Twenty Years of European Union Support to Gene Therapy and Gene Transfer

Nucleic acid transfer can be used to treat many different disorders, including cardiovascular, neurodegenerative, infectious or rare diseases, and cancer. Twenty-five years ago, in Europe, a group of experts founded the European Working Group on Human Gene Therapy (EWGT), whose aim was to develop and coordinate clinical and scientific research in the field of gene transfer and therapy. Later on, the dimension of cell therapy was included in the remit of the group, leading to the current European Society of Gene and Cell Therapy (ESGCT), celebrating its 25th anniversary this year. Besides its scientific programme, the ESGCT annual congress includes dedicated sessions on product commercialization, clinical trials, training nurses and practitioners, and informing patients and patients' associations. Scientific achievements and the relevance of the field have been boosted by Yamanaka's discovery of inducible pluripotent stem cells, as well as the development of gene editing techniques, including the blockbuster CRISPR/CAS9. In addition, the recent release of gene therapy advanced therapy medicinal products (ATMPs) on the European market and recent publication of successful gene therapy clinical trials for (rare) monogenic diseases and leukemias has contributed to highlight this research.

Already in 1994, the European Union (EU) supported the field of gene therapy with its Biomedical and Health research programme Biomed2 and its Biotechnology programme Biotech2 (1994–1998). In these programmes, more than 36 projects directly addressed the topic of gene transfer and/or gene therapy for various disorders, for a total amount of >€40 million. Of note, all but four investigated the development of new vectors or oligonucleotides and preclinical work. Of these four, one project dealt with the biomedical ethics issues raised by in vitro fertilization and its connection with genetic diagnosis and therapy, another focused on regulatory issues, a third was dedicated to support the creation of a European e-bank for gene therapy (consisting of a gene vector database and repository ¹ ), and one project involved a clinical trial using a suicide gene transduced in donor lymphocytes to fight leukemia and graft-versus-host disease. The later would ultimately lead to the release of Zalmoxis^® on the European market in 2016.

In this period (1994–1998), the EU also commissioned studies that analyzed the overall situation of gene transfer and gene therapy (research, development, and clinical trials) in Europe compared to the United States. ² In >50% of the protocols, the vectors used to transfer the genetic materials were derived from retroviral vectors. At the time, the obstacles to the development of clinical gene therapy were the poor specificity and efficiency of the vectors, the poor understanding of the biological interaction of these vectors with the host, the lack of relevant preclinical models, the difficulty in producing GMP-grade lots of vectors (as such facilities were rarely funded by public bodies) and the testing and distribution of such products, the lack of investments from venture capital in Europe in the field (as compared to the United States), and the variable regulatory frameworks between countries that could impair the development of multicentric international studies in Europe.

Another EU-commissioned study published in May 2000 analyzed the landscape of gene therapy exploitation and commercial development in Europe. ³ The main barriers to the exploitation of the gene therapy science base and proposed ways of strengthening European competitiveness in this area were analyzed. In addition to searches and interviews, a postal questionnaire was sent to the members of the EWGT. It was estimated then that the EWGT represented at least 50% of the main European laboratories working in the field, representing 216 research groups, mainly from France, the United Kingdom, Germany, Italy, and Netherlands. In general, the teams were supported by charities and national funding programmes. There were 26 biotechnology firms in Europe (considered in the study as composed of 15 EU Member States and Switzerland) dedicated to the development of gene therapy. This represented a 160% increase compared to 1996. These firms were located in France (n = 3), Germany (n = 11), the United Kingdom (n = 5), Denmark (n = 2), Netherlands (n = 2), Finland (n = 1), Italy (n = 1), and Switzerland (n = 1). In the United States, in May 2000, 22 firms were detected. At that time, it appeared that the European gene therapy industry was growing at a much greater rate than in the United States. Similarly, analysis of the number of industry-sponsored clinical trials showed an increase of 320% (from 5 in 1996 to 21 in 2000) in Europe, and of 15% in North America (from 14 in 1996 to 16 in 2000). Overall, the number of trials recorded in 1996 was 46 in Europe compared to 160 in the United States. In 1999, Europe had 69 trials and the United States had 278. Today (April 2017), these numbers have reached 584 in Europe and 1,587 in America. ⁴

From an EU perspective, through the subsequent Framework Programmes (FPs) for research (Table 1), support for the field of nucleic acid transfer and therapy has been increased, and a clear evolution from support to fundamental science-based projects has been witnessed, aiming at the development of the new generation of vectors (improved safety and specificity, pseudotyping, choice of the promoter, use of codon-optimized cDNA, use of regulatory RNA, insulators, etc.), of new animal models or preclinical toxicity tests, to the performance of clinical trials for rare diseases and cancer mainly in FP7 and Horizon 2020. Examples of successful consortia receiving grants from successive FPs are those focusing on disorders such as Duchenne muscular dystrophy, primary immunodeficiencies, epidermolysis bullosa, graft-versus-host disease, or lysosomal storage diseases. Of note, in FP6, a European Network of Excellence (NoE) for the advancement of clinical gene transfer and therapy, CliniGene (2006–2011), was funded in order to gather and spread the European expertise in the field. The NoE was organized in platforms focusing on the various gene delivery tools, training and interactions between the participants, and the specific ethical and regulatory aspects of gene therapy. In FP7, additional funding for research (see Table 1) became available from the European Research Council (founded in 2007), with individual grants awarded to outstanding researchers in the field.

Today, eight collaborative EU projects of the Horizon 2020 research and innovation programme (2014–2020 ⁵ ) are supporting the latest technological (n = 4) and clinical developments (n = 4) in the field.

If the trials now planned or underway are successful, these could potentially lead to the release of new ATMPs on the European market. Of the eight ATMPs that have been approved by the European Medicines Agency since 2009 (Table 2 and Abou-El-Enein et al. ⁶ ), only four are still on the market today. It is striking to note that the technology developed by the academic teams involved in the release of the ATMPs Strimvelis^®, Holoclar^®, and Zalmoxis^® benefitted from EU financial support through successive framework programmes. For these three products, about 20 years were needed to reach the market, and this could only be achieved thanks to the involvement of industry in the final stages.

Although the situation undoubtedly looks more favorable today compared to 20 years ago, the lack of venture capital investment in Europe, the variable intra-European regulatory requirements, and the lack of (large-scale) GMP manufacturing of gene therapy vectors and/or cells remain the major issues in the field. Such hurdles might be overcome in the future with the development of cost-effective gene editing technologies, provided that they are demonstrated to be safe, specific, and efficient in human cells and tissues. An optimistic sign for the field is the recent creation of several new European small and medium-size enterprises (SMEs), possibly triggered by the optimal performance in clinical trials of the latest generation of (viral) vectors, the hopes generated by the spectacular results in treatment of B-cell leukemias obtained with chimeric-antigen receptor T-cell therapies, the approval of gene therapy ATMPs, and the recent interest and investments of pharmaceutical industries in the field.

In summary, throughout its research programmes, the EU has supported the entire innovation chain for gene transfer and gene therapy for >20 years, with a focus in the last 5 years on the performance of clinical trials for rare diseases, some cancers, and regenerative medicine. This positive trend will hopefully continue in the future, with SMEs and pharmaceutical industries taking closer to market the most mature products in order to satisfy the huge demand for ATMPs by patients suffering from deadly diseases that might now be cured by genetic transfer.