Innovative Approaches to Treating Alport Syndrome

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Project Summary Kidney disease is worldwide health problem that is becoming increasingly common. Primary glomerular disease, both genetic and acquired, represents a significant proportion of cases. We are interested in understanding the makeup of the glomerular filtration barrier and how it becomes damaged, leaky to plasma proteins, and eventually non-functional. Our focus has been to investigate the composition and function of the glomerular basement membrane (GBM), a specialized extracellular matrix that is an integral component of the kidney’s filtration barrier. The GBM contains collagen IV, laminin, nidogen, and the heparan sulfate proteoglycan agrin, and likely dozens of other less abundant matrix proteins. Although the GBM is synthesized by both podocytes and glomerular endothelial cells, it is exclusively podocytes that make the major collagen IV isoform, which consists of the 3, 4, and 5 chains that assemble to form a secreted heterotrimer. Mutations that affect this collagen IV component of the GBM cause Alport syndrome, which leads to end-stage kidney disease (ESKD) as well as hearing and eye defects. The prevalence of Alport syndrome has been estimated to be 1 in 5,000 to 10,000 newborns, so there are hundreds of thousands of affected patients around the world. Structural GBM abnormalities secondary to the collagen IV defect lead to thickening and splitting of the GBM and eventually podocyte foot process effacement, glomerulosclerosis, and tubulointerstitial fibrosis. Until recently there has been no treatment for Alport syndrome. However, studies in mice and dogs had shown that ACE inhibition slows kidney disease progression to ESKD. These animal studies have been validated in human Alport syndrome patients, for whom ACE inhibitors or angiotensin II receptor blockers are now considered the standard of care. Despite this treatment breakthrough that delays ESKD, it is not a cure; there is still a need for new targeted therapies. The goal of this proposal is to use innovative, state of the art technologies that involve small molecule, genetic, and protein biochemistry approaches to attempt to either restore the Alport GBM to a somewhat normal composition or to alter its composition through removal of pathogenic components. In either case, the expectation is that improving GBM composition will at least partially normalize GBM structure and function. Together with renin-angiotensin system blockade as a standard of care, these treatments should greatly delay the time to ESKD and be beneficial for patients.