ADTKD -
Research
WHAT THERAPY APPROACHES ARE THERE?
Currently, there is no targeted therapy for ADTKD (yet). However, a promising approach will be tested in a
clinical trial
in the foreseeable future.
LONG-TERM OBSERVATIONAL STUDY
Since ADTKD is very rare, knowledge about the disease is based on a limited number of families worldwide. Therefore, it is most important to systematically record and scientifically monitor all these families. So-called registry studies serve to collect the data of the patients and to observe the course of their disease over a long period of time. These data are essential for a better scientific understanding of the disease. Anthony Bleyer from Wake Forest University in Winston-Salem (USA) has built up such a patient registry over many years and has made great contributions to the recording and characterization of the disease.
There are also ADTKD patients in Germany. The center of ADTKD research here is at the Uniklinikum Erlangen (University of Erlangen). The scientists of Michael Wiesener's working group cooperate with Tony Bleyer in an international network.
Unfortunately, we know very little about ADKDT patients in other European countries. One of the goals of this website is to raise knowledge about the ADTKD spreading in Europe and to connect affected European families to eachother.
HOW CAN I PARTICIPATE IN THE REGISTER STUDY?
European ADTKD patients can also be included in the joint, international registry after appropriate education and consent. Participation is voluntary and the data will be anonymized to the extent that the original person can no longer be traced.
Every ADTKD patient can support research and thus the development of therapies in this way.
If you are interested, you yourself or your doctor are welcome to send an e-mail to the clinic in Erlangen:
ADTKD.M4[at]uk-erlangen.de.
ADTKD.M4[at]uk-erlangen.de.
ON THE WAY TO A SPECIFIC TREATMENT
The molecular causes of the disease are not yet fully understood. In the vast majority of ADTKD forms, it is assumed that the gene mutation leads to an excessive deposition of altered proteins, which results in damage to the tubule cells. This is a so-called "gain-of-function mutation", which means that the gene acquires a poor function that it did not have before. A therapeutic approach could be to find a way to degrade these proteins in the cells.
RESEARCH IN ADTKD-MUC1
In ADTKD-MUC1, the mutation of the MUC1 gene leads to the formation of a completely new type of protein that is deposited in the cell plasma of the tubule cells. The researchers in Erlangen, like other scientists, were able to demonstrate in tissues and cells of affected patients that this process actually takes place in this way.
The research group led by Anna Greka at the Broad Institute in Boston (USA) found out that the altered, misfolded protein mucin 1 is no longer transported away in certain structures (vesicles) within the cells but gets "stuck". This leads to damage in the cells, which causes the disease. At the same time, compounds were sought that could potentially be able to intervene in these processes. With the substance BRD4780, an compound was found that makes the altered mucin 1 largely disappear. This was at least the case in cell culture models and in a mouse model. Therefore, there is hope that an evolved derivat in tablet form could be suitable as a drug treatment. Apparently, this effect is not specific to MUC1, but could also be applicable in other subtypes such as ADTKD-UMOD. It is planned to test the safety and efficiency of the compound in a clinical trial, which is expected to start in 2024.
The research group in Erlangen has developed models of cell cultures that can be obtained from the urine of ADTKD patients. In these cells, the development of the disease can be studied in more detail. The models are very useful because they can be applied to analyze effects of therapeutic approaches. In addition, the scientists are researching other, different mechanisms that could possibly prevent the formation of the altered mucin-1 protein. Innovative therapies might be developed on this basis.
RESEARCH IN ADTKD-UMOD
More than 100 different mutations of the UMOD gene have been found in patients with this disease worldwide. These mutations cause an altered uromodulin protein to accumulate in a different area of the cell (endoplasmic reticulum) than in MUC1 disease. This is an intracellular channel system in which numerous important functions take place. The misfolded uromodulin gets "stuck" in it. As a result, the tubule cell comes under prolonged stress, but can no longer restore normal cell function and dies. This has been demonstrated in cell cultures as well as in mouse models for various UMOD mutations. These models are also used intensively to test substances that reduce the cell's "overreaction" to the stress generated by the misfolded protein.
Since the ADTKD proteins are also deposited in other organs than the kidney causing further diseases, the compounds for ADTDK treatment might have a broader range than anticipated today.
STUDY PLANNING: PRELIMINARY SCHEDULE
2023: Safety studies
2023 - 2024: Phase 1 (dosing healthy persons)
2024/25: Phase 2 Clinical Trial
It is expected that ADTKD patients from Europe will also be included in the phase 2 study!
NOT ALL SUBFORMS KNOWN YET
ADTKD-UMOD and ADTKD-MUC1 are the most common subtypes, accounting for up to 70% of all cases.In a few families with ADTKD, genetic testing does not find any of the known gene mutations. It is possible that other genes are responsible, but these have not yet been identified. These cases are called ADTKD-NOS ("not otherwise specified"). Internationally networked scientists, including some from Germany, are working intensively to find out the genetic cause in these families as well.
LITERATURE
Bernascone I, et al. A transgenic mouse model for uromodulin-associated kidney diseases shows specific tubulo-interstitial damage, urinary concentrating defect and renal failure. Hum Mol Genet. 2010 Aug 1;19(15):2998-3010
Dvela-Levitt, M, et al. Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy. Cell. 2019 Jul 25;178(3):521-535.e23
Eckardt KU, et al. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management--A KDIGO consensus report. Kidney Int. 2015 Oct;88(4):676-83
Ekici AB, et al. Renal fibrosis is the common feature of autosomal dominant tubulointerstitial kidney diseases caused by mutations in mucin 1 or uromodulin. Kidney Int. 2014 Sep;86(3):589-99
Knaup, KX, Wiesener, MS. Autosomal dominant tubulointerstitial kidney disease (ADTKD). Nephrologist 14, 112–119 (2019)
Olinger E, et al. Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1. Kidney Int. 2020 Sep;98(3):717-731
Žvirna M, et al. Noninvasive Immunohistochemical Diagnosis and Novel MUC1 Mutations Causing Autosomal Dominant Tubulointerstitial Kidney Disease. J Am Soc Nephrol. 2018 Sep;29(9):2418-2431