EpiCure gewinnt 2. Runde beim Businessplanwettbewerb der BayStartUp
Body Short (Textauszug mit 100 Zeichen automatisch aus Blogbeitrag erstellt)
EisbachBio GmbH: Allosterischen Inhibitors für ALC1 erhält FDA-Freigabe
Body Short (Textauszug mit 100 Zeichen automatisch aus Blogbeitrag erstellt)
LMU Spin-off: Gründung der QuGen GmbH
Body Short (Textauszug mit 100 Zeichen automatisch aus Blogbeitrag erstellt)
Efficient Tandem Cu-Catalyzed Click Synthesis of Multi-Sugar-Modified Oligonucleotides.
12. April 2024
Angewandte Chemie Internation Edition
Tölke AJ, Gaisbauer JF, Gärtner YV, Steigenberger B, Holovan A, Streshnev F, Schneider S, Müller M, Carell T.
Nucleic acids in the form of siRNA, antisense oligonucleotides or mRNA are currently explored as new promising modalities in the pharmaceutical industry. Particularly, the success of mRNA-vaccines against SARS-CoV-2, along with the successful development of the first sugar-modified siRNA therapeutics has inspired the field. The development of nucleic acid therapeutics requires efficient chemistry to link oligonucleotides to chemical structures that can improve stability, boost cellular uptake, or enable specific targeting. For the siRNA therapeutics currently in use, modification of the 3′-end of the oligonucleotides with triple-N-acetylgalactosamine (GalNAc)3 was shown to be of significance. This modification is currently achieved via a cumbersome multi-step synthesis and subsequent loading onto the solid support material. Here, we report the development of a bifunctional click-reactive linker that allows the modification of oligonucleotides in a tandem click reaction with multiple sugars, regardless of the position within the oligonucleotide, with remarkable efficiency and in a one-pot reaction.
Cu-Catalyzed Azide–Alkyne–Thiol Reaction Forms Ubiquitous Background in Chemical Proteomic Studies.
12. Januar 2024
Journal of the American Chemical Society
Wriest, A and Kielkowski P.
We report here a Cu-catalyzed azide–alkyne–thiol reaction forming thiotriazoles as the major byproduct under widely used bio-orthogonal protein labeling “click” conditions. The development of Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) had a tremendous impact on many biological discoveries. However, the considered chemoselectivity of CuAAC is hampered by the high reactivity of cysteine free thiols, yielding thiotriazole protein conjugates. The reaction byproducts generate false-positive protein hits in functional proteomic studies. The reported detail investigation of conjugates between chemical probes containing terminal alkynes, azide tags, and cell lysates reveals the formation of thiotriazoles, which can be readily detected by in-gel fluorescence scanning or after peptide and protein enrichment by mass spectrometry-based proteomics. In protein level identification and quantification experiments, the produced fluorescent bands or enriched proteins may not result from the important enzymatically driven reaction and can be falsely assigned as hits. This study provides a complete list of the most common background proteins. The knowledge of this previously overlooked reactivity now leads to the introduction of modified CuAAC conditions, which avoids the undesired product formation, diminishes the background, and hence improves the signal-to-noise ratio.
CNATM Lecture: Patrick Baumhof
23. Januar 2024, 17:15 Uhr
Developing mRNA based Therapeutics
Over the past years mRNA based therapeutics moved into the focus of drug development. With mRNA based vaccines in the market now the field is looking towards broader application of the technology. As a pioneer in the field CureVac has discovered several main principles that are relevant in development. The presentation discusses different applications of mRNA in drug development.
Patrick Baumhof is Senior Vice President of Technology at CureVac (Tübingen)
Location: ICEM / House L, Seminarraum, Würmtalstr. 201, 81377 Munich
Für die Teilnahme ist eine Anmeldung per E-Mail erforderlich.
CNATM Meeting
18. January 2024
We would like to thank all the participants of our cluster meeting who helped to make the event a great success. The presentations on the progress of our projects were exciting and highlighted the commitment and innovative strength of our cluster members.
We look forward to the next meeting and to continuing our dialogue in the future.
Lipoamino bundle LNPs for efficient mRNA transfection of dendritic cells
and macrophages show high spleen selectivity
06. Dezember 2023
European Journal of Pharmaceutics and Biopharmaceutics
Messenger RNA (mRNA) is a powerful tool for nucleic acid-based therapies and vaccination, but efficient and specific delivery to target tissues remains a significant challenge. In this study, we demonstrate lipoamino xenopeptide carriers as components of highly efficient mRNA LNPs. These lipo-xenopeptides are defined as 2D sequences in different 3D topologies (bundles or different U-shapes). The polar artificial amino acid tetraethylene pentamino succinic acid (Stp) and various lipophilic tertiary lipoamino fatty acids (LAFs) act as ionizable amphiphilic units, connected in different ratios via bisamidated lysines as branching units. A series of more lipophilic LAF4-Stp1 carriers with bundle topology is especially well suited for efficient encapsulation of mRNA into LNPs, facilitated cellular uptake and strongly enhanced endosomal escape. These LNPs display improved, faster transfection kinetics compared to standard LNP formulations, with high potency in a variety of tumor cell lines (including N2a neuroblastoma, HepG2 and Huh7 hepatocellular, and HeLa cervical carcinoma cells), J774A.1 macrophages, and DC2.4 dendritic cells. High transfection levels were obtained even in the presence of serum at very low sub-microgram mRNA doses. Upon intravenous application of only 3 µg mRNA per mouse, in vivo mRNA expression is found with a high selectivity for dendritic cells and macrophages, resulting in a particularly high overall preferred expression in the spleen.
CNATM-Lecture: Roy van der Meel
30. November 2023, 17:15
Gene Silencing in HSPCs with an Apolipoprotein A1-Based Nanodelivery Platform
Nucleic acid therapeutics are revolutionizing healthcare via gene inhibition, addition, replacement or editing. Lipid nanoparticle (LNP) technology is the current gold standard platform that enabled the clinical translation of the first siRNA drug Onpattro and the COVID-19 mRNA vaccines. Nevertheless, current LNP systems are mostly suited for vaccine purposes following local administration or hepatic delivery following intravenous administration. To unleash RNA’s full therapeutic potential, Roy van der Meel introduces modular nanoplatform technology for systemic nucleic acid delivery to immune cells in hematopoietic organs using apolipoproteins.
Roy van der Meel is Professor of Precision Medicine in the Department of Biomedical Engineering at Eindhoven University of Technology. ist Professor für Präzisionsmedizin in der Abteilung für Biomedizinische Technik an der Technischen Universität Eindhoven.
Location: ICEM / House L, Seminarraum, Würmtalstr. 201, 81377 Munich
Für die Teilnahme ist eine Anmeldung erforderlich.
ERC Strating Grant for Dr. Daniel Andergassen
November 2023
Dr Daniel Andergassen received an ERC Starting Grant for his research on the molecular causes of gender-specific differences in heart failure.
m4 Award for Prof. Urlike Protzer and her Project TherVacB
25. Oktober. 2023
Prof. Ulrike Protzer and her project TherVacB was one of the 5 winners of the Bavarian m4 Award from BioM. TherVacB is a project for the development of a therapeutic vaccine against Hepatitis B virus.
The m4 Award is a pre-funding award for innovative, high-potential medical biotechnology projects, with prize funds to further explore solutions to innovative medical problems.
An Aminoisoxazole-Based Proto-RNA
12. Oktober 2023
Chemistry Europe 2023, e202300057
Felix Xu, Stefan Wiedemann, Jonas Feldmann, Sidney Becker and Thomas Carell
The RNA world hypothesis predicts that life started with the development of replicating and catalytically active RNA, which evolved in a process of molecular evolution to increasingly complex chemical structures. RNA is, however, so complex that it has most likely formed from a precursor (proto-RNA) that was more easily accessible in a prebiotic world. Recently, 3-aminoisoxazoles (IO3) were identified as building blocks that can form under prebiotic conditions and can rearrange to give the nucleoside cytidine (C). The present study shows that the constitutional isomer 5-aminoisoxazole (IO5) can undergo the same reaction to give uridine (U). Both compounds (IO3 and IO5), if embedded in RNA, react selectively to C and U, which are the main pyrimidine nucleosides of the genetic system. Importantly, the stereochemical outcome of the IO5 reaction in RNA depends on the neighboring bases. If they are β- configured RNA nucleosides, the reaction proceeds with high selectivity to give exclusively the β-configured U RNA base (anomeric control).
ERC Starting Grant for Prof. Baer de Oliveira Mann
September 2023
Prof Baer de Oliveira Mann received an ERC Starting Grant for her NTase Pro project.
Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage
28. Juli 2023
Christina Beck, Deepak Ramanujam, Paula Vaccarello, Florenc Widenmeyer, Martin Feuerherd, Cho-Chin Cheng, Anton Bomhard, Tatiana Abikeeva, Julia Schädler, Jan-Peter Sperhake, Matthias Graw, Seyer Safi, Hans Hoffmann, Claudia A. Staab-Weijnitz, Roland Rad, Ulrike Protzer, Thomas Frischmuth, Stefan Engelhardt
Recent studies of severe acute inflammatory lung disease including COVID-19 identify macrophages to drive pulmonary hyperinflammation and long-term damage such as fibrosis. Here, we report on the development of a first-in-class, carbohydrate-coupled inhibitor of microRNA-21 (RCS-21), as a therapeutic means against pulmonary hyperinflammation and fibrosis. MicroRNA-21 is among the strongest upregulated microRNAs in human COVID-19 and in mice with acute inflammatory lung damage, and it is the strongest expressed microRNA in pulmonary macrophages. Chemical linkage of a microRNA-21 inhibitor to trimannose achieves rapid and specific delivery to macrophages upon inhalation in mice. RCS-21 reverses pathological activation of macrophages and prevents pulmonary dysfunction and fibrosis after acute lung damage in mice. In human lung tissue infected with SARS-CoV-2 ex vivo, RCS-21 effectively prevents the exaggerated inflammatory response. Our data imply trimannose-coupling for effective and selective delivery of inhaled oligonucleotides to pulmonary macrophages and report on a first mannose-coupled candidate therapeutic for COVID-19.
Press release for publication in Nature Communications
08. August 2023
Click here for the article about the publication: "Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung injury" in Nature Communications
CNATM Lecture: Muthiah Manoharan
19 July 2023
Living in the World of RNA Therapeutics
Synthetic small interfering RNAs (siRNAs) are potent inhibitors of gene expression. These molecules are perfect examples of biomimetic chemistry as synthetic siRNAs act through the natural RNA interference (RNAi) pathway. To deliver therapeutic siRNAs into human liver, Manoharan and his team developed approaches that include chemical modification of the siRNAs and either lipid nanoparticle (LNP) formulation or multivalent N-acetylgalactosamine (GalNAc) conjugation, making possible intravenous and subcutaneous administration, respectively. This presentation will cover the molecular basis of RNA therapeutics and their delivery including the chemical modifications and motifs used in each RNA strand to ensure uptake into cells of the targeted tissue, Ago2 recognition, silencing efficiency, metabolic stability, and safety.
Muthiah Manoharan ist Senior Vice President of Drug Discovery bei Alnylam Pharmaceuticals, Cambridge.
Location: ICEM/ House L, Seminar Room, Würmtalstr. 201, 81377 Munich, Germany
Registration is required for participation:
Link to registration
CNATM Kick-Off Meeting
26 June 2023
On June 26, the first kick-off meeting of CNATM took place successfully at the LMU campus in Großhadern. This served as a short kick-off and information event for the beginning of the cluster. Many members and partners of the future cluster were represented there and were able to introduce themselves personally. We are particularly looking forward to working together in the future.
Nucleic Acid Isar valley begins work
12 May 2023
On May 1, the Cluster for Nucleic Acid Therapeutics Munich (CNATM) started its work.
CNATM is an innovation network of science and industry, which is funded with five million euros annually by the federal government, the Free State of Bavaria and participating companies. The research network consists of scientists from the leading universities LMU and TUM. The universities of Regensburg and Würzburg, the Helmholtz Center Munich and 17 companies from the region around Munich are also involved. A total of 22 applications were awarded funding, marking the start of the Nucleic Acid Isar Valley.
The multilateral collaborations of CNATM are creating a network from which novel nucleic acid-based drugs and next-generation vaccines will be developed. Recent discoveries give rise to the hope that the ability to design nucleic acids in a highly specific and theoretically predictable way will open up completely new therapeutic approaches in medicine and thus help many people. There is no substance class that is better suited to personalized medicine than nucleic acids. The Future Cluster wants to help nucleic acid therapies achieve a breakthrough and thus make a contribution that makes sense: curing people and creating jobs in and around Munich.
CNATM one of only 7 future clusters in Germany
18 July 2022
We are very pleased, to be one of only 7 clusters4future in Germany and in Bavaria the only one of the second round of the competition.
Our thanks go to all members and partner companies who made this possible.