ADTKD -
Research


WHAT THERAPY APPROACHES ARE THERE FOR ADTKD?

In the vast majority of cases of ADTKD, it is believed that the genetic mutation leads to excessive deposition of altered proteins (“toxic proteinopathy”), which causes damage to the tubular cells. This is what is known as a gain-of-function mutation, meaning that the gene acquires a (harmful) function that it did not previously have.


WHAT THERAPEUTIC APPROACHES ARE CURRENTLY BEING INVESTIGATED FOR ADTKD?


There is currently no approved treatment for ADTKD, but several strategies are emerging—ranging from orally administered small-molecule drugs to RNA-based therapies and gene editing.


  • The most advanced approach involves small molecules that can be administered orally. Preclinical data from mouse models show that such agents can break down mutated proteins within the cells. While they cannot cure the disease, they can modify its course and thus slow its progression. The compound BRD4780 has been identified as an agent that largely eliminates the altered protein. Consequently, there is now hope that a further-improved version of this compound in tablet form could be suitable as a drug treatment. Since increased protein deposits are also the cause of diseases in entirely different organ systems, it cannot be ruled out that treatment options currently being investigated for ADTKD may also be effective in those conditions.


  • Another strategy involves antisense oligonucleotides (ASOs), which are administered via injection. These nucleic acid-based therapies degrade mutated mRNA, thereby preventing the production of misfolded proteins. In animal models, the concentration of the mutated proteins was reduced by over 75% without any side effects.


  • In the more distant future, genome-editing technologies such as CRISPR, base editing, and prime editing offer the prospect of a true cure. The biggest challenge is delivery, as it is difficult to efficiently target kidney cells. Although there are proof-of-concept results for other organs, Greka emphasized that “the kidney is lagging behind.”


U.S. ADTKD researcher Anna Greka of the Broad Institute in Boston (USA) estimates that within 3 to 5 years, at least one or two clinical trials—likely involving small molecules or ASOs—could begin. In 10 to 15 years, gene therapy could enable curative approaches.

LONG-TERM OBSERVATIONAL STUDY: EVERY PATIENT COUNTS


Since ADTKD is very rare, knowledge of the disease worldwide is based on a limited number of families. This makes it all the more important to systematically document these families and provide them with scientific support. So-called registry studies serve to collect patient data and monitor the course of their disease over a long period of time. This data is essential for gaining a better scientific understanding of the disease. In Europe, an ADTKD registry is currently being established. Coordination is handled by Charité Universitätsmedizin Berlin.

HOW CAN I PARTICIPATE IN THE REGISTER STUDY?

European ADTKD patients can be included in the European registry ADTKD.net 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 or your doctor are welcome to send an email to Prof. Jan Halbritter: jan.halbritter[at]charité.de.
More info: erknet.org/subregistries/adtkd-registry

PATHOPHYSIOLOGY OF ADTKD-MUC1


In ADTKD-MUC1  , the mutation in the MUC1 gene leads to the formation of a completely novel protein that accumulates in the cytoplasm of tubular cells. The research group led by Anna Greka has discovered that the altered, misfolded mucin 1 protein is no longer transported out of certain structures (vesicles) within the cells, but instead “gets stuck” there. This leads to damage within the cells, which causes the disease.


The research group in Erlangen has developed cell culture models derived from the urine of ADTKD patients. These cells allow for a more detailed investigation of the disease’s pathogenesis. The models are very helpful because they also allow researchers to analyze the effects of potential therapeutic approaches. In addition, the scientists are investigating other, distinct mechanisms that might prevent the formation of the altered Mucin 1 protein. Based on this research, innovative therapies could also be developed.

PATHOPHYSIOLOGY OF ADTKD-UMOD


To date, more than 100 different mutations in the UMOD gene have been identified in patients with this disease worldwide. These mutations cause an altered uromodulin protein to accumulate in a different part of the cell (the endoplasmic reticulum) than in MUC1 disease. This is an intracellular channel system in which numerous important functions take place. The misfolded uromodulin becomes “trapped” within it. As a result, the tubular cell is subjected to sustained stress but is unable to restore normal cell function and eventually dies. This has been demonstrated in cell cultures as well as in mouse models for various UMOD mutations. These models are also extensively used to test substances that reduce the cell’s “overreaction” to the stress caused by the misfolded protein.

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