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Article ; Online: Co-administration of an effector antibody enhances the half-life and therapeutic potential of RNA-encoded nanobodies.

Thran, Moritz / Pönisch, Marion / Danz, Hillary / Horscroft, Nigel / Ichtchenko, Konstantin / Tzipori, Saul / Shoemaker, Charles B

Scientific reports

2023 Volume 13, Issue 1, Page(s) 14632

Abstract: The incidence of Clostridioides difficile infection (CDI) and associated mortality have increased rapidly worldwide in recent years. Therefore, it is critical to develop new therapies for CDI. Here we report on the development of mRNA-LNPs encoding ... ...

Abstract	The incidence of Clostridioides difficile infection (CDI) and associated mortality have increased rapidly worldwide in recent years. Therefore, it is critical to develop new therapies for CDI. Here we report on the development of mRNA-LNPs encoding camelid-derived V
MeSH term(s)	Swine ; Animals ; Mice ; Single-Domain Antibodies ; RNA ; Clostridioides difficile ; Half-Life ; Antibodies ; RNA, Messenger
Chemical Substances	Single-Domain Antibodies ; RNA (63231-63-0) ; Antibodies ; RNA, Messenger
Language	English
Publishing date	2023-09-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-41092-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: mRNA as novel technology for passive immunotherapy

Schlake, Thomas / Thess, Andreas / Thran, Moritz / Jordan, Ingo

Cellular and molecular life sciences. 2019 Jan., v. 76, no. 2

2019

Abstract: While active immunization elicits a lasting immune response by the body, passive immunotherapy transiently equips the body with exogenously generated immunological effectors in the form of either target-specific antibodies or lymphocytes functionalized ... ...

Abstract	While active immunization elicits a lasting immune response by the body, passive immunotherapy transiently equips the body with exogenously generated immunological effectors in the form of either target-specific antibodies or lymphocytes functionalized with target-specific receptors. In either case, administration or expression of recombinant proteins plays a fundamental role. mRNA prepared by in vitro transcription (IVT) is increasingly appreciated as a drug substance for delivery of recombinant proteins. With its biological role as transient carrier of genetic information translated into protein in the cytoplasm, therapeutic application of mRNA combines several advantages. For example, compared to transfected DNA, mRNA harbors inherent safety features. It is not associated with the risk of inducing genomic changes and potential adverse effects are only temporary due to its transient nature. Compared to the administration of recombinant proteins produced in bioreactors, mRNA allows supplying proteins that are difficult to manufacture and offers extended pharmacokinetics for short-lived proteins. Based on great progress in understanding and manipulating mRNA properties, efficacy data in various models have now demonstrated that IVT mRNA constitutes a potent and flexible platform technology. Starting with an introduction into passive immunotherapy, this review summarizes the current status of IVT mRNA technology and its application to such immunological interventions.
Keywords	DNA ; adverse effects ; antibodies ; bioreactors ; cytoplasm ; drugs ; genomics ; immune response ; immunization ; lymphocytes ; manufacturing ; messenger RNA ; models ; pharmacokinetics ; receptors ; recombinant proteins ; risk ; transcription (genetics) ; translation (genetics) ; covid19
Language	English
Dates of publication	2019-01
Size	p. 301-328.
Publishing place	Springer International Publishing
Document type	Article
Note	Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-018-2935-4
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: mRNA as novel technology for passive immunotherapy.

Schlake, Thomas / Thess, Andreas / Thran, Moritz / Jordan, Ingo

Cellular and molecular life sciences : CMLS

2018 Volume 76, Issue 2, Page(s) 301–328

Abstract	While active immunization elicits a lasting immune response by the body, passive immunotherapy transiently equips the body with exogenously generated immunological effectors in the form of either target-specific antibodies or lymphocytes functionalized with target-specific receptors. In either case, administration or expression of recombinant proteins plays a fundamental role. mRNA prepared by in vitro transcription (IVT) is increasingly appreciated as a drug substance for delivery of recombinant proteins. With its biological role as transient carrier of genetic information translated into protein in the cytoplasm, therapeutic application of mRNA combines several advantages. For example, compared to transfected DNA, mRNA harbors inherent safety features. It is not associated with the risk of inducing genomic changes and potential adverse effects are only temporary due to its transient nature. Compared to the administration of recombinant proteins produced in bioreactors, mRNA allows supplying proteins that are difficult to manufacture and offers extended pharmacokinetics for short-lived proteins. Based on great progress in understanding and manipulating mRNA properties, efficacy data in various models have now demonstrated that IVT mRNA constitutes a potent and flexible platform technology. Starting with an introduction into passive immunotherapy, this review summarizes the current status of IVT mRNA technology and its application to such immunological interventions.
MeSH term(s)	Animals ; Antibodies/genetics ; Antibodies/metabolism ; Genetic Vectors/genetics ; Genetic Vectors/metabolism ; Humans ; Immunization, Passive ; Immunotherapy, Adoptive ; RNA Caps/chemistry ; RNA Caps/genetics ; RNA Caps/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
Chemical Substances	Antibodies ; RNA Caps ; RNA, Messenger
Keywords	covid19
Language	English
Publishing date	2018-10-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-018-2935-4
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Article: Optimised Non-Coding Regions of mRNA SARS-CoV-2 Vaccine CV2CoV Improves Homologous and Heterologous Neutralising Antibody Responses.

Roth, Nicole / Schön, Jacob / Hoffmann, Donata / Thran, Moritz / Thess, Andreas / Mueller, Stefan O / Petsch, Benjamin / Rauch, Susanne

Vaccines

2022 Volume 10, Issue 8

Abstract: More than two years after the emergence of SARS-CoV-2, 33 COVID-19 vaccines, based on different platforms, have been approved in 197 countries. Novel variants that are less efficiently neutralised by antibodies raised against ancestral SARS-CoV-2 are ... ...

Abstract	More than two years after the emergence of SARS-CoV-2, 33 COVID-19 vaccines, based on different platforms, have been approved in 197 countries. Novel variants that are less efficiently neutralised by antibodies raised against ancestral SARS-CoV-2 are circulating, highlighting the need to adapt vaccination strategies. Here, we compare the immunogenicity of a first-generation mRNA vaccine candidate, CVnCoV, with a second-generation mRNA vaccine candidate, CV2CoV, in rats. Higher levels of spike (S) protein expression were observed in cell culture with the CV2CoV mRNA than with the CVnCoV mRNA. Vaccination with CV2CoV also induced higher titres of virus neutralising antibodies with accelerated kinetics in rats compared with CVnCoV. Significant cross-neutralisation of the SARS-CoV-2 variants, Alpha (B.1.1.7), Beta (B.1.351), and the 'mink' variant (B1.1.298) that were circulating at the time in early 2021 were also demonstrated. In addition, CV2CoV induced higher levels of antibodies at lower doses than CVnCoV, suggesting that dose-sparing could be possible with the next-generation SARS-CoV-2 vaccine, which could improve worldwide vaccine supply.
Language	English
Publishing date	2022-08-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines10081251
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Article ; Online: mRNA: A Novel Avenue to Antibody Therapy?

Schlake, Thomas / Thran, Moritz / Fiedler, Katja / Heidenreich, Regina / Petsch, Benjamin / Fotin-Mleczek, Mariola

Molecular therapy : the journal of the American Society of Gene Therapy

2019 Volume 27, Issue 4, Page(s) 773–784

Abstract: First attempts to use exogenous mRNA for protein expression in vivo were made more than 25 years ago. However, widespread appreciation of in vitro transcribed mRNA as a powerful technology for supplying therapeutic proteins to the body has evolved only ... ...

Abstract	First attempts to use exogenous mRNA for protein expression in vivo were made more than 25 years ago. However, widespread appreciation of in vitro transcribed mRNA as a powerful technology for supplying therapeutic proteins to the body has evolved only during the past few years. Various approaches to turning mRNA into a potent therapeutic have been developed. All of them share utilization of specifically designed, rather than endogenous, sequences and thorough purification protocols. Apart from this, there are two fundamental philosophies, one promoting the use of chemically modified nucleotides, the other advocating restriction to unmodified building blocks. Meanwhile, both strategies have received broad support by successful mRNA-based protein treatments in animal models. For such in vivo use, specifically optimized mRNA had to be combined with potent formulations to enable efficient in vivo delivery. The present review analyzes the applicability of mRNA technology to antibody therapy in all main fields: antitoxins, infectious diseases, and oncology.
MeSH term(s)	Animals ; Antibodies, Monoclonal/genetics ; Communicable Diseases/therapy ; Drug Compounding/methods ; Drug Delivery Systems/methods ; Humans ; Immunization, Passive/methods ; Lipids/chemistry ; Nanoparticles/chemistry ; Neoplasms/therapy ; RNA, Messenger/administration & dosage ; RNA, Messenger/therapeutic use ; Toxins, Biological/immunology
Chemical Substances	Antibodies, Monoclonal ; Lipids ; RNA, Messenger ; Toxins, Biological
Language	English
Publishing date	2019-03-06
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1016/j.ymthe.2019.03.002
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Book ; Online: Optimised non-coding regions of mRNA SARS-CoV-2 vaccine CV2CoV improves homogeneous and heterogenous neutralising antibody responses

Roth, Nicole / Schön, Jacob / Hoffmann, Donata / Thran, Moritz / Thess, Andreas / Mueller, Stefan O. / Petsch, Benjamin / Rauch, Susanne

[Preprint] ; CV2CoV, an enhanced mRNA-based SARS-CoV-2 vaccine candidate, supports higher protein expression and improved immunogenicity in rats

2022

Abstract	More than two years after the emergence of SARS-CoV-2, 33 COVID-19 vaccines, based on different platforms, have been approved in 197 countries. Novel variants that are less efficiently neutralised by antibodies raised against ancestral SARS-CoV-2 are circulating, highlighting the need to adapt vaccination strategies. Here, we compare the immunogenicity of a first-generation mRNA vaccine candidate, CVnCoV, with a second-generation mRNA vaccine candidate, CV2CoV, in rats. Higher levels of spike (S) protein expression were observed in cell culture with CV2CoV mRNA than with CVnCoV mRNA. Vaccination with CV2CoV also induced higher titres of virus neutralising antibodies with accelerated kinetics in rats compared with CVnCoV. Significant cross-neutralization of the SARS-CoV-2 variants, Alpha (B.1.1.7), Beta (B.1.351), and the ‘mink’ variant (B1.1.298) that were circulating at the time in early 2021 was also demonstrated. In addition, CV2CoV induced higher levels of antibodies at lower doses than CVnCoV, suggesting that dose-sparing could be possible with the next generation SARS-CoV-2 vaccine which could improve worldwide vaccine supply.
Keywords	Text ; ddc:570 ; SARs-CoV-2 -- mRNA vaccine -- COVID-19 -- COVID-19 variant -- immunogenicity -- virus neutralising antibody titre
Language	English
Publishing date	2022-07-14
Publisher	Cold Spring Harbor Laboratory
Publishing country	de
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Optimised Non-Coding Regions of mRNA SARS-CoV-2 Vaccine CV2CoV Improves Homologous and Heterologous Neutralising Antibody Responses

Roth, Nicole / Schön, Jacob / Hoffmann, Donata / Thran, Moritz / Thess, Andreas / Mueller, Stefan O. / Petsch, Benjamin / Rauch, Susanne

2022

Abstract	More than two years after the emergence of SARS-CoV-2, 33 COVID-19 vaccines, based on different platforms, have been approved in 197 countries. Novel variants that are less efficiently neutralised by antibodies raised against ancestral SARS-CoV-2 are circulating, highlighting the need to adapt vaccination strategies. Here, we compare the immunogenicity of a first-generation mRNA vaccine candidate, CVnCoV, with a second-generation mRNA vaccine candidate, CV2CoV, in rats. Higher levels of spike (S) protein expression were observed in cell culture with the CV2CoV mRNA than with the CVnCoV mRNA. Vaccination with CV2CoV also induced higher titres of virus neutralising antibodies with accelerated kinetics in rats compared with CVnCoV. Significant cross-neutralisation of the SARS-CoV-2 variants, Alpha (B.1.1.7), Beta (B.1.351), and the ‘mink’ variant (B1.1.298) that were circulating at the time in early 2021 were also demonstrated. In addition, CV2CoV induced higher levels of antibodies at lower doses than CVnCoV, suggesting that dose-sparing could be possible with the next-generation SARS-CoV-2 vaccine, which could improve worldwide vaccine supply.
Keywords	Text ; ddc:570 ; SARs-CoV-2 -- mRNA vaccine -- COVID-19 -- COVID-19 variant -- immunogenicity -- virus neutralising antibody titre
Language	English
Publishing date	2022-08-04
Publisher	Cold Spring Harbor Laboratory
Publishing country	de
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Book ; Online: CV2CoV, an enhanced mRNA-based SARS-CoV-2 vaccine candidate, supports higher protein expression and improved immunogenicity in rats

Roth, Nicole / Schön, Jacob / Hoffmann, Donata / Thran, Moritz / Thess, Andreas / Mueller, Stefan O. / Petsch, Benjamin / Rauch, Susanne

[Preprint]

2021

Abstract: More than a year after emergence of the SARS-CoV-2 pandemic, multiple first-generation vaccines are approved and available for vaccination. Still, many challenges remain. The ongoing vaccination programs across the globe suffer from insufficient vaccine ... ...

Abstract	More than a year after emergence of the SARS-CoV-2 pandemic, multiple first-generation vaccines are approved and available for vaccination. Still, many challenges remain. The ongoing vaccination programs across the globe suffer from insufficient vaccine supply. The virus is adapting to the human host and novel variants are circulating that are neutralised less efficiently by antibodies raised against ancestral SARS-CoV-2 variants. Here, we describe CV2CoV, a second-generation mRNA vaccine developed for enhanced protein expression and immunogenicity. CV2CoV supports increased levels of protein expression in cell culture compared to our clinical candidate CVnCoV. Vaccination with CV2CoV induces high levels of virus neutralising antibodies with accelerated kinetics in rats. Robust antibody responses are reflected in significant cross-neutralisation of circulating SARS-CoV-2 variants of concern, i.e. B.1.1.7 and B.1.351. Together, these results underline the value of CV2CoV as next-generation SARS-CoV-2 mRNA vaccine
Keywords	Text ; ddc:570 ; Pressespiegel -- Friedrich-Loeffler-Institut -- Forschung -- Coronavirus -- SARS-CoV-2 -- Covid-19 -- Impfstoff -- CureVac -- CV2CoV -- second-generation mRNA vaccine
Subject code	570
Language	English
Publishing date	2021-05-13
Publishing country	de
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: CV2CoV, an enhanced mRNA-based SARS-CoV-2 vaccine candidate, supports higher protein expression and improved immunogenicity in rats

Roth, Nicole / Schoen, Jacob / Hoffmann, Donata / Thran, Moritz / Thess, Andreas / Mueller, Stefan O. / Petsch, Benjamin / Rauch, Susanne

bioRxiv

Abstract	More than a year after emergence of the SARS-CoV-2 pandemic, multiple first-generation vaccines are approved and available for vaccination. Still, many challenges remain. The ongoing vaccination programs across the globe suffer from insufficient vaccine supply. The virus is adapting to the human host and novel variants are circulating that are neutralised less efficiently by antibodies raised against ancestral SARS-CoV-2 variants. Here, we describe CV2CoV, a second-generation mRNA vaccine developed for enhanced protein expression and immunogenicity. CV2CoV supports increased levels of protein expression in cell culture compared to our clinical candidate CVnCoV. Vaccination with CV2CoV induces high levels of virus neutralising antibodies with accelerated kinetics in rats. Robust antibody responses are reflected in significant cross-neutralisation of circulating SARS-CoV-2 variants of concern, i.e. B.1.1.7 and B.1.351. Together, these results underline the value of CV2CoV as next-generation SARS-CoV-2 mRNA vaccine
Keywords	covid19
Language	English
Publishing date	2021-05-13
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.05.13.443734
Database	COVID19

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Article ; Online: The Arabidopsis DCP2 gene is required for proper mRNA turnover and prevents transgene silencing in Arabidopsis.

Thran, Moritz / Link, Katrin / Sonnewald, Uwe

The Plant journal : for cell and molecular biology

2012 Volume 72, Issue 3, Page(s) 368–377

Abstract: Post-transcriptional gene silencing often limits the over-expression of transgenes in transgenic plants. It involves RNA-DEPENDENT RNA POLYMERASE 6 (RDR6), which recognizes aberrant transcripts, such as inaccurately processed or uncapped mRNA, and ... ...

Abstract	Post-transcriptional gene silencing often limits the over-expression of transgenes in transgenic plants. It involves RNA-DEPENDENT RNA POLYMERASE 6 (RDR6), which recognizes aberrant transcripts, such as inaccurately processed or uncapped mRNA, and triggers silencing of target transcripts. Here, we describe the isolation and characterization of an Arabidopsis mutant displaying increased transgene silencing (its1). Reduced accumulation of transgene mRNA in the its1 mutant background was accompanied by accumulation of transgene-specific siRNAs and was overcome by potyvirus infection. We therefore speculated that ITS1 is a suppressor of post-transcriptional gene silencing. Map-based cloning and subsequent complementation revealed that ITS1 encodes DECAPPING 2 (DCP2), which is crucial for decapping, a prerequisite for mRNA degradation. In agreement with the proposed function of DCP2, we found a reduced accumulation of uncapped mRNA in the its1 mutant. Furthermore, silencing in the its1 mutant was dependent on RDR6 function, suggesting that reduced decapping leads to accumulation of aberrant capped mRNA. Hence, we provide evidence for a class of aberrant mRNA that accumulates upon impaired mRNA decapping and triggers post-transcriptional gene silencing in Arabidopsis. As DCP2 knockouts cause post-embryo lethality, we isolated a hypomorphic dcp2 allele, providing insights into mRNA degradation and its interplay with post-transcriptional gene silencing.
MeSH term(s)	Amino Acid Sequence ; Arabidopsis/genetics ; Arabidopsis/growth & development ; Arabidopsis/metabolism ; Arabidopsis Proteins/genetics ; Arabidopsis Proteins/metabolism ; Chromosome Mapping ; Endoribonucleases/genetics ; Endoribonucleases/metabolism ; Gene Knockout Techniques ; Green Fluorescent Proteins ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Phenotype ; Plants, Genetically Modified ; RNA Caps/metabolism ; RNA Interference ; RNA Processing, Post-Transcriptional ; RNA Replicase/genetics ; RNA Replicase/metabolism ; RNA Stability ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Recombinant Fusion Proteins ; Seedlings/genetics ; Seedlings/growth & development ; Seedlings/metabolism ; Sequence Alignment ; Transgenes
Chemical Substances	Arabidopsis Proteins ; RNA Caps ; RNA, Messenger ; RNA, Small Interfering ; Recombinant Fusion Proteins ; Green Fluorescent Proteins (147336-22-9) ; RDR6 protein, Arabidopsis (EC 2.7.7.48) ; RNA Replicase (EC 2.7.7.48) ; Endoribonucleases (EC 3.1.-) ; Dcp2 protein, Arabidopsis (EC 3.1.27.-)
Language	English
Publishing date	2012-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1088037-9
ISSN	1365-313X ; 0960-7412
ISSN (online)	1365-313X
ISSN	0960-7412
DOI	10.1111/j.1365-313X.2012.05066.x
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