With oligonucleotides against "diseased" cells
Therapeutic Gene Regulation
We aim to identify and characterize cells that trigger and drive the pathogenesis of rheumatic diseases. We apply state-of-the-art methods (particularly Single-Cell-Sequencing approaches) to determine which genes and regulatory ribonucleic acids (RNAs) are selectively switched on in “disease causing” pathogenic cells versus healthy cells. The identified genes and regulatory RNAs are further functionally characterized in order to elucidate whether they influence the disease directly or indirectly. Genes and regulatory RNAs which keep the pathogenic cells alive would be ideal targets for new therapies. Their suitability as novel therapeutic targets is tested in preclinical models for rheumatic diseases.
All the identified regulatory RNAs and many of the identified genes that are selectively expressed by cells which are involved in the pathogenesis of rheumatic diseases, encode for proteins that act inside these cells, making them inaccessible to modern biologics. We are therefore developing short nucleic acids (oligonucleotides) that inhibit the RNAs that translate information from these genes into proteins. Such oligonucleotides are small inhibitory RNAs (siRNAs) that directly inhibit gene expression, and antagomirs that inhibit regulatory microRNAs and thus indirectly influence gene expression. When these oligonucleotides are coupled to cholesterol, they easily enter all cells, but only affect gene expression in the cells in which a particular gene or regulatory RNA is switched on in, making them therefore, very selective. We want to utilize them for therapeutic manipulation of chondrocytes in patients with osteoarthritis (OA). In OA, chondrocytes fail to build cartilage tissue or even destroy the existing extracellular matrix by secreting matrix-degrading enzymes. In cooperation with the Löhning group, we are determining target genes in order to reactivate the cartilage production of degenerated chondrocytes or to turn precursor cells into active chondrocytes.
Therapeutic oligonucleotides also have great potential for the treatment of chronic inflammatory rheumatic diseases. In an animal model, we were able to show that antagomirs against the microRNA-148a specifically deplete the disease-causing T-helper (Th) lymphocytes and significantly attenuate chronic inflammation due to the dependence on miR-148a for their survival. Protective memory Th lymphocytes generated by a vaccine-like immunization were not affected because they do not express miR-148a. We have thus provided the fundamental proof that therapeutic oligonucleotides can act selectively and efficiently in the organism without significant undesirable side effects.
Dr. rer. nat. Mir-Farzin Mashreghi
Dr. rer. nat. Gitta Anne Heinz
Dr. rer nat. Patrick Maschmeyer
Dr. rer. nat. Frederik Heinrich
Cam Loan Tran
- PD Dr. med. Tilmann Kallinich, Department of Pediatrics, Charité-Universitätsmedizin Berlin
- Tobias Alexander, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin
- Dr. Klemens Budde, Department of Nephrology, Charité-Universitätsmedizin Berlin
- Dr. Falk Hiepe, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin
- Jürgen Wittmann, Molecular Immunology, Universitätsklinikum Erlangen
- PD Dr. Anja Kühl, Institute for Pathology, Charité-Universitätsmedizin Berlin
- Dr. Michael Lohoff, Institute for Medical Mikrobiology Philipps University Marburg
- Dr. Stefan Kaufmann, Max-Planck-Institute for Infektion Biology
- Dr. Fritz Melchers, DRFZ
- Andreas Hutloff, DRFZ
- Andrey Kruglov, DRFZ
- Dr. Chiara Romagnani, DRFZ
- Dr. Andreas Radbruch, DRFZ
- Dr. Andreas Diefenbach, DRFZ
- Dr. Max Löhning, DRFZ
- Dr. Bastian Opitz, Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin
- Dr. Simon Fillatreau, Institut Necker-enfants-malades (INEM), Paris, France.
- George Goulielmos, Molecular Medicine and Human Genetics Laboratory, University of Crete, Heraklion, Greece.
- Dr. Andreas Krüger, institute for Molecular Medicine, Goethe Universität Frankfurt
- Dr. Dirk Ostareck, Department of Intensive Care, University Hospital Aachen
- Dr. Antje Ostareck-Lederer, Department of Intensive Care University Hospital Aachen
1: Bardua M, Haftmann C, Durek P, Westendorf K, Buttgereit A, Tran CL, McGrath M, Weber M, Lehmann K, Addo RK, Heinz GA, Stittrich AB, Maschmeyer P, Radbruch H, Lohoff M, Chang HD, Radbruch A, Mashreghi MF. MicroRNA-31 Reduces the Motility of Proinflammatory T Helper 1 Lymphocytes. Front Immunol. 2018 Dec 6;9:2813. doi:10.3389/fimmu.2018.02813. eCollection 2018. PubMed PMID: 30574141; PubMed Central PMCID: PMC6291424.
2: Maschmeyer P, Petkau G, Siracusa F, Zimmermann J, Zügel F, Kühl AA, Lehmann K, Schimmelpfennig S, Weber M, Haftmann C, Riedel R, Bardua M, Heinz GA, Tran CL, Hoyer BF, Hiepe F, Herzog S, Wittmann J, Rajewsky N, Melchers FG, Chang HD, Radbruch A, Mashreghi MF. Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo. J Autoimmun. 2018 May;89:41-52. doi: 10.1016/j.jaut.2017.11.005. Epub 2017 Dec 1. PubMed PMID: 29183643; PubMed Central PMCID: PMC5916452.
3: Matz M, Heinrich F, Zhang Q, Lorkowski C, Seelow E, Wu K, Lachmann N, Addo RK, Durek P, Mashreghi MF*, Budde K*. The regulation of interferon type I pathway-related genes RSAD2 and ETV7 specifically indicates antibody-mediated rejection after kidney transplantation. Clin Transplant. 2018 Dec;32(12):e13429. doi: 10.1111/ctr.13429. Epub 2018 Nov 18. PubMed PMID: 30341925. *equal Contribution
4: Matz M, Heinrich F, Lorkowski C, Wu K, Klotsche J, Zhang Q, Lachmann N, Durek P, Budde K, Mashreghi MF. MicroRNA regulation in blood cells of renal transplanted patients with interstitial fibrosis/tubular atrophy and antibody-mediated rejection. PLoS One. 2018 Aug 13;13(8):e0201925. doi: 10.1371/journal.pone.0201925. eCollection 2018. PubMed PMID: 30102719; PubMed Central PMCID: PMC6089438.
5: Hammer Q, Rückert T, Borst EM, Dunst J, Haubner A, Durek P, Heinrich F, Gasparoni G, Babic M, Tomic A, Pietra G, Nienen M, Blau IW, Hofmann J, Na IK, Prinz I, Koenecke C, Hemmati P, Babel N, Arnold R, Walter J, Thurley K, Mashreghi MF, Messerle M, Romagnani C. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Nat Immunol. 2018 May;19(5):453-463. doi: 10.1038/s41590-018-0082-6. Epub 2018 Apr 9. PubMed PMID: 29632329.