Use of inhibitors of cubilin for the treatment of chronic kidney diseases

Chronic Kidney Disease (CKD) is a major burden of public health affecting millions of people around the world. Even though many aspects of the complex mechanisms orchestrating progression of renal disease have been identified, so far there is no specific treatment to slow down or prevent CKD progression.CUBNencodes for cubilin that is a proximal tubular uptake receptor with 27 CUB domains for ligand binding. The inventors now identify 26 patients, in whom rarebiallelicCUBNvariants are associated with isolated proteinuria. Yet, renal function was normal in all cases. Most of the 35 novel CUBNvariants were localized to C-terminal CUB domains of the protein, unlikethe more N-terminal I-GS mutations. Finally, the inventors show that four low-frequency and common C-terminal CUBN variants with strong albuminuria associations in GWAS studies are associated with slightly higher eGFR in a meta-analysis of over half a million individuals from the general population compared to their ancestral alleles. Collectively, the data suggest that CUBN-associated albuminuria is an unexpectedly common benign condition that does not require any treatment and may even have protective effects with respect to renal filtration function. More importantly, the results suggest that inhibitor of cubilin would be suitable for the treatment of CKD, particularly those CKD forms in which glomerular proteinuria is causing tubular damage due to albumin overload.

Keywords: CKD, Nephrology
Patent Application number: PCT/EP2019/078592
J Clin Invest. 2019 Dec 3. pii: 129937. doi: 10.1172/JCI129937. [Epub ahead of print]

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