European Society for Gene and Cell Therapy—Inaugural Learned Society in the Field Worldwide: A Vision on Its Birth,Life,and Prospects for Sustainability

Introduction

Some three decades ago, the first promises of gene therapy to cure a broad range of human diseases began to glitter with limitless and somewhat naive enthusiasm from the research community with inversely correlated fear from the general public. Since then, the field has experienced many ups and downs, but its practitioners have remained steadfast in generating improved delivery systems, demystifying the immune problems, solving production issues, and undertaking clinical trials. Having believed since its beginning in gene transfer for the ultimate purpose of gene therapy, ^1,2 it is quite gratifying to observe that the realm of experimental human gene transfer ^3,4 transforming into gene therapy has now turned into reality. ⁵ Indeed, there are now >10 conditions in which gene therapy has had a clinical impact in at least one case, and in one of these diseases—adenosine deaminase severe combined immunodeficiency (ADA-SCID)—gene therapy can be regarded as the standard of care, at least if a bone-marrow donor is not available. ^{6 –8} Thus, there has been success in treating children with near fatal immunodeficiencies, ^9,10 in improving the outlook and quality of life of patients with a variety of blood disorders, including hemophilia, ^11,12 Wiskott–Aldrich syndrome, ^13,14 and metabolic disorders such as lysosomal storage diseases, ^{15 –17} in restoring some vision to someone nearly blind, ^{18 –20} and in restoring cell adhesion in epidermolysis bullosa. ²¹ There are also encouraging developments with respect to debilitating degenerative diseases, and glimmers of hope for major illness such as diabetes, ²² cancer, ^{23 –26} and human immunodeficiency virus infection. ²⁷ Finally, the two first marketing authorizations have been granted in Europe to UniQure (formerly known as AMT) for the treatment of severe lipoprotein lipase deficiency and ADA-SCID (Strimvelis™) to Glaxo Smith-Kline.

While appreciating the enormous potential of gene transfer technology, the scientific and medical community has always recognized the possible limitations toward clinical translation in terms of feasibility, safety, economical constraints, and ethical issues. The establishment of treatments involving gene transfer technology is analogous to that of any biological products in that it is translational in essence, ranging from experimental and preclinical research to product manufacture and clinical trials and development (Fig. 1). Gene therapy can only reach its true potential if advances can be achieved in technology on both the safety and efficacy sides. It also requires adequate resources, including high-level training of personnel and sustained funding of projects in the long run. When referring to pharmaceutical drug development, a minimum of 10 years is required, while monoclonal antibodies have entered the clinic more than two decades after introducing the concept and showing its targeting potential in vitro. Successful development of gene therapy is therefore complex, which also encompasses three additional salient issues in this particular area: first, regulatory policies for gene therapy medicinal products, in particular since vectors can be derived from defective viruses or integrate in the genome of the host target cells or might elicit an immune response; second, related ethical issues, noticeably addressing the decision on when to “go” or “no-go” to the clinic; and finally, patenting certain processes, while several technologies are intricate and need to be combined toward clinical implementation. Because of this complexity, sustained exchanges of ideas, concepts, data, methods, and material are pivotal to the advancement of the field that gave birth to the European Society for Gene and Cell Therapy (ESGCT)²⁸ and, later on, to its companion EC-DG research network of excellence, the CliniGene-NoE. ²⁹

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Figure 1.

Clinical development of gene therapeutics: from the basic science of gene regulation through gene transfer vectors, experimental research to clinical translation of products qualifying for use in human patients.

A Historical View: the First Learned Society On Human Gene Transfer and Therapy

Launching the ESGCT

The European Working Group on Human Gene Transfer and Therapy, later to be called the ESGCT, was officially founded in January 1992. ³³ The Society's main goal was to develop and coordinate clinical and scientific research in the area of gene transfer and gene therapy in Europe. The Society aimed at disseminating coordinated information and exchange of technology, material, and human expertise, which it did in the following ways:

• The annual meeting provided a forum for the exchange of information and the presentation of peer-reviewed data;

The Society was founded with the initial support of the European Haematology Association (EHA) established by Michel Boiron. Lucio Luzzatto's support and commitment were also critical. The first meeting was held on October 17, 1992, at Chateau de Maffliers, where the first elected Board was formed, gathering Claudio Bordignon as president, Erwin Wagner as vice-president, and the following members: Olivier Danos, Jean-Michel Heard, Stephen Russell, Dinko Valerio, Thierry Velu as Treasurer, and Odile Cohen-Haguenauer as Scientific Secretary based in Paris, France. The Society bylaws were registered in Belgium as a European nonprofit association. By 1996, this unique group had achieved the federation of all major European teams working in the field and included >550 members, including company personnel from 18 countries, including Israel, Eastern Europe, North America, and Asia, as Associate Members.

The Society faced difficult times when major adverse events showed in clinical trials, first in 1998 in the United States, with the tragic death of a young boy infused systemically with an adenovirus-derived vector, and later in 2001, when a first case of leukemia developed in a X-SCID infant treated in France as a direct consequence of the integration into the host cell genome of the gammaretrovirus vector carrying the otherwise therapeutic gene, which triggered enhancer-mediated genotoxicity and uncontrolled proliferation of gene-modified cells. ³⁴

During this complicated period for the field in general, Bernd Gänsbacher took over as president in 1999 and remained extremely active in reshuffling and reshaping the Society during five consecutive years up until 2004. With his action, the ESGCT started to recover and progressively upgrade again both in membership and in the quality of the yearly meeting, which currently stands as an international reference.

Focusing On Scientific Expertise: Yearly Meeting and Education

Scientific Expertise and Regulation of Advanced Therapy Medicinal Products for Gene Therapy At the European Medicines Agency

The development of promising new medicines to address unmet medical needs is challenging from a scientific and regulatory point of view. Early consultation and scientific advice with regulators and other healthcare decision makers is key to ensuring that data are generated to the standards required for regulatory approval and market access.

Scientific Developments: EU DG Research Funding

With the fourth framework program of the EC-DG research (DGXII), somatic gene therapy was registered for the first time as a priority in both the Biomed 2 and Biotechnology programs. This represented a significant step forward, because up until 1994, official recognition of this field by the European Parliament and the Commission of the European Union was strongly disputed. Both the acting president and scientific secretary of the Society initiated action from 1992 onward to convince members of the European Parliament and decision makers at EC DGXII research that gene therapy was not meant to modify the inherited genetic make-up of the human race but rather to provide innovative options and hope for lethal diseases, many of which were orphan or rare disorders affecting infants and children. Since then, a number of EC-funded projects have markedly helped advancement of the field, as stated by Draghia-Akli. ³⁹

Created with the main objectives of bottom-up and overcoming fragmentation, the CliniGene-NoE EU DG research funded program acted as the ESGCT companion in ELSA, bridging with the industry sector and expanding the scope through funding of experimental research with a 6-year budget of €12 million. The main goal of CliniGene was to integrate multidisciplinary research in order to identify the “critical path” to accelerate the transit phase from preclinical to clinical stage by integrating expertise and generating new knowledge that can lead to improved safety and clinical efficacy of gene transfer and therapy. Indeed, safety is of germane concern, since in the event where the treatment would be proven safe, it could be administered early enough in the course of the disease to achieve a genuine cure so that clinical gene transfer may be called therapy.

While encompassing a broad range of technologies and their potential applications, the NoE has succeeded in establishing intensive networking, which crosses the boundaries between technology platforms, including emerging technologies and a human induced pluripotent stem cells (iPS) platform. This challenge has been successfully fulfilled, with the NoE achieving integration and translating into the facilitation and multiplication of clinical trials initiatives with as many as 29 clinical trials, while the initial target was in the range of 10 at the most, among which first clinical successes have been in ADA-SCIDs, Leber congenital amaurosis, Parkinson's disease, and X-linked adrenoleukodystrophy, with the first clinical use of lentivectors in the EU. ²⁹

Central to these successes and their acceleration was the constant development of cutting-edge technology, with the implementation of both the Emerging Technologies platform and the General Biosafety platform. The Emerging Technologies platform funded competitive start-up international collaborative projects and exchange of personnel (Fig. 2), with >90 projects targeting novelty between 45 laboratories and companies. The mechanism of flexibility funds through so-called flexifunds involved 20% of the NoE total budget. The General Biosafety platform focused on the translational aspects addressing safety and efficiency of current and newly developed systems in vitro and in vivo with two main focuses: (1) transgene integration, with Christof von Kalle and Eugenio Montini in charge; and (2) immunotoxicology, with David Klatzmann in charge, in collaboration with Federico Mingozzi who was still in the United States at that time.

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Figure 2.

Funding and integration of emerging technologies through the CliniGene-NoE “flexifunds” international collaborative program including short term exchanges of personnel and young investigators awards. WP1 stands for integration; WP4.1 to WP4.6 relate to the six gene transfer vector platforms (4.1: AAV; 4.2: gammaretrovirus; 4.3: lentivirus; 4.4: gene-modified cells; 4.5: adenovirus; 4.6: non-viral) and WP4.7 to iPS; WP6 represents general biosafety and novel assessment tools.

In order to streamline the clinical translation of the most advanced technologies, this joint research program developed and concentrated on five main directions:

(1) Preclinical evaluation of a new generation of safer and more efficacious gene transfer vectors, whether viral or non-viral, including transposon-derived non-viral integrating vectors, and comparing them to available technologies.

Installing Industry Workshops As Satellites of the ESGCT Annual Congress

The CliniGene industry workshops held as satellites of the ESGCT Annual Congress provided unique opportunities to gather professionals from the private sector and academic centers of excellence. These meetings had a positive feedback, with their attendance growing from one year to the next. The first meeting took place in Rotterdam on October 31, 2007, and was entitled “Gene therapy and gene transfer: from basic research in centres of excellence to industry development.” The second meeting was held in Brugge on November 16, 2008, with two main sessions: (1) a regulation round table, and (2) a “freedom-to-operate” workshop. On the occasion of the third meeting in Hannover on November 24, 2009, the theme was “GMP manufacture of gene therapy vectors and genetically modified cells: present status and future needs.” The fourth meeting took place during the ESGCT Congress in Milan on October 25, 2010, and was dedicated to “Bottlenecks in the industrial development of cell and gene-based therapeutics,” addressing five main topics: (1) R&D—how the industry can cooperate with academic research and clinical centers of excellence; (2) intellectual property issues in gene transfer research; (3) GMP manufacture and development of common standards: usefulness of a pan-European Infrastructure; (4) regulation—fostering simplification and accuracy; and (5) models for industry development—financing the development of gene and genetically modified cell therapies. The fifth meeting took place at the ESGCT Congress in Brighton on October 31, 2011, and was dedicated to “Industry–academic centres of excellence collaboration in challenges for early-phase clinical trials,” which focused on the following issues: (1) how academia and industry collaborate and on which ground it is maintained; (2) the main bottlenecks—research, intellectual property, timelines, management, regulatory issues, and so on; and (3) suggestions to improve these collaborations in the future.

In fact, these first attempts, along with first evidence of clinical successes, have now materialized into a major involvement of the private sector into the gene therapy field. Of note, the issues that were initially considered still hold in so far as collaboration between academic centers of excellence, cutting-edge technologies, and ethical issues in their clinical translation are concerned. While the private sector is pivotal to the clinical development of gene therapeutics, it is not the appropriate place to overlook and regulate all of the above-mentioned issues.

Integrating Ethics and Regulation With Science and Clinical Translation

Education, policy development, advisory ethical review, information sharing through conferences, publications, and public education that combines ethics and science and involves all relevant stakeholders in a comprehensive advisory role, as developed in CliniGene with enlightening views provided by Nancy King, hold the potential for complementing that of the regulatory authorities. This is to ensure early dialogue, robust accountability, high levels of transparency, open, clear, and timely flow of communications, and clarity of decision-making roles, all of which represent key values for safe clinical trials and, ultimately, effective gene and cell therapy medicinal products (GCTMPs). ^{41 –43} Indeed, research on GCTMPs must be translational, that is, coordinated across the development of technologies, assays, and materials, and from preclinical through clinical trials, rather than simply focusing on research with human subjects.

In order to foster safe and high-quality clinical gene transfer treatments, the CliniGene-NoE approached the definition of key criteria resulting from interesting preclinical results, which enable the decision as to whether it is a “go” or a “no-go” to the clinic with a reasonable enough margin of confidence toward foreseeable success. ⁴¹ Patient advocates have been involved all along, providing pivotal added value. The Clinigene-NoE has aimed to: (1) avoid the reproduction of Phase I trials asking the same questions; (ii) prevent predictable failures from entering the clinical phase; and (iii) deliver practical results, opening new opportunities for funding research and clinical development, thereby favoring the expansion of a high-tech industry sector.

Prospective Vision for a Sustained European Society On Gene and Cell Therapy

Whatever the interest raised by gene therapy and its innovatory potential, the relevance of this approach constantly needs to be carefully considered in terms of feasibility, economical constraints, and ethical issues and confronting alternative treatments such as targeted drugs. When considering a specific disease, the schedule of conditions to achieve therapeutic benefit must be scrutinized. Indeed, there might be alternative or complementary approaches to gene and cell therapies, constituting its own therapeutic armamentarium, the review of which belongs to the relevant clinical communities.

The raison d'être of a Society for gene and cell therapy therefore lies first in the technology and the knowhow to design its specificity and safety, whatever the application under consideration. In fact, the life-science community at large owes a lot to the gene transfer community, as mentioned by the ESGCT President in his recent letter: “The development of powerful technologies for efficient and safe gene transfer with minimal impact on target cell biology, regulated transgene expression and precise genome editing are just some examples of our legacy to the daily work of countless investigators and laboratories.”²⁸

Because of the CliniGene program and actions, the necessity of streamlining experimental research and overcoming fragmentation has become evident. ⁴⁴ The creation of a Pan-European resource for gene transfer vectors toward clinical application has emerged. ^29,45 A nonprofit initiative, a EU-funded infrastructure would be well positioned to respond quickly to the changing demands of this rapidly developing area of science. This would provide the opportunity not only to incorporate novel scientific and technical possibilities, but also to create the appropriate ethical, regulatory, and public communication frameworks necessary to secure public endorsement to legitimate clinical gene transfer and cell therapy research. In structuring a distributed infrastructure with integrated governance, coordinated services, one-stop-shop access to services, the objectives are the following: (1) to build up a Pan-European infrastructure of vector engineering facilities providing state-of-the art gene transfer vectors toward preclinical developments of gene therapy and stem-cell engineering; (2) to serve a community of users in providing advice on the best system and accompany their project in providing prototypes and material; (3) to develop efficient and safer emerging technologies relying on multidisciplinary expertise in a coordinated manner; and (4) to provide access to complementary skills in order to answer the needs of the scientific community addressing a wide scope of applications and conditions. This infrastructure will help harmonize practices and quality in the design and production of vectors and genetically modified cells, thereby favoring the expansion of a high-tech industry sector through appropriate technology transfer. In fact, once proof of efficacy is gathered, technology can be transferred to the private sector, which is the appropriate channel to take over further phases of development toward marketing authorization (Fig. 3).

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Figure 3.

Added value of a non-profit EU-infrastructure: (i) integration through the European Society for Gene and Cell Therapy including a strong Ethics and Policy component; (ii) funding of innovative experimental research and emerging technologies; (iii) fostering technology transfer and clinical translation in collaboration with the private sector.

The EC-DG research has been approached with view to launching a specific line of call. A European gene and cell therapy infrastructure is likely to expand the scope of the Society, with a capacity to fund experimental and ethical research toward accelerating clinical translation of cutting-edge technology. Such a prospect is particularly relevant at a time where (1) multiple companies are currently entering the field, a significant move that requires strong reference material, methods, and ethical standards; and (2) CRISPR-Cas9 and other systems pertaining to homologous recombination toward precise genome editing are currently revolutionizing the field, with the added advantage of being immediately applicable to dominant as well as recessive inherited genetic diseases. ^46,47 For therapeutic purposes, such technology still needs to be accurately shuttled to the nucleus of target cells, calling on the expertise of the gene therapy community in so far as targeting, safety, and efficacy constraints are concerned.

Conclusion

Behind the disease and the tentative therapy, there is first and foremost the patient. Patients are the most concerned with innovative therapies, which they might perceive as hope for a miracle to happen. The community has a responsibility to move ahead and at the same time convey to patients measured and concerted expectations. Multidisciplinary interaction only makes fruitful exchanges possible between investigators in basic science and clinicians in order to help overcome the many bottlenecks and draw a critical path between basic genetic discovery and clinical implementation. This has been the basis for the creation of the ESGCT and later of CliniGene as its professional companion in the ethical and regulatory field and experimental arm funded by the EC. It will soon be inevitable that a continuation of the CliniGene-NoE ⁴⁸ actions will be necessary, taking from Inder Verma's (Chair of the Clinigene International Committee) word of wisdom : “In science, we build up on what already exists, learning from others. Creativity comes from the ability to see the data, integrate them and extrapolate from them. You multiply by sharing: share your reagents, share your ideas openly and freely because science is a collaborative effort: no single person can do everything” (Vilcek Prize, 2008). The prospect of building up a strong nonprofit European infrastructure also warrants the robust expansion of a high-tech industry sector, with best possible ethical landmarks.