Chronic administration of drisapersen, a 2'-OMe phosphorothioate antisense 
oligonucleotide (AON) to mice and monkeys resulted in renal tubular 
accumulation, with secondary tubular degeneration. Glomerulopathy occurred in 
both species with species-specific characteristics. Glomerular lesions in mice 
were characterized by progressive hyaline matrix accumulation, accompanied by 
the presence of renal amyloid and with subsequent papillary necrosis. Early 
changes involved glomerular endothelial hypertrophy and degeneration, but the 
chronic glomerular amyloid and hyaline alterations in mice appeared to be 
species specific. An immune-mediated mechanism for the glomerular lesions in 
mice was supported by early inflammatory changes including increased expression 
of inflammatory cytokines and other immunomodulatory genes within the renal 
cortex, increased stimulation of CD68 protein, and systemic elevation of 
monocyte chemotactic protein 1. In contrast, kidneys from monkeys given 
drisapersen chronically showed less severe glomerular changes characterized by 
increased mesangial and inflammatory cells, endothelial cell hypertrophy, and 
subepithelial and membranous electron-dense deposits, with ultrastructural and 
immunohistochemical characteristics of complement and complement-related 
fragments. Lesions in monkeys resembled typical features of C3 glomerulopathy, a 
condition described in man and experimental animals to be linked to 
dysregulation of the alternative complement pathway. Thus, inflammatory/immune 
mechanisms appear critical to glomerular injury with species-specific 
sensitivities for mouse and monkey. The lower observed proinflammatory activity 
in humans as compared to mice and monkeys may reflect a lower risk of glomerular 
injury in patients receiving AON therapy.