#5441 evidence that chaperone 4-pba treatment alleviates the renal phenotype in alport syndrome mouse models

Abstract Background and Aims Alport Syndrome (AS) is a severe inherited glomerulopathy caused by mutations in the genes encoding the α-chains of type IV collagen, the most abundant component of the glomerular basement membrane (GBM). Alport patients lack effective therapies beyond blockade of the renin-angiotensin system). This work describes the repurposing of two FDA-approved chemical chaperones (4-PBA and TUDCA) to rescue two AS mouse models: a knock-in and a compound heterozygous model bearing the Col4a3-p.Gly1332Glu mutation, recapitulating the most common mutation found in Cypriot patients. Method In either a short-term or long-term treatment, AS and wild type (WT) mice received chaperones or vehicle daily. To examine the biochemical and histological effects of chaperones on treated mice, kidney, blood, and urine samples were collected after therapy. Results Electron microscopy studies showed that the GBM of the 4-PBA treated AS mice after the long-term treatment has a considerable improvement in morphology, compared with vehicle-treated or TUDCA-treated AS mice. Importantly, EM measurements displayed a significant (p-value<0.0001) reduction of lesions and a decline of the lesions-severity in the GBM of 4-PBA treated AS mice. No adverse effects were noted in the GBM of the chaperone-treated wild-type mice. Also, the interstitial fibrosis, global and segmental glomerulosclerosis were ameliorated in the 4-PBA treated AS mice. Additionally, the treatment with 4-PBA maintained proteinuria and hematuria at low levels in AS mice. Importantly the de novo 35 kDa Col4a3 fragment which was previously detected in non-treated AS mice, was reduced after treatment with 4-PBA. Conclusion Together, these results suggest a therapeutic potential for the 4-PBA agent in combating renal dysfunction in AS.