Human genetic evidence is well known to support approvals of new drug or drug indications (Minikel et al, Nature 2024). Therefore, a general strategy in my lab is to use Mendelian genes and genome-wide association studies for mechanistic studies and for developing therapeutic strategies. Chronic kidney disease (CKD) is a major burden on society, causing significant morbidity and mortality. In many CKD types, a defective glomerulus leads to proteinuria or albuminuria, resulting in damage of the neighboring proximal tubular cells due to the protein or albumin overload, respectively. While nephrologists normally associate any form of proteinuria with a bad prognosis, our human genetic data suggest that tubular proteinuria, which is caused by reduced protein uptake into the proximal tubular cells (PTCs), is clinically benign (Bedin et al., JCI 2020). This was demonstrated in individuals with biallelic variants in CUBN, encoding for the uptake receptor cubilin, showing significant proteinuria (between 0.2-1.5g/24h) but normal renal function. Moreover, genome-wide association studies (GWAS) suggest that variants in CUBN and also LRP2 (encoding for the other uptake receptor megalin) might even be renoprotective (Bedin et al, JCI 2020; Wuttke et al, Nat Genetics 2019). In this proposal, we therefore want to go one step further and test the therapeutic effects of inhibiting both cubilin and megalin in Alport syndrome, a hereditary form of glomerular proteinuria. Specifically, we want to explore the innovation potential of the essential amino acid lysine, which has been shown to block tubular protein uptake.
For our proof-of-concept studies, we have chosen Col4a3 KO mice as glomerular proteinuria model. Col4a3 deficiency causes Alport syndrome, an important genetic kidney disease. Therefore, our findings could have direct implications for the treatment of Alport syndrome patients.
