamburg-Eppendorf University Hospital. He has been dealing with gene therapy issues for around 20 years and knows from experience that the regulatory authorities tend to approve orphan drugs, i.e. drugs for the treatment of rare diseases, more quickly than others. It goes without saying that orphan drug trials involve far fewer patients (in the case of uniQure’s Glybera® only 27) than trials testing the efficiency of drugs for the treatment of more common diseases.

Prof. Dr. rer. nat. Boris Fehse, gene therapy expert at the Hamburg-Eppendorf University Hospital © UKE

Fehse believes that gene therapy approaches for the treatment of rare inherited degenerative retinal disorders are also quite promising. Over the last ten years, clinical trials have shown that gene therapy approaches used to treat retinal disorders have an excellent safety profile and have produced excellent clinical data. This has also been the case with gene therapy approaches for the treatment of haemophilia. Fehse believes that gene therapies for the treatment of the aforementioned disorders will be approved within the not-too-distant future. He also foresees the approval of gene therapy products for the treatment of monogenic immune system diseases, most likely in Italy where a research institution in Milan is working with the pharma giant GlaxoSmithKline to transfer research results from the bench to bedside. According to Fehse, the field of gene therapy in Germany tends to be academic; although research on the application of oncoloytic viruses for the treatment of diseases is also carried out in Germany, the subsequent clinical studies are carried out in the USA. 

Fehse is only aware of a single phase III study currently being carried out in Germany. The trial involves vaccinia viruses and is being done by the American company Generex. Vaccinia viruses have been shown to destroy the cells of advanced tumours. This approach is highly experimental and is only used for cancer patients who do not respond to any other therapy. Fehse went on to explain that the majority of expert associations and regulatory authorities agree that highly experimental and relatively dangerous therapies such as gene therapy are ethically only acceptable for the treatment of life-threatening diseases or disorders (e.g. blindness) that considerably affect the quality of a person’s life and only when other therapeutic options (e.g. transplantation in the case of immunodeficiencies) are associated with high mortality rates.

Numerous clinical trials in the field of oncology

Around a dozen or so new gene therapy trials have recently been initiated in the USA. Fehse also expects a gene therapy treatment to be found for leukaemia, where CD19 has been shown to be an excellent target for immunotherapeutic approaches. Large European research consortia, which also involve partners from Germany, also focus on the development of gene therapy products for oncological application. Fehse believes that as far as more complex diseases such as cancer are concerned, gene therapies can broaden the existing portfolio of therapies (irradiation, chemo- and immunotherapies). The research community is very hopeful about the results of ongoing cancer genome projects (e.g. of the International Cancer Genome Consortium). Such projects improve existing knowledge on the relevance of genes for the pathogenesis of diseases and help to improve the specificity of gene therapies.

Greatest focus must be put on vectors

The fact that appropriate gene shuttles need to be found for each disease does not really accelerate the gene therapy product discovery process. Fehse explains that a non-integrating AAV vector such as the one used in uniQure’s product that is injected into muscle cells does not work for haematopoietic stem cells that divide extremely quickly. “The ideal situation would be to know that an integrating vector always integrates its therapeutic cargo, i. e. its nucleic acid, into the same site; this would be a breakthrough for heritable diseases,” said Fehse who is convinced that it is important to concentrate specifically on vectors as all vectors have their own specific safety profile which depends on a patient’s age and immune system as well as the disease itself. He is also convinced that the knowledge required to improve vectors will increase with the number of patients treated.

Gene therapy products are still extremely expensive and are usually financed with tax money and foundation funds. Around two years ago, big pharmaceutical companies were barely interested in gene therapy products. However, both Fehse and Kreppel are now observing a growing interest in industry, a particularly notable example being Novartis’ 20-million-dollar injection (New York Times, 9th December 2012) into building a research centre of the University of Pennsylvania (UP) campus to bring an experimental therapy to market. The scientists are seeking to develop and manufacture therapies to treat patients with advanced chronic lymphocytic leukaemia. In addition, it is probably no accident that the German Association of Research-based Pharmaceutical Companies expressly supports the further development and application of somatic gene therapy (position paper of November 2012); concrete figures were not disclosed.

The lead must not be lost

Boris Fehse knows all too well that Novartis’ multimillion dollar injection is just a drop in the ocean and hopes that the German Research Foundation (DFG) and the German Ministry of Education and Research (BMBF) will continue to fund gene therapy research projects. He is convinced that German gene therapy research is definitely not in a position to progress without public funding. He also believes that German researchers who deal with the development of vectors, the safety of gene transfer and the molecular analysis of genetically modified cells and who have achieved an international lead (Fehse/Domasch, p. 103f) are at major risk of being left behind if public funding is not provided.

The EU funds experimental gene therapy. Countries like Great Britain and the Netherlands seem to provide more funds than Germany for the translation of laboratory results into the clinic. In Germany, the DFG and the BMBF have announced a clinical study programme on innovative therapies in general, including gene therapy. “As current developments are progressing rapidly, it would be good if the DFG and the BMBF continue funding gene therapy research,” said Fehse.

Another interesting development is that biomedical areas are merging. Fehse has observed that in the USA and Europe previously separate gene- and cell therapy journals and associations have now joined forces.

Further reading:

Akst, J.: Targeting DNA, in: The Scientist, 1st June 2012

Anliker, B., Renner, M., Schweizer, M.: Insertionsonkogenese bei der Gentherapie monogenetischer Erbkrankheiten, in: Bulletin zur Arzneimittelsicherheit. Informationen aus BfArM und PEI, 2nd ed., June 2012.

Dolgin, E.: Gene therapies advance, but some see manufacturing challenges, in: Nature Medicine Vol. 18, No. 12, Dec. 2012

Fehse, B./Domasch, S. (Eds.): Gentherapie in Deutschland. Eine interdisziplinäre Bestandsaufnahme. Themenband der interdisziplinären Arbeitsgruppe "Gentechnologiebericht" Forum W – Wissenschaftlicher Verlag, Dornburg, 2011.

Grady, D.: In girl’s last hope, altered immune cells beat leukemia, New York Times, 9.12.2012 (https://www.gesundheitsindustrie-bw.dewww.nytimes.com/2012/12/10/health/a-breakthrough-against-leukemia-using-altered-t-cells.html?pagewanted=all)

Szentpetery, V.: Bemerkenswert erfolgreiche Gentherapie, in Technology Review, 29th Oct. 2012 (Interview with the president of the Paul-Ehrlich-Institut)

VfA (Eds.): Position paper on somatic gene therapy (as of 21st Nov. 2012)

Young, S.: Company aims to cure blindness with optogenetics, in: Technology Review, 28th Aug. 2012.

Wildermuth, V.: Niederländischer Hersteller entwickelte Medikament für Stoffwechselkrankheit, Deutschlandradio, 1st August 2012, 16.35 (www.dradio.de/dlf/sendungen/forschak/1828173)

Will the floodgates open for gene therapy? Nature Biotechnology, Editorial, V. 30., No. 9, Sept. 2012. 

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