Searching for a treatment for Alport syndrome using mouse models

Abstract

Alport syndrome (AS) is a hereditary nephritis caused by mutations in COL4A3, COL4A4 or COL4A5 encoding the type IV collagen α3, α4, and α5 chains, which are major components of the glomerular basement membrane. About 20 years have passed since COL4A3, COL4A4, and COL4A5 were identified and the first Alport mouse model was developed using a knockout approach. The phenotype of Alport mice is similar to that of Alport patients, including characteristic thickening and splitting of the glomerular basement membrane. Alport mice have been widely used to study the pathogenesis of AS and to develop effective therapies. In this review, the newer therapies for AS, such as pharmacological interventions, genetic approaches and stem cell therapies, are discussed. Although some stem cell therapies have been demonstrated to slow the renal disease progression in Alport mice, these therapies demand continual refinement as research advances. In terms of the pharmacological drugs, angiotensin-converting enzyme inhibitors have been shown to be effective in Alport mice. Novel therapies that can provide a better outcome or lead to a cure are still awaited.

Keywords: Alport syndrome; Angiotensin-converting enzyme; Genetic; Hereditary nephritis; Pharmacological; Renal injury; Stem cell therapy

Core tip: There is currently no curative treatment for Alport syndrome, a progressive hereditary nephritis. However, many drugs have been demonstrated to slow the progression of renal injury in Alport mouse models. Alport mice treated with vasopeptidase inhibitors or angiotensin-converting enzyme inhibitors showed a more than two-fold longer survival than untreated Alport mice. A human clinical trial of an angiotensin-converting enzyme inhibitor is currently in progress. Genetic approaches have been used to elucidate the pathogenesis of this progressive renal disease. Stem cell therapies were also attempted, with some beneficial effects; however, they need to be improved before being tested in clinical trials.