Project Details
Projekt
Theranostic targeting of renal myofibroblasts
Subject Area
Nephrology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 445703531
Kidney fibrosis is a key predictor of chronic kidney disease (CKD) progression, yet non-invasive approaches for its quantification are lacking. We demonstrated that molecular imaging can reveal kidney fibrosis in animal models. We also developed imaging protocols to capture excess extracellular matrix deposition and the matrix-producing mesenchymal cells, particularly PDGFR-β-expressing myofibroblasts. However, there are currently no theranostic approaches that simultaneously enable imaging and targeted treatment of activated myofibroblasts, aiming to prevent the progression from early CKD to advanced fibrosis stages. We hypothesize that the development of theranostic probes enabling combined molecular imaging of and targeted drug delivery to activated myofibroblasts could promote precision medicine applications in nephrology. To achieve this, we will combine complementary expertise in experimental pathology and kidney disease modeling (Klinkhammer), probe design, molecular imaging and drug delivery, (Lammers), and translational nuclear imaging and theranostics (Mottaghy). In WP1, we will focus on quantitative imaging of active fibrogenesis in mouse models at early and thus potentially treatable CKD stages. We will refine existing and generate novel peptide and nanobody probes targeting PDGFR-β and tenascin C. Target expression will be validated in human and murine tissue, and sequencing data sets (with P1, P2, P3 and P4). In WP2, to promote the translation of the probes, we will establish protocols for radiolabeling with 123/131I or 89Zr. We will perform proof-of-concept experiments with these probes using single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging, integrating them into our clinical molecular imaging and theranostic pipelines in WP3. In WP3, diagnostic computed tomography coupled with fluorescence tomography (CT-FLT) or CT-SPECT imaging will be combined with targeted therapy, by functionalizing the probes with fluorescent dyes, anti-fibrotic drugs, or therapeutic radionuclides. In such theranostic setups, peptides and nanobodies will first be employed for in vivo imaging-based target validation and fibrosis staging. Next, drug-coupled probes will be used to pharmacologically inhibit or radiotherapeutically eradicate myofibroblasts. Treatment efficacy will be monitored via non-invasive imaging (with P7), kidney function assessment, and pathomics (with P4). This will allow correlating probe accumulation with therapeutic efficacy, which could be particularly relevant for patient stratification in clinical trials. In conclusion, we aim to advance translational kidney research by establishing the first theranostic approach for renal fibrosis imaging, targeting, and treatment, combining non-invasive and quantitative in vivo diagnosis with myofibroblast-specific drug therapy.
DFG Programme
Clinical Research Units
