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Viruses
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State-of-the-Art Viral Vector Gene Therapy in Germany
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State-of-the-Art Viral Vector Gene Therapy in Germany

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 22318

Special Issue Editors

Dr. Manfred Schmidt

E-Mail Website
Guest Editor
GeneWerk GmbH, Heidelberg, Germany
Interests: hematology; oncology; virology; gene therapy; vector safety
Dr. Irene Gil-Farina

E-Mail Website
Guest Editor
GeneWerk GmbH, Heidelberg, Germany
Interests: cell and gene therapy; vectorology; virology; gene therapy safety; vector persistence; genotoxicity; immunotoxicity; NGS

Special Issue Information

Dear Colleagues,

Three decades after the first approved viral gene therapy clinical study, viral vectors are consolidated candidates for a wide range of therapeutic applications in clinical gene therapy, immunotherapy, and vaccination. R approvals of vector-based drugs have significantly boosted preclinical and clinical research in the field, providing the basis to understand and overcome the existing hurdles for effective and safe viral gene therapy products.

Since its early contribution to pioneering gammaretroviral clinical gene therapy studies, Germany has been actively participating in this evolution, and this Special Issue of Viruses aims to provide an overview of viral gene therapy and its state-of-the-art within the country. We cordially invite you to contribute reviews or original research articles giving insights into any step of the roadmap from basic research to preclinical and clinical studies, advances in viral and gene editing technologies, safety considerations, as well as awareness of the current regulatory framework.

Dr. Manfred Schmidt
Dr. Irene Gil-Farina
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • viral vectors
  • in vivo gene therapy
  • ex vivo gene therapy
  • immunotherapy
  • oncolytic viral vectors
  • viral vector immunogenicity
  • genotoxicity
  • gene therapy efficacy
  • viral vector manufacturing
  • regulatory aspects

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Published Papers (4 papers)

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Research

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17 pages, 2436 KiB  
Article
Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123
by Michael A. Morgan, Arnold Kloos, Daniela Lenz, Nadine Kattre, Juliette Nowak, Marco Bentele, Maximilian Keisker, Julia Dahlke, Katharina Zimmermann, Martin Sauer, Michael Heuser and Axel Schambach
Viruses 2021, 13(7), 1365; https://doi.org/10.3390/v13071365 - 14 Jul 2021
Cited by 25 | Viewed by 4860
Abstract
Anti-cancer activity can be improved by engineering immune cells to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens. Retroviral vector gene transfer strategies allow stable and durable transgene expression. Here, we used alpharetroviral vectors to modify NK-92 cells, a natural killer cell [...] Read more.
Anti-cancer activity can be improved by engineering immune cells to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens. Retroviral vector gene transfer strategies allow stable and durable transgene expression. Here, we used alpharetroviral vectors to modify NK-92 cells, a natural killer cell line, with a third-generation CAR designed to target the IL-3 receptor subunit alpha (CD123), which is strongly expressed on the surface of acute myeloid leukemia (AML) cells. Alpharetroviral vectors also contained a transgene cassette to allow constitutive expression of human IL-15 for increased NK cell persistence in vivo. The anti-AML activity of CAR-NK-92 cells was tested via in vitro cytotoxicity assays with the CD123+ AML cell line KG-1a and in vivo in a patient-derived xenotransplantation CD123+ AML model. Unmodified NK-92 cells or NK-92 cells modified with a truncated version of the CAR that lacked the signaling domain served as controls. Alpharetroviral vector-modified NK-92 cells stably expressed the transgenes and secreted IL-15. Anti-CD123-CAR-NK-92 cells exhibited enhanced anti-AML activity in vitro and in vivo as compared to control NK-92 cells. Our data (1) shows the importance of IL-15 expression for in vivo persistence of NK-92 cells, (2) supports continued investigation of anti-CD123-CAR-NK cells to target AML, and (3) points towards potential strategies to further improve CAR-NK anti-AML activity. Full article
(This article belongs to the Special Issue State-of-the-Art Viral Vector Gene Therapy in Germany)
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17 pages, 2748 KiB  
Article
Transduction Enhancers Enable Efficient Human Adenovirus Type 5-Mediated Gene Transfer into Human Multipotent Mesenchymal Stromal Cells
by Robin Nilson, Olivia Lübbers, Linus Weiß, Karmveer Singh, Karin Scharffetter-Kochanek, Markus Rojewski, Hubert Schrezenmeier, Philip Helge Zeplin, Wolfgang Funk, Lea Krutzke, Stefan Kochanek and Astrid Kritzinger
Viruses 2021, 13(6), 1136; https://doi.org/10.3390/v13061136 - 12 Jun 2021
Cited by 4 | Viewed by 5002
Abstract
Human multipotent mesenchymal stromal cells (hMSCs) are currently developed as cell therapeutics for different applications, including regenerative medicine, immune modulation, and cancer treatment. The biological properties of hMSCs can be further modulated by genetic engineering. Viral vectors based on human adenovirus type 5 [...] Read more.
Human multipotent mesenchymal stromal cells (hMSCs) are currently developed as cell therapeutics for different applications, including regenerative medicine, immune modulation, and cancer treatment. The biological properties of hMSCs can be further modulated by genetic engineering. Viral vectors based on human adenovirus type 5 (HAdV-5) belong to the most frequently used vector types for genetic modification of human cells in vitro and in vivo. However, due to a lack of the primary attachment receptor coxsackievirus and adenovirus receptor (CAR) in hMSCs, HAdV-5 vectors are currently not suitable for transduction of this cell type without capsid modification. Here we present several transduction enhancers that strongly enhance HAdV-5-mediated gene transfer into both bone marrow- and adipose tissue-derived hMSCs. Polybrene, poly-l-lysine, human lactoferrin, human blood coagulation factor X, spermine, and spermidine enabled high eGFP expression levels in hMSCs. Importantly, hMSCs treated with enhancers were not affected in their migration behavior, which is a key requisite for many therapeutic applications. Exemplary, strongly increased expression of tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6) (a secreted model therapeutic protein) was achieved by enhancer-facilitated HAdV-5 transduction. Thus, enhancer-mediated HAdV-5 vector transduction is a valuable method for the engineering of hMSCs, which can be further exploited for the development of innovative hMSC therapeutics. Full article
(This article belongs to the Special Issue State-of-the-Art Viral Vector Gene Therapy in Germany)
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Review

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29 pages, 1547 KiB  
Review
Virotherapy in Germany—Recent Activities in Virus Engineering, Preclinical Development, and Clinical Studies
by Dirk M. Nettelbeck, Mathias F. Leber, Jennifer Altomonte, Assia Angelova, Julia Beil, Susanne Berchtold, Maike Delic, Jürgen Eberle, Anja Ehrhardt, Christine E. Engeland, Henry Fechner, Karsten Geletneky, Katrin Goepfert, Per Sonne Holm, Stefan Kochanek, Florian Kreppel, Lea Krutzke, Florian Kühnel, Karl Sebastian Lang, Antonio Marchini, Markus Moehler, Michael D. Mühlebach, Ulrike Naumann, Roman Nawroth, Jürg Nüesch, Jean Rommelaere, Ulrich M. Lauer and Guy Ungerechtsadd Show full author list remove Hide full author list
Viruses 2021, 13(8), 1420; https://doi.org/10.3390/v13081420 - 21 Jul 2021
Cited by 27 | Viewed by 7157
Abstract
Virotherapy research involves the development, exploration, and application of oncolytic viruses that combine direct killing of cancer cells by viral infection, replication, and spread (oncolysis) with indirect killing by induction of anti-tumor immune responses. Oncolytic viruses can also be engineered to genetically deliver [...] Read more.
Virotherapy research involves the development, exploration, and application of oncolytic viruses that combine direct killing of cancer cells by viral infection, replication, and spread (oncolysis) with indirect killing by induction of anti-tumor immune responses. Oncolytic viruses can also be engineered to genetically deliver therapeutic proteins for direct or indirect cancer cell killing. In this review—as part of the special edition on “State-of-the-Art Viral Vector Gene Therapy in Germany”—the German community of virotherapists provides an overview of their recent research activities that cover endeavors from screening and engineering viruses as oncolytic cancer therapeutics to their clinical translation in investigator-initiated and sponsored multi-center trials. Preclinical research explores multiple viral platforms, including new isolates, serotypes, or fitness mutants, and pursues unique approaches to engineer them towards increased safety, shielded or targeted delivery, selective or enhanced replication, improved immune activation, delivery of therapeutic proteins or RNA, and redirecting antiviral immunity for cancer cell killing. Moreover, several oncolytic virus-based combination therapies are under investigation. Clinical trials in Germany explore the safety and potency of virotherapeutics based on parvo-, vaccinia, herpes, measles, reo-, adeno-, vesicular stomatitis, and coxsackie viruses, including viruses encoding therapeutic proteins or combinations with immune checkpoint inhibitors. These research advances represent exciting vantage points for future endeavors of the German virotherapy community collectively aimed at the implementation of effective virotherapeutics in clinical oncology. Full article
(This article belongs to the Special Issue State-of-the-Art Viral Vector Gene Therapy in Germany)
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Other

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11 pages, 2686 KiB  
Brief Report
Efficient Pseudotyping of Different Retroviral Vectors Using a Novel, Codon-Optimized Gene for Chimeric GALV Envelope
by Manuela Mirow, Lea Isabell Schwarze, Boris Fehse and Kristoffer Riecken
Viruses 2021, 13(8), 1471; https://doi.org/10.3390/v13081471 - 27 Jul 2021
Cited by 6 | Viewed by 4122
Abstract
The Gibbon Ape Leukemia Virus envelope protein (GALV-Env) mediates efficient transduction of human cells, particularly primary B and T lymphocytes, and is therefore of great interest in gene therapy. Using internal domains from murine leukemia viruses (MLV), chimeric GALV-Env proteins such as GALV-C [...] Read more.
The Gibbon Ape Leukemia Virus envelope protein (GALV-Env) mediates efficient transduction of human cells, particularly primary B and T lymphocytes, and is therefore of great interest in gene therapy. Using internal domains from murine leukemia viruses (MLV), chimeric GALV-Env proteins such as GALV-C4070A were derived, which allow pseudotyping of lentiviral vectors. In order to improve expression efficiency and vector titers, we developed a codon-optimized (co) variant of GALV-C4070A (coGALV-Env). We found that coGALV-Env mediated efficient pseudotyping not only of γ-retroviral and lentiviral vectors, but also α-retroviral vectors. The obtained titers on HEK293T cells were equal to those with the classical GALV-Env, whereas the required plasmid amounts for transient vector production were significantly lower, namely, 20 ng coGALV-Env plasmid per 106 293T producer cells. Importantly, coGALV-Env-pseudotyped γ- and α-retroviral, as well as lentiviral vectors, mediated efficient transduction of primary human T cells. We propose that the novel chimeric coGALV-Env gene will be very useful for the efficient production of high-titer vector preparations, e.g., to equip human T cells with novel specificities using transgenic TCRs or CARs. The considerably lower amount of plasmid needed might also result in a significant cost advantage for good manufacturing practice (GMP) vector production based on transient transfection. Full article
(This article belongs to the Special Issue State-of-the-Art Viral Vector Gene Therapy in Germany)
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