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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 ; Conference proceedings: [No title information]

Khanal, Rajendra / Yang, Taihua / Poenisch, Marion / Taubert, Richard / Engel, Bastian / Jaeckel, Elmar / Vogel, Arndt / Cantz, Tobias / Chevessier, Frédéric / Balakrishnan, Asha / Ott, Michael / Sharma, AmarDeep

Zeitschrift für Gastroenterologie

2022 Volume 60, Issue 01

Event/congress	38. Jahrestagung der Deutsche Arbeitsgemeinschaft zum Studium der Leber, Mannheim, 2022-01-28
Language	English
Publishing date	2022-01-01
Publisher	Georg Thieme Verlag
Publishing place	Stuttgart ; New York
Document type	Article ; Conference proceedings
ZDB-ID	201387-3
ISSN	1439-7803 ; 0044-2771 ; 0172-8504
ISSN (online)	1439-7803
ISSN	0044-2771 ; 0172-8504
DOI	10.1055/s-0041-1740682
Database	Thieme publisher's database

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Article ; Online: Corrigendum to 'Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model' [J Hepatol (2021) 1420-1433].

Yang, Taihua / Poenisch, Marion / Khanal, Rajendra / Hu, Qingluan / Dai, Zhen / Li, Ruomeng / Song, Guangqi / Yuan, Qinggong / Yao, Qunyan / Shen, Xizhong / Taubert, Richard / Engel, Bastian / Jaeckel, Elmar / Vogel, Arndt / Falk, Christine S / Schambach, Axel / Gerovska, Daniela / Araúzo-Bravo, Marcos J / Vondran, Florian W R /

Cantz, Tobias / Horscroft, Nigel / Balakrishnan, Asha / Chevessier, Frédéric / Ott, Michael / Sharma, Amar Deep

Journal of hepatology

2022 Volume 77, Issue 1, Page(s) 270

Language	English
Publishing date	2022-04-07
Publishing country	Netherlands
Document type	Published Erratum
ZDB-ID	605953-3
ISSN	1600-0641 ; 0168-8278
ISSN (online)	1600-0641
ISSN	0168-8278
DOI	10.1016/j.jhep.2022.03.023
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Article ; Online: New insights into structure and replication of the hepatitis C virus and clinical implications.

Poenisch, Marion / Bartenschlager, Ralf

Seminars in liver disease

2010 Volume 30, Issue 4, Page(s) 333–347

Abstract: With the advent of efficient systems to propagate the hepatitis C virus (HCV) in cultured cells important new discoveries have been made. For instance, several molecules required for HCV infection of hepatocytes have been identified and first insights ... ...

Abstract	With the advent of efficient systems to propagate the hepatitis C virus (HCV) in cultured cells important new discoveries have been made. For instance, several molecules required for HCV infection of hepatocytes have been identified and first insights into the entry pathway have been gained. Ribonucleic acid (RNA) replication and virion assembly were found to be tightly linked to lipid metabolism and numerous host factors contributing to viral replication have been identified. Some of them such as cyclophilin A or microRNA-122 are attractive targets for antiviral therapy as are the viral serine-type protease residing in nonstructural protein 3 (NS3) and the NS5B RNA-dependent RNA polymerase. More recently, the viral phosphoprotein NS5A emerged as an additional and very promising target for selective therapy. These results illustrate the great progress that has been made in the HCV field and how this knowledge can be used to devise innovative strategies to counteract this pathogen.
MeSH term(s)	Animals ; Cyclophilin A/physiology ; Genome, Viral/physiology ; Hepacivirus/genetics ; Hepacivirus/physiology ; Hepatitis C/genetics ; Hepatitis C/physiopathology ; Humans ; MicroRNAs/physiology ; Protein Biosynthesis/physiology ; RNA, Viral/physiology ; Viral Nonstructural Proteins/physiology ; Viral Proteins/genetics ; Viral Proteins/physiology ; Virion/physiology ; Virus Replication/physiology
Chemical Substances	MicroRNAs ; NS4B protein, flavivirus ; RNA, Viral ; Viral Nonstructural Proteins ; Viral Proteins ; Cyclophilin A (EC 5.2.1.-)
Language	English
Publishing date	2010-11
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	603177-8
ISSN	1098-8971 ; 0272-8087
ISSN (online)	1098-8971
ISSN	0272-8087
DOI	10.1055/s-0030-1267535
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Article: mRNA as a Novel Treatment Strategy for Hereditary Spastic Paraplegia Type 5.

Hauser, Stefan / Poenisch, Marion / Schelling, Yvonne / Höflinger, Philip / Schuster, Stefanie / Teegler, Axel / Betten, Rabea / Gustafsson, Jan-Åke / Hübener-Schmid, Jeannette / Schlake, Thomas / Chevessier-Tünnesen, Frédéric / Horscroft, Nigel / Björkhem, Ingemar / Schöls, Ludger

Molecular therapy. Methods & clinical development

2019 Volume 15, Page(s) 359–370

Abstract: Hereditary spastic paraplegia type 5 is a neurodegenerative disease caused by loss-of-function mutations in ... ...

Abstract	Hereditary spastic paraplegia type 5 is a neurodegenerative disease caused by loss-of-function mutations in the
Language	English
Publishing date	2019-10-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2872938-9
ISSN	2329-0501 ; 2329-0501
ISSN (online)	2329-0501
ISSN	2329-0501
DOI	10.1016/j.omtm.2019.10.011
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Article: New Insights into Structure and Replication of the Hepatitis C Virus and Clinical Implications

Poenisch, Marion / Bartenschlager, Ralf

Seminars in Liver Disease

2010 Volume 30, Issue 04, Page(s) 333–347

Abstract	With the advent of efficient systems to propagate the hepatitis C virus (HCV) in cultured cells important new discoveries have been made. For instance, several molecules required for HCV infection of hepatocytes have been identified and first insights into the entry pathway have been gained. Ribonucleic acid (RNA) replication and virion assembly were found to be tightly linked to lipid metabolism and numerous host factors contributing to viral replication have been identified. Some of them such as cyclophilin A or microRNA-122 are attractive targets for antiviral therapy as are the viral serine-type protease residing in nonstructural protein 3 (NS3) and the NS5B RNA-dependent RNA polymerase. More recently, the viral phosphoprotein NS5A emerged as an additional and very promising target for selective therapy. These results illustrate the great progress that has been made in the HCV field and how this knowledge can be used to devise innovative strategies to counteract this pathogen.
Keywords	STAT-C ; NS3 protease ; NS5A protein ; NS5B RNA-dependent RNA polymerase ; miR-122 ; cyclophilin A
Language	English
Publishing date	2010-10-19
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	603177-8
ISSN	1098-8971 ; 0272-8087
ISSN (online)	1098-8971
ISSN	0272-8087
DOI	10.1055/s-0030-1267535
Database	Thieme publisher's database

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Article: Second-site mutations in Borna disease virus overexpressing viral accessory protein X.

Poenisch, Marion / Wille, Sandra / Schneider, Urs / Staeheli, Peter

The Journal of general virology

2009 Volume 90, Issue Pt 8, Page(s) 1932–1936

Abstract: The X protein of Borna disease virus (BDV) is an essential factor that regulates viral polymerase activity and inhibits apoptosis of persistently infected cells. We observed that a BDV mutant which carries an additional X gene replicated well in cell ... ...

Abstract	The X protein of Borna disease virus (BDV) is an essential factor that regulates viral polymerase activity and inhibits apoptosis of persistently infected cells. We observed that a BDV mutant which carries an additional X gene replicated well in cell culture only after acquiring second-site mutations that selectively reduced expression of the endogenous X gene. In rat brains, the virus acquired additional mutations which inactivated the ectopic X gene or altered the sequence of X. These results demonstrate that BDV readily acquires mutations if strong selection pressure is applied. They further indicate that fine-tuning of X expression determines viral fitness.
MeSH term(s)	Animals ; Borna disease virus/genetics ; Borna disease virus/physiology ; Brain/virology ; DNA Mutational Analysis ; Gene Dosage ; Gene Expression Regulation, Viral ; Gene Knockout Techniques ; Mutation, Missense ; Rats ; Sequence Analysis, DNA ; Viral Regulatory and Accessory Proteins/biosynthesis ; Viral Regulatory and Accessory Proteins/genetics ; Virus Replication
Chemical Substances	Viral Regulatory and Accessory Proteins
Language	English
Publishing date	2009-05-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219316-4
ISSN	1465-2099 ; 0022-1317
ISSN (online)	1465-2099
ISSN	0022-1317
DOI	10.1099/vir.0.011841-0
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Article ; Online: Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model.

Cantz, Tobias / Horscroft, Nigel / Balakrishnan, Asha / Chevessier, Frédéric / Ott, Michael / Sharma, Amar Deep

Journal of hepatology

2021 Volume 75, Issue 6, Page(s) 1420–1433

Abstract: Background & aims: Therapeutic targeting of injuries that require transient restoration of proteins by mRNA delivery is an attractive approach that, until recently, has remained poorly explored. In this study, we examined the therapeutic utility of mRNA ...

Abstract	Background & aims: Therapeutic targeting of injuries that require transient restoration of proteins by mRNA delivery is an attractive approach that, until recently, has remained poorly explored. In this study, we examined the therapeutic utility of mRNA delivery for liver fibrosis and cirrhosis. Specifically, we aimed to demonstrate the therapeutic efficacy of human hepatocyte nuclear factor alpha (HNF4A) mRNA in mouse models of fibrosis and cirrhosis. Methods: We investigated restoration of hepatocyte functions by HNF4A mRNA transfection in vitro, and analyzed the attenuation of liver fibrosis and cirrhosis in multiple mouse models, by delivering hepatocyte-targeted biodegradable lipid nanoparticles (LNPs) encapsulating HNF4A mRNA. To identify potential mechanisms of action, we performed microarray-based gene expression profiling, single-cell RNA sequencing, and chromatin immunoprecipitation. We used primary liver cells and human liver buds for additional functional validation. Results: Expression of HNF4A mRNA led to restoration of the metabolic activity of fibrotic primary murine and human hepatocytes in vitro. Repeated in vivo delivery of LNP-encapsulated HNF4A mRNA induced a robust inhibition of fibrogenesis in 4 independent mouse models of hepatotoxin- and cholestasis-induced liver fibrosis. Mechanistically, we discovered that paraoxonase 1 is a direct target of HNF4A and it contributes to HNF4A-mediated attenuation of liver fibrosis via modulation of liver macrophages and hepatic stellate cells. Conclusion: Collectively, our findings provide the first direct preclinical evidence of the applicability of HNF4A mRNA therapeutics for the treatment of fibrosis in the liver. Lay summary: Liver fibrosis and cirrhosis remain unmet medical needs and contribute to high mortality worldwide. Herein, we take advantage of a promising therapeutic approach to treat liver fibrosis and cirrhosis. We demonstrate that restoration of a key gene, HNF4A, via mRNA encapsulated in lipid nanoparticles decreased injury in multiple mouse models of fibrosis and cirrhosis. Our study provides proof-of-concept that mRNA therapy is a promising strategy for reversing liver fibrosis and cirrhosis.
MeSH term(s)	Animals ; Disease Models, Animal ; Hepatocyte Nuclear Factor 4/pharmacology ; Hepatocyte Nuclear Factor 4/therapeutic use ; Liver Cirrhosis/drug therapy ; Mice ; RNA, Messenger/pharmacology ; RNA, Messenger/therapeutic use
Chemical Substances	HNF4A protein, human ; Hepatocyte Nuclear Factor 4 ; RNA, Messenger
Language	English
Publishing date	2021-08-25
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605953-3
ISSN	1600-0641 ; 0168-8278
ISSN (online)	1600-0641
ISSN	0168-8278
DOI	10.1016/j.jhep.2021.08.011
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Article: Viral accessory protein X stimulates the assembly of functional Borna disease virus polymerase complexes.

Poenisch, Marion / Staeheli, Peter / Schneider, Urs

The Journal of general virology

2008 Volume 89, Issue Pt 6, Page(s) 1442–1445

Abstract: The Borna disease virus (BDV) proteins X and P are translated from a bicistronic viral mRNA. Here, it was shown that the rescue of recombinant BDV from cDNA was enhanced approximately eightfold if reconstitution of the viral polymerase complex was ... ...

Abstract	The Borna disease virus (BDV) proteins X and P are translated from a bicistronic viral mRNA. Here, it was shown that the rescue of recombinant BDV from cDNA was enhanced approximately eightfold if reconstitution of the viral polymerase complex was performed with an expression vector encoding X and P rather than P alone. The results provide evidence that appropriate amounts of X reduce the previously reported high sensitivity of the BDV polymerase to imbalances between the viral proteins N and P. These data indicate that X buffers an unfavourable excess of P, thereby stimulating the assembly of functional BDV polymerase complexes.
MeSH term(s)	Animals ; Borna Disease/virology ; Borna disease virus/chemistry ; Borna disease virus/physiology ; Cell Line ; DNA-Directed RNA Polymerases/metabolism ; Humans ; Nucleoproteins ; Viral Regulatory and Accessory Proteins/physiology ; Virus Replication
Chemical Substances	Nucleoproteins ; Viral Regulatory and Accessory Proteins ; DNA-Directed RNA Polymerases (EC 2.7.7.6)
Language	English
Publishing date	2008-04-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219316-4
ISSN	1465-2099 ; 0022-1317
ISSN (online)	1465-2099
ISSN	0022-1317
DOI	10.1099/vir.0.2008/000638-0
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Article ; Online: Polymerase read-through at the first transcription termination site contributes to regulation of borna disease virus gene expression.

Poenisch, Marion / Wille, Sandra / Staeheli, Peter / Schneider, Urs

Journal of virology

2008 Volume 82, Issue 19, Page(s) 9537–9545

Abstract: An unusually long noncoding sequence is located between the N gene of Borna disease virus (BDV) and the genes for regulatory factor X and polymerase cofactor P. Most of these nucleotides are transcribed and seem to control translation of the bicistronic ... ...

Abstract	An unusually long noncoding sequence is located between the N gene of Borna disease virus (BDV) and the genes for regulatory factor X and polymerase cofactor P. Most of these nucleotides are transcribed and seem to control translation of the bicistronic X/P mRNA. We report here that Vero cells persistently infected with mutant viruses containing minor alterations in this control region showed almost normal levels of N, X, and P proteins but exhibited greatly reduced levels of mRNAs coding for these viral gene products. Surprisingly, cells infected with these BDV mutants accumulated a viral transcript 1.9 kb in length that represents a capped and polyadenylated mRNA containing the coding regions of the N, X, and P genes. Cells infected with wild-type BDV also contained substantial amounts of this read-through mRNA, which yielded both N and P protein when translated in vitro. Viruses carrying mutations that promoted read-through transcription at the first gene junction failed to replicate in the brain of adult rats. In the brains of newborn rats, these mutant viruses were able to replicate after acquiring second-site mutations in or near the termination signal located downstream of the N gene. Thus, sequence elements adjacent to the core termination signal seem to regulate the frequency by which the polymerase terminates transcription after the N gene. We conclude from these observations that BDV uses read-through transcription for fine-tuning the expression of the N, X, and P genes which, in turn, influence viral polymerase activity.
MeSH term(s)	Animals ; Base Sequence ; Borna disease virus/genetics ; Borna disease virus/metabolism ; Brain/metabolism ; Chlorocebus aethiops ; Gene Expression Regulation, Viral ; Models, Genetic ; Molecular Sequence Data ; Mutation ; Polyadenylation ; RNA, Messenger/metabolism ; Rats ; Transcription, Genetic ; Vero Cells ; Virus Replication
Chemical Substances	RNA, Messenger
Language	English
Publishing date	2008-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00639-08
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