A polymeric dexamethasone prodrug attenuates focal segmental glomerulosclerosis (FSGS) in an Adriamycin-induced mouse model with minimal glucocorticoid side effects

Abstract

Focal segmental glomerulosclerosis (FSGS) is chronic renal injury characterized by proteinuria and podocyte injury with glomerulus scarring and tubulointerstitial fibrosis. Glucocorticoids (GCs) are the current first-line treatment. Long-term use of GCs, however, is associated with numerous off-target adverse effects. Thus, there is an urgent unmet clinical need for novel FSGS therapies. Recognizing potent efficacy of GCs in managing FSGS, we proposed the use of a polyethylene glycol (PEG)-based nephrotropic dexamethasone (Dex) prodrug (ZSJ-0228 or PEG-Dex) to mitigate the GC side effects. The focus of the present study was to assess the therapeutic efficacy and safety of PEG-Dex in an Adriamycin-induced BALB/c mouse model of FSGS. A single dose of PEG-Dex treatment (35 ​mg/kg Dex dose equivalent) effectively reduced the proteinuria level, ameliorated FSGS lesions and restored kidney function when compared to the dose equivalent daily Dex treatment and Saline control. Additionally, PEG-Dex treatment also showed a much-improved safety profile than Dex with minimal adverse events detected. Collectively, these data suggest that PEG-Dex may be established as a promising drug candidate for more effective and safe clinical treatment of FSGS.