Preventing Alport syndrome with a natural amino acid

Objetivo

Chronic kidney disease (CKD) is a major burden on society, causing significant morbidity and mortality. A typical symptom of CKD is the loss of protein into the urine, also termed proteinuria, which is usually associated with a poor prognosis. In most cases, a defective glomerulus leads to proteinuria, resulting in damage of the neighboring proximal tubular cells due to protein and lipid overload.
In RENOTREAT, we aim to treat Alport syndrome with a natural amino acid, that is known to inhibit the tubular protein uptake receptors cubilin and megalin. This amino acid is already available as a safe treatment in humans, but has never been used for kidney disease. Alport syndrome is a rare disease with underestimated prevalence. It is caused by defective collagen fibers due to pathogenic genetic variants in collagen IV genes. The lack of functional collagen fibers leads to a more permeable glomerular basement membrane, resulting in proteinuria with subsequent proximal tubular damage. In our therapeutic strategy, we will induce tubular proteinuria by blocking protein uptake into the proximal tubule, overturning the paradigm that the degree of proteinuria correlates with kidney damage. First, we will test dosing regimens and bioavailability for three different formulations of the amino acid with regard to the induction of a stable tubular proteinuria in wild-type mice. Using a murine model of Alport syndrome, we will then evaluate these treatments for their potential to slow CKD progression and prolong the survival of the mutant mice. In parallel, we will conduct a pilot trial in healthy human volunteers with the already available form of the amino acid to prepare for a future clinical trial in Alport patients.
In summary, we will verify the innovation potential of a novel therapeutic approach of managing Alport syndrome and potentially other proteinuric kidney diseases by performing proof-of-concept preclinical and clinical trials.