ERA CONGRESS 2022: A POTENTIAL THERAPY FOR ADTKD-MUC1
Research into the causes led to the identification of a promising substance
5/20/2022 - At this year's European Renal Association (ERA) congress in Paris in May, scientific papers on ADTKD were also presented. Using ADTKD-MUC1 as an example, Moran Dvela-Levitt, Israel, reported on how basic research succeeded in finding a potentially effective substance. Using cell cultures in mice and in organoids (kidney tubules reproduced from human stem cells), it was initially demonstrated that a change in the MUC1 gene (mutation) is responsible for the fact that more and more incorrectly folded (toxic ) deposit proteins. This eventually leads to kidney failure.
How does this deposit come about? Normally, the proteins are packaged in small bubbles (vesicles) in which they are transported within the cell from one functional unit (organelle) to the next and processed further. When searching for the cause of the disrupted transport, the researchers came across the cargo receptor TMED9. This ensures that the misfolded MUC1 protein is retained in the vesicles and thus continues to accumulate.
Active substance BRD4780 corrects disturbed transport
In order to find an active substance that can correct this malfunction, the scientists searched a large database with more than 4,000 substances that were already known. In doing so, they came across BRD4780, an active ingredient that was originally developed to treat high blood pressure. One speaks of drug repurposing when substances that were actually intended for other diseases are reused. The researchers were able to show that this active ingredient binds TMED9, which means that the "wrong" MUC1 protein is removed from the cell spaces and brought to the lysosomes. As the cellular "garbage can", these are responsible for breaking down and breaking down the proteins.
Other proteinopathies could also be treated
Diseases such as ADTKD-MUC1, in which incorrectly folded proteins are stored in the cells, are called proteinopathies. The UMOD variant is also included. There are also many other diseases of this type, for example Alzheimer's disease, amyotrophic lateral sclerosis (ALS), retinitis pigmentosa, Parkinson's or sickle cell disease. Therefore, there is hope that one day these too can be treated with drugs that affect TMED9. A clinical trial of BRD4780 in ADTKD-MUC1 is expected in 2023.
Sources:
Dvela-Levitt M: New therapeutic approaches for toxic proteinopathies, the example of ADTKD-MUC1. Symposium 2.6 Inherited Cystic And Tubulointerstitial Nephropathies: New Genes, New Mechanisms, New Therapies. ERA-Conference, 20.5.2022
https://www.era-online.org/en/virtualcongress2021
Literature:
Dvela-Levitt M, et al. A Rare Kidney Disease To Cure Them All? Towards Mechanism-Based Therapies for Proteinopathies. Trends Mol Med. 2021 Apr;27(4):394-409.