Supported Research

Co-Applicant(s):  James Scholey

Lay Abstract

Drug-repurposing for treatment of Alport Syndrome Alport syndrome (AS) is a rare inherited kidney disease caused by mutations in one of three collagen genes named COL4A3, COL4A4, or COL4A5 and is associated with premature kidney failure, deafness, and eye problems. Although one of two classes of drugs called angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARB) is commonly used for lowering blood pressure and urinary protein (a marker of disease severity) in AS, there is currently no proven treatment to delay or prevent kidney failure of this disease. In a pilot study, we generated a disease gene pathway map using the Col4a3 knock-out mice (a model of AS) to identify potential targets for developing new therapy to slow kidney failure in human AS. We found two disease gene pathways linking defective metabolism (i.e. mis-direction of food substrates in our cells for energy use) and activation of inflammation (i.e. overactive defense by the body’s immune system in response to kidney damage) to kidney damage in AS. Interestingly, we had also previously observed that these two gene pathways were associated with kidney damage in a mouse model of polycystic kidney disease (PKD). Furthermore, treatment with a drug called Salsalate in the PKD mouse model significantly decreased the kidney damage and reversed the two abnormal gene pathways. These findings strongly suggest that Salsalate may be a promising candidate to treat AS. Of note, Salsalate is an old and inexpensive drug related to the aspirin family which has a high safety profile. We hypothesize that defective metabolism and inflammation are shared mechanisms that mediate disease damage in PKD and AS. We further expect that Salsalate should also be effective in slowing kidney failure in AS. To test the above hypothesis, we will: Aim 1. Compare the effects with Salsalate vs. Ramipril (an ACEi commonly used as standard therapy for AS) vs. no treatment on kidney disease progression in Col4 knock-out mice. This will be done by studying markers of kidney injuries and function. Aim 2. Characterize key gene pathways and protein markers associated with disease progression in Aim 1 so that we can gain better insight on how the drug treatment works. Clinical Relevance: Our pilot study has provided strong data suggesting that defective metabolism and activation of inflammation are shared mechanisms for kidney damage in both ADPKD and AS. By targeting these disease-causing mechanisms, Salsalate is a highly promising candidate for drug repurposing to treat AS. Our study will provide an essential foundation to advance clinical testing of salsalate in patients with AS.