Gene Therapy “Made in Germany”: A Historical Perspective,Analysis of the Status Quo,and Recommendations for Action by the German Society for Gene Therapy

Abstract

Gene therapies have been successfully applied to treat severe inherited and acquired disorders. Although research and development are sufficiently well funded in Germany and while the output of scientific publications and patents is comparable with the leading nations in gene therapy, the country lags noticeably behind with regard to the number of both clinical studies and commercialized gene therapy products. In this article, we give a historical perspective on the development of gene therapy in Germany, analyze the current situation from the standpoint of the German Society for Gene Therapy (DG-GT), and define recommendations for action that would enable our country to generate biomedical and economic advantages from innovations in this sector, instead of merely importing advanced therapy medicinal products. Inter alia, we propose (1) to harmonize and simplify regulatory licensing processes to enable faster access to advanced therapies, and (2) to establish novel coordination, support and funding structures that facilitate networking of the key players. Such a center would provide the necessary infrastructure and know-how to translate cell and gene therapies to patients on the one hand, and pave the way for commercialization of these promising and innovative technologies on the other. Hence, these courses of action would not only benefit the German biotech and pharma landscape but also the society and the patients in need of new treatment options.

Introduction

In the mid-1960s, Nobel laureate Edward L. Tatum presented at a symposium in New York his ideas of “genetic engineering” for the future of medicine, which “could be accomplished by direct mutation or by the replacement of existing genes by others.”¹ A few years later, the visionary Theodore Friedmann hypothesized in another seminal article that the introduction of “therapeutic genes” into the cells of patients using viral vectors would be an effective treatment for hereditary diseases.² He suggested that such a “gene therapy” would have the advantage that a single treatment could achieve permanent and curative benefits. Indeed, one of the first gene therapy studies, initiated in 1970 in Cologne, Germany, by pediatrician Heinz Terheggen, employed viruses. Three siblings suffering from hyperarginemia were infected with the Shope papilloma virus (SPV) under the hope that serum arginine levels could be reduced by the enzyme arginase that was assumed to be either encoded by SPV or induced after infection. From today's ethical perspective undoubtedly controversial, the motivation for the study was based on in vitro cell culture experiments and on the observation of decreased arginine levels in staff members in Richard Shope's laboratory, where the rabbit virus had been discovered and investigated. In the patients, this study was unsuccessful³ and this specific approach had not been further pursued.

Although the concept of gene therapy may have several origins, the path to the first successful clinical applications was long and marked by many setbacks. More than 50 years later, however, 10 gene therapy medicinal products (GTMPs) have been approved by the European Medicines Agency (EMA) in the EU (https://www.pei.de/EN/medicinal-products/atmp/gene-therapy-medicinal-products/gene-therapy-list.html). They enable the treatment of diseases, for which alternative treatment modalities are hardly available, including monogenic inherited disorders and certain types of cancer. There is no doubt that many more GTMPs will be approved in this decade.

The Early Stages and Foundation of the German Society for Gene Therapy

The regular implementation of gene therapy concepts into clinical application began in the early 1990s. In the midst of this initial euphoria, the German Society for Gene Therapy (DG-GT; www.dg-gt.de) was established in 1994 (originally as the German Working Group for Gene Therapy). It is thus one of the world's oldest national gene therapy societies, being only 2 years younger than the European Society of Gene and Cell Therapy (ESGCT). Since these early days, the DG-GT's mission has been to promote science and research in all areas of gene therapy, including basic research and clinical gene therapy. Deplorably, gene therapy in the 1990s was characterized by sobering results in clinical trials. In the year the DG-GT was founded, the two very first investigator-initiated trials that aimed at triggering antitumor immune responses by infusing gene-modified, irradiated tumor cells that secrete immune-stimulatory factors into the patients were performed in Germany.^4,5 Clinical efficacy in both clinical studies was rather limited.

Gene Therapy for Inherited Disorders

In the course of the genetic revolution, which began in the early 2000s and enabled the reading of a person's whole genome in combination with a better understanding of genetic networks, gene therapy made groundbreaking advances. The first successful trial with sustained benefit for the patients was reported in the early 2000s, particularly in the field of congenital immunodeficiencies.^6,7 The enrolled patients were successfully treated by transplantation of autologous hematopoietic stem cells (HSCs) that were modified by γ-retroviral vectors to express the missing/defective gene. Notably, many of these retroviral vectors used in these first studies were based on work performed in Wolfram Ostertag's laboratory in Hamburg.⁸

However, the tools used 20 years ago, mostly adenoviral and γ-retroviral vectors, were not fully developed yet, and, in some cases, triggered severe inflammatory and even fatal reactions,⁹ or resulted in the development of malignant diseases. Christopher Baum, Boris Fehse, and colleagues in Hamburg and later Hannover made the worrying finding that HSCs transduced with γ-retroviral vectors, similar to those used in clinical trials, had the potential to cause leukemia in mice after HSC transplantation (HSCT).¹⁰ Sadly, soon thereafter, the first cases of leukemia were also seen in gene therapy patients in Paris and London.^11,12 Molecular and functional analyses in Christof von Kalle's (Heidelberg) and Christopher Baum's (Hannover) laboratories identified insertional mutagenesis as the underlying cause to trigger malignant transformation.^11

–17 Gene therapy clinical trials in Germany reported cases of insertional mutagenesis, too. For instance, in one of the seminal gene therapy trials for patients suffering from X-linked chronic granulomatous disease (X-CGD) in Frankfurt a. M., two patients developed myelodysplasia with monosomy 7, mainly due to insertion of the γ-retroviral vector in the MDS1-EV1 gene.^18,19 Furthermore, in a clinical trial conducted in Hannover to treat children with Wiskott-Aldrich syndrome, the use of γ-retroviral vectors was associated with substantial genotoxicity, with seven patients developing acute leukemia.²⁰

In the following years, German laboratories contributed groundbreaking work on analyzing and monitoring of gene-modified cells in clinical trials. The systematic genetic analyses uncovering the genetic causes of insertional mutagenesis by Christoph von Kalle's and Manfred Schmidt's laboratory (Heidelberg)^{11,12,19,21
–23} led to important insights into the genetic mechanisms driving retroviral-associated genotoxicity. Furthermore, methods for assessing the genotoxic potential of γ-retroviral and lentiviral vector systems as well as improved vector designs were developed by Axel Schambach and colleagues in Hannover.^24

–27

Although γ-retroviral vectors were the first tool for ex vivo modification of HSCs, adenoviral vectors (AdVs) were initially the vector of choice for in vivo approaches. German scientists, including Stefan Kochanek, André Lieber, and Anja Ehrhardt, contributed to major advances of that technology, such as the development of gutless AdVs, capsid modification, or the generation of novel AdVs derived from types other than HAdV-C5.^28

–33

In the meantime, adeno-associated virus (AAV) vectors have largely replaced AdV vectors as delivery tools for in vivo approaches. With an impressive number of 370 human clinical trials and three marketing-authorized gene therapies, AAV vectors are currently taking the lead among the virus-based in vivo delivery tools (https://asgct.org/research/news/april-2021/gene-cell-rna-therapy-landscape-q1–2021). Some of these studies are conducted in Germany. For instance, the academic consortium RD-CURE around Bernd Wissinger in Tübingen successfully completed the first clinical trial testing AAV-mediated gene supplementation for the treatment of achromatopsia, a form of inherited day blindness.^34,35 Phase IIb was recently initiated (NCT02610582). RD-CURE is also currently running the first clinical trial of gene therapy for PDE6A-linked retinitis pigmentosa.

From early on, Jürgen Kleinschmidt (Heidelberg) contributed seminally to decipher the biology of AAV and to develop AAV as a vector for gene therapy.^36

–40 Michael Hallek and his team (at that time in Munich) were the first to report on a successful genetic cell surface targeting of AAV vectors.⁴¹ Both laboratories independently developed the AAV peptide display technology, a landmark technology to optimize AAV vectors for basic research, preclinical and clinical applications.^42,43 Also, the error-prone PCR-based library and the shuffled AAV capsid library technologies do have some German roots. Specifically, Perabo et al., in parallel to David Schaffer's laboratory in the United States, were the first to report on successful production and selection of capsid variants with distinct features through error-prone PCR.^44,45 Dirk Grimm (Heidelberg, at that time in the team of Mark Kay, Stanford) developed in competition to Jude Samulski's laboratory (United States) the shuffled AAV capsid library technology.^46,47 Improving and applying these technologies, among them by the laboratories of Jürgen Kleinschmidt, Martin Trepel (Hamburg), Dirk Grimm and Hildegard Büning (now in Hannover), filled the AAV tool box with a plethora of capsid variants, specifically tailored for their future tasks in gene therapy.⁴⁸ Furthermore, the first report on a precise on-target in vivo delivery by AAV vectors using a novel capsid design as well as the AAV prime-boost vaccine platform are developments “Made in Germany”.^49,50

Cardiac Gene Therapy

The heart is not a privileged organ for gene therapy: due to its indispensable necessity to function, the heart does not offer the amenities of temporally whole or partial explantation for accomplishing gene modification, quality control, and selection, such as, for example, the bone marrow. Moreover, dose optimization has to be performed in similar-sized, but otherwise young and healthy hearts of the preclinical arena (e.g., primates, pigs, and dogs), and then translated to end-stage heart failure patients, carrying several cardiovascular risk factors that potentially reduce efficacy. These challenges have led to a paucity of cardiac gene therapy trials. However, the steady drumbeat of vector and transgene improvements in a few laboratories around the globe as well as the demonstration that cardiac gene therapy is safe and feasible by Roger Hajjar (New York, Boston), inspired a dedicated group of German researchers to enter the field. Oliver Mueller (Heidelberg, Kiel) developed AAV vectors for treatment of genetic diseases, such as Duchenne muscular dystrophy (DMD) and Marfan syndrome^43,51,52; Patrick Most took on postischemic heart failure using AAV-based S100A1 in a pig model^53
–55; Lucie Carrier turned to a hypertrophic cardiomyopathy, caused by mutations of MYBPC3, for which she successfully developed AAV-based supplementation therapy^56,57; and the laboratory of Christian Kupatt and Rabea Hinkel took therapeutic neovascularization one step further by focusing on AAV-Thymosin-ß4^58,59 and AAV-MRTF-A⁶⁰ mediated capillary maturation. Moreover, together with Alessandra Moretti, Eckhard Wolf, and Wolfgang Wurst, they provided the first porcine model of DMD (loss of exon 52), in which designer nuclease based excision of exon 51 showed functional improvement of peripheral muscles and heart.⁶¹

Cell and Gene Therapy to Treat Cancer

Current cell-based immunotherapies to treat cancer are basically founded on decades of experience in the use of HSCT and donor lymphocyte infusion (DLI).^62,63 Clinical translation of manipulated DLIs has been promoted in Germany, for example, to treat virus infection using antigen-specific T cells or boost graft versus leukemia/tumor (GvL/T) effect with allogeneic donor NK cells by Ulrike Köhl and others.^64

–68 To prevent or abrogate severe graft-versus-host disease in the context of adoptive immunotherapy with allogeneic T cells, suicide-gene transfer had been suggested.⁶⁹ German groups participated both in the development^70,71 and clinical translation of this strategy.^72,73

With the turn of the century, the combination of knowledge in cell-based therapies and genetic cell manipulation led to a wave in cancer treatment using genetically engineered primary human T cells. In Germany, the work with chimeric antigen receptor (CAR) T cells was pioneered by Hinrich Abken (now in Regensburg),^74

–77 and later extended by Michael Bachmann (Dresden),⁷⁸ Michael Hudecek (Würzburg)^79

–82 as well as by Claudia Rössig (Münster)⁸³ and Ruppert Handgretinger (Tübingen).^84,85 T cell receptor (TCR) transgenic T cells, in contrast, were extensively investigated and explored by Thomas Blankenstein and Wolfgang Uckert in Berlin and Dolores Schendel in Munich.^86
–88 Based on these initiatives, first clinical trials with CAR T cells and TCR-transgenic T cells were initiated. Other CAR effector cells, such as allogeneic “off the shelf” CAR NK cells, are for instance in preclinical and clinical development at Hannover Medical School and Fraunhofer IZI in Leipzig (collaboration of Ulrike Köhl and Axel Schambach)^89,90 as well as in in Frankfurt by Winfried Wels, Evelyn Ullrich, and many collaborators.^91
–93 Of note, our colleagues in Nuremberg demonstrated in a recent case report that CD19-targeting CAR T cells can also be used to treat an autoimmune disorder. The CAR T cell therapy led to the elimination of B cells within 7 days, which was associated with a rapid remission of refractory systemic lupus erythematosus (SLE).⁹⁴

Oncolytic viruses represent another class of approved cancer gene therapies. Corresponding research activities in Germany have focused on innovative approaches of virus engineering and establishing virotherapeutic regimens. Utilizing an increasing panel of virus platforms, German virotherapy investigators have covered diverse approaches from virus capsid or envelope engineering to the insertion of therapeutic genes into oncolytic virus genomes.^95,96 Pioneering work on oncolytic viruses in Germany has been performed on AAV's cousins, the autonomously replicating parvoviruses, by Jean Rommelaere and team at the German Cancer Research Center in Heidelberg. Decades of research, with the first publication in 1982,⁹⁷ lead to the first German virotherapy study in 2011, exploring local and systemic application of H1 parvovirus in patients who suffer from advanced glioblastoma.⁹⁸ Dorothee von Laer's group (at that time in Frankfurt a. M.) had successfully turned vesicular stomatitis virus into an oncolytic virus⁹⁹ that is now being further developed by Boehringer Ingelheim. Recently, German virotherapists have explored and developed oncolytic viruses as cancer immunotherapeutics.⁹⁶ Furthermore, efforts on translating oncolytic virus innovations into clinical application have triggered several spin-off companies and, increasingly, clinical studies.⁹⁶ However, these evolving translational activities clearly lag behind prominent efforts in the United States, Canada, and the United Kingdom, and would benefit from institutionalized networks and from gene therapy-focused funding schemes.

Alternatives to Viral Vectors

More than five decades of quest for efficacious nonviral gene transfer systems have yielded robust physical transfection methods, which have been used, inter alia, for ex vivo transfer of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) - CRISPR-associated protein (Cas) nucleases to HSCs.¹⁰⁰ Pioneering contributions to this field were made in Munich, such as the development of electroporation by Eberhard Neumann and Peter Hans Hofschneider¹⁰¹ or of magnetofection by Christian Plank.^102,103 Furthermore, continuous chemical evolution of cationic nanoparticles yielded lipidic and polymeric nanocarriers for various synthetic nucleic acids beyond DNA, including mRNA and CRISPR-Cas ribonucleoprotein complexes.¹⁰⁴ Applications of mRNA lipid nanoparticles have also been successfully applied in vivo, as highlighted in a recent phase 1 clinical study in patients with hereditary transthyretin amyloidosis. A single intravenous dose of lipid nanoparticles encapsulating Cas9-encoding mRNA and a gRNA targeting the transthyretin-encoding gene TTR demonstrated efficacious in significantly reducing the concentration of TTR in serum.¹⁰⁵ Short-term in vivo mRNA expression also presents an interesting perspective for passive immunotherapy based on ‘tumor vaccination’.^106,107 In this direction, Ugur Sahin and colleagues in Mainz developed lipid nanoparticle formulation of tumor antigen encoding mRNA, demonstrating in vivo delivery to dendritic cells and antitumoral immune responses.¹⁰⁸ Of note, this concept was translated into the globally used SARS-CoV-2 mRNA-based vaccines by BioNTech and Pfizer.¹⁰⁹

Alternative platforms that bypass the need to package a therapeutic gene into a virus particle have been benefitting enormously from improved transfection methods and nonviral vector platforms. These include transposon-based systems. Transposons are nature's simplest gene delivery vehicles that unite favorable characteristics of integrating viral vectors (i.e., stable chromosomal integration and long-lasting transgene expression) with those of nonviral delivery systems (i.e., lower immunogenicity, enhanced safety profile, and reduced costs of good manufacturing practice [GMP]). A prime example for a clinically applicable transposon vector system is Sleeping Beauty (SB), a synthetic transposon that was constructed based on sequences of transpositionally inactive elements isolated from fish genomes.¹¹⁰ Preclinical development of SB transposon technology¹¹¹ largely took place in the laboratories of Zoltán Ivics (Langen) and Zsuzsanna Izsvák (Berlin). The European clinical debut of SB has recently taken place in a multicenter first-in-human clinical trial targeting multiple myeloma with SLAMF7-specific CAR T cells⁸¹ as well as a German proof-of-concept study using ROR1-specific CAR T cells. Both studies are coordinated by Michael Hudecek (Würzburg).

Genome and Epigenome Editing

In addition to the traditional gene addition type therapies, the targeted modification of the genome is attracting increasing attention. Therapeutic genome editing with CRISPR-Cas and other programmable designer nucleases, such as transcription activator-like effector nucleases (TALENs) and zinc-finger nucleases (ZFNs), do and will contribute to the treatment of infectious and hereditary diseases as well as cancer.^{112

–117} Scientists in Germany made seminal contributions to the genome editing field, including the deciphering of the DNA binding codes of transcription activator-like effectors by Ulla Bonas and coworkers in Halle¹¹⁸ and of CRISPR-Cas9 by Emmanuelle Charpentier and colleagues (now in Berlin).¹¹⁹ Furthermore, the laboratories of Toni Cathomen and Claudio Mussolino in Freiburg have substantially contributed to improving the specificity of these genome editing tools, ZFNs,^120
–122 TALENs,^123,124 and CRISPR-Cas,¹²⁵ for their applications in human cells. More recently, they developed a novel genome-wide assay that enables developers of programmable nucleases to nominate and quantify off-target effects associated with the use of these tools in primary human cells,¹²⁶ in particular in HSCs, in which genotoxicity is a major risk factor associated with leukemia.

Two patients in Regensburg who suffered from ß-thalassemia or sickle cell disease, respectively, were among the first to be treated with CRISPR-Cas.¹⁰⁰ Both of them were infused in 2019 with autologous genome-edited HSCs, and both of them reached transfusion independence within the first 2 months after treatment. These promising results should not detract from the fact that the study was not investigator-initiated but sponsored by two U.S. biotech companies. Another forthcoming application of genome editing in Germany is the treatment of infection with the human immunodeficiency virus (HIV). Following the principles of HIV eradication in the so-called Berlin patient,¹²⁷ several studies employed designer nucleases to knock out CCR5, the gene encoding the major coreceptor of HIV type 1.¹¹² This includes work performed in the laboratories of Boris Fehse (Hamburg)^128
–130 and Toni Cathomen (Freiburg),^123,124,131 who demonstrated that CCR5 disruption confers resistance to R5-tropic HIV-1 in T cells. In this context, it must be noted that preventing HIV entry has been attempted already 20 years ago by Dorothee von Laer and coworkers by the use of peptide inhibitors.^132,133 In an ensuing clinical trial, 10 patients were infused with CD4⁺ T lymphocytes expressing this C46 peptide. However, for ethical reasons, the patients were continuously treated with antiretroviral therapy and, therefore, no selective advantage of cells harboring the C46 peptide in patients could be observed.¹³⁴

Editing of CCR5 in HSCs represents a promising treatment scenario as CCR5-edited stem cells will give rise to all lineages of the blood and immune system, and hence will create an HIV-1-resistant immune system in HIV-positive cancer patients transplanted with CCR5-knockout HSCs. An interesting alternative approach to designer nuclease-based gene editing is engineering of the genome with designer recombinases, which do not depend on the cellular DNA repair machinery. The laboratories of Joachim Hauber (Hamburg) and Frank Buchholz (Dresden) engineered the recombinase Tre and, as a further evolution, Brec1, which was developed to recognize the HIV long-terminal repeat (LTR) sequences to excise the provirus from latently infected cells, a key step toward HIV cure.¹³⁵ Yet, clinical translation of these investigator-initiated studies, both CCR5 knockout and HIV excision, has turned out to be difficult because of structural problems and/or funding restraints.

The potential of designer nuclease-associated genotoxicity has fueled the development of alternative concepts, such as targeted epigenome editing. Synthetic epigenome editors, typically based on TALEs or catalytically inactive CRISPR-Cas, catalyze the deposition of epigenetic marks at defined genomic sites to activate or silence target genes. The laboratories of Albert Jeltsch (Stuttgart)¹³⁶ and Thomas Jenuwein (Freiburg)¹³⁷ have contributed to dissect the mechanisms of generation and maintenance of epigenetic patterns in mammalian cells. This knowledge has been exploited in the laboratory of Claudio Mussolino (Freiburg) to generate designer epigenome modifiers for preclinical applications,^138,139 such as, for example, the simultaneous silencing of both HIV coreceptors, CCR5 and CXCR4, in primary human T lymphocytes.¹⁴⁰

A Critical Look at the Gene Therapy Situation in Germany

Owing to the numerous successfully conducted clinical gene therapy studies worldwide, it is to be expected that the number of approved GTMPs will increase sharply in this decade. Because of their high costs, gene therapeutics are associated with particular challenges for the health system. However, they are often administered as a single dose and usually result in long-term (ideally lifelong) beneficial effects on the clinical course of the disease, especially in the case of hereditary disorders. Although data on long-term safety and efficacy are often limited at the time of approval, the published studies indicate that the effectiveness of a GTMP is dependent on the time of administration. Starting treatment before the first symptoms of disease appearance is particularly promising, as shown in clinical trials for adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD), and spinal muscular atrophy (SMA).^141

–144 The screening of newborns for hereditary diseases will, therefore, become even more important in the future, and the introduction of newborn screening for severe combined immunodeficiency in Germany is a good step in this direction.

Beyond the development of corona vaccines, where German biotech companies have been in the lead, there are only few examples of German companies being ahead of the competition. BioNTech and Miltenyi have been successfully working in the area of cancer immunotherapies for several years, PlasmidFactory has developed the revolutionary minicircle technology, which is used, for example, to transfer SB transposons to clinically relevant cells,¹⁴⁵ and Bayer has successfully entered the CRISPR space.¹⁴⁶ As outlined earlier, Germany still keeps up well with the United States, China, and other European countries when assessing the numbers of scientific publications or patent applications,¹⁴⁷ but gene therapy “Made in Germany” lags well behind our competitors, with Germany having <5% of the share of gene therapy clinical trials worldwide.¹⁴⁸ How come that Germany trails other countries when it comes to the numbers of investigator-initiated gene therapy trials or developed commercial products, including market authorizations? Germany invests more in research and development (3.0% of gross domestic product [GDP]) than some of the European neighbors (2.3% in France; 1.7% in Britain; 1.4% in Italy) or the United States (2.8% of GDP). Although all political parties of the federal government have committed to reducing bureaucracy, translational research has seen little of it. Our colleagues in the United Kingdom and the United States do better without compromising on safety. For instance, the adoption of a risk-adapted system for gene therapy products in accordance with the classification used in the United States would help to speed up the implementation of clinical gene therapy trials in Germany.^149,150

Another part of the problem stems from decentralization of the regulatory processes that lead to a clinical trial: whereas approval of the clinical study is executed by a federal agency (the Paul Ehrlich Institute), the manufacturing license of a gene therapy product is issued by local authorities run by the federal states (altogether 16 in Germany). This is a country-specific complication incompatible with the principle of “streamlining” manufacturing of innovative therapies. Furthermore, harmonization of GTMP regulation within the EU moves too slowly and further increases the “translation gap” as compared with the United States or China.¹⁵¹

The more centralized structures in our neighboring countries, such as the gene therapy centers in Paris (Hopital Necker/INSERM/Imagine), London (UCL/Great Ormond Street Hospital), Milan (TIGET/San Raffaele), and Madrid (CIEMAT), enable the concentration of resources and know-how for early translational studies in a few locations. Germany lacks both national gene therapy centers and centralized support structures, such as the “Cell and Gene Therapy Catapult” in the United Kingdom. Catapult is a center of excellence that was established to advance the growth of the United Kingdom cell and gene therapy industry by supporting industry and academia with unique technical facilities as well as expertise in manufacturing, regulatory affairs, and industrialization, with the final goal to bridge the gap between scientific research and commercialization. In agreement with a recent report of the vfa.bio (the association of the research-based pharmaceutical companies in Germany),¹⁴⁸ the DG-GT strongly supports the implementation of a national “Center for Cell and Gene Therapy.” Such national centers, which interconnect the leading national treatment centers and researchers of a particular field, are chiefly supported by the Federal Ministry of Education and Research (BMBF) and have already proven their worth in many other areas of health research, such as the German Center for Infection Research (DZIF), the German Center for Cardiovascular Research (DZHK), and the German Cancer Consortium (DKTK).

Conclusions and Recommendations for Action

With their potential to cure severe diseases, such as cancer, chronic viral infections, and inherited disorders, cell and gene therapies have heralded a radical change in the academic world as well as the pharmaceutical and biotech industries. The cell and gene therapy market is set to grow rapidly and is expected to reach sales of EUR 27.9 billion by 2026.¹⁵² Some biotech companies involved in research, technology development, and clinical trials reach billions of dollars in market valuations even before their first sales. So, there is little doubt that cell and gene therapies are a promising new business segment.

To be competitive on an international level, academic institutions as well as biotech and pharmaceutical companies in Germany not only need to be prepared on the scientific and technical levels but also on an organizational layer: (1) Continuous development of the underlying technology platforms is of highest strategic importance to stay ahead of the competition. (2) A deep knowledge of the manufacturing and quality control processes as well as an early interaction with regulators and access to funders are crucial to enter the clinical phase. (3) A solid know-how of business development and market access are prerequisites to introduce new therapies successfully.

To meet these objectives, we propose the following course of action:

to establish a centralized support structure that includes clean room facilities to produce GTMPs (vectors and cell products) and that provides specialized expertise in manufacturing, regulatory affairs, and commercialization;

to establish a centralized coordination structure that interconnects and aligns the efforts of German gene therapists and regional advanced therapy treatment centers with each other, with the competent authorities, with the biotech/pharma industry, and with financial partners;

to establish a national task force that aims at harmonizing the regulatory processes to license GTMPs in the Federal States as well as at simplifying and speeding up the approval process of gene therapy clinical trials in Germany; and

to provide a tailored training program to inspire the next generation of talents to enter this promising field and to educate today's workforce to face tomorrow's challenges in cell and gene therapy.

Most of these efforts could be assigned to a National Center for Cell and Gene Therapy with the goal to maintain the international competitiveness of the German cell and gene therapy sector as well as to develop robust systems that enable the delivery of GTMPs as a standard of care to patients in need throughout the Federal Republic of Germany.

Footnotes

Disclaimer

The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the positions of the institutions the authors are affiliated with.

Acknowledgments

We acknowledge the work of the many researches who made seminal contributions to the development of the gene therapy field in Germany but who we could not mention in this article due to space constraints. We further thank Hinrich Abken, Regensburg, for helpful comments on the article.

Author Disclosure

A.S. is a consultant for Avrobio and Apriligen, holds gene therapy patents, and has research collaborations with Rocket and Avrobio. B.F. holds patents/IP in the field of gene therapy, which were licensed by UKE to AGCT and Bio-Rad, and serves as a consultant to AGCT. E.W. is a consultant for Coriolis Pharma Research, TargImmune Therapeutics, and has a research collaboration with Ethris. T.C. and C.M. have sponsored research collaborations with Cellectis, Cimeio Therapeutics, and Lepton Pharmaceuticals. T.C. serves on the scientific advisory board of Excision BioTherapeutics. U.K. is a consultant for Affimed, AstraZeneca, GammaDelta, Glycostem, and Zelluna, and has collaborations with Miltenyi Biotec and Novartis. The other authors declare no conflict of interest.

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