Third party funded individual grant
Acronym: M4-EKFS_2023_EKSE.70
Start date : 01.08.2024
End date : 31.07.2027
Glomerulonephropathies are a group of glomerular diseases that affect the glomerular filtration barrier causing proteinuria as well as progressive decline in renal function. Previous studies in cell culture, zebrafish and mouse models showed that immune mediated factors, microRNAs (miRs), as well as podocyte mutations play a role in the pathophysiology of glomerulonephritis. At present, there is no renal-specific therapy, as the glomerular filtration barrier prevents delivery of larger molecules to podocytes. Immunosuppressants are still the gold standard therapy for many kinds of glomerular diseases. However, systemic side effects such as increased risk for infections, osteoporosis, hypertension, increased long term risk for cancer and more are major drawbacks. Recently, miR-inhibitors, gene editing as well as small molecules targeting the podocyte actin cytoskeleton have been suggested as novel therapeutic options. However, as with immunosuppression, specific delivery to the kidney was not yet possible and degradation in the circulation made these approaches rather inefficient. Targeted therapy with main effects on podocytes/ the glomerulus but little systemic side effects is of great interest for different glomerular diseases. Utilizing functionalized nanoparticles to encapsulate or conjugate therapeutics can improve pharmacokinetics, increase potency and facilitate delivery to specific tissues.
In this project the potential of lipid nanoparticles, functionalized with a RGD sequence to target αVβ3 integrin and loaded with novel therapeutic substances including gen therapeutic strategies will be investigated as a potential glomerulus-specific therapy.
For this aim we will use three different zebrafish models for glomerular damage which include podocyte-specific overexpression of miR-378a for membranous glomerulonephritis, inf2 knockout to mimic genetic focal segmental glomerulosclerosis and puromycin treatment as a model for minimal change disease. We will characterize the uptake of the nanoparticles in diseased and control condition and expect a higher delivery to the glomerulus when the glomerular filtration barrier is damaged. Afterwards a miR-378a inhibitor, an inf2 plasmid, an actin modulating agent or different immunosuppressive drugs will be loaded into the functionalized nanoparticles before injecting them in the blood circulation of zebrafish larvae. The potential of the loaded nanoparticles to rescue proteinuric phenotypes of the different glomerular disease models, as well as potential side effects will be investigated. These experiments enable in vivo analysis of nanocarriers as potential cell type-specific drug delivery systems in a high throughput fashion.