title: Species-specific inflammatory responses as a primary component for the development of glomerular lesions in mice and monkeys following chronic administration of a second-generation antisense oligonucleotide.
abstract: 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.
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania, USA kendall.s.frazier@gsk.com.
authors.forename: Kendall S
authors.initials: KS
authors.lastname: Frazier
authors.affiliation: CiToxLab, Evreux, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Sobry
authors.affiliation: Pathology, Microbiology and Immunology, University of California-Davis, California, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Derr
authors.affiliation: Departments of Safety Assessment and Scinovo, GlaxoSmithKline, Ware, United Kingdom.
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Adams
authors.affiliation: Prosensa Therapeutics, Leiden, The Netherlands.
authors.forename: Cathaline Den
authors.initials: CD
authors.lastname: Besten
authors.affiliation: Prosensa Therapeutics, Leiden, The Netherlands.
authors.forename: Sjef
authors.initials: S
authors.lastname: De Kimpe
authors.affiliation: Departments of Safety Assessment and Scinovo, GlaxoSmithKline, Ware, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Francis
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Gales
authors.affiliation: Departments of Safety Assessment and Scinovo, GlaxoSmithKline, Ware, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Haworth
authors.affiliation: Departments of Safety Assessment and Scinovo, GlaxoSmithKline, Ware, United Kingdom.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Maguire
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
authors.forename: Rosanna C
authors.initials: RC
authors.lastname: Mirabile
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mullins
authors.affiliation: CiToxLab, Evreux, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Palate
authors.affiliation: Prosensa Therapeutics, Leiden, The Netherlands.
authors.forename: Yolanda Ponstein-Simarro
authors.initials: YP
authors.lastname: Doorten
authors.affiliation: Departments of Safety Assessment and Scinovo, GlaxoSmithKline, Ware, United Kingdom.
authors.forename: James E
authors.initials: JE
authors.lastname: Ridings
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Scicchitano
authors.affiliation: CiToxLab, Evreux, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Silvano
authors.affiliation: Departments of Safety Assessment and Scinovo, GlaxoSmithKline, Ware, United Kingdom.
authors.forename: Jennie
authors.initials: J
authors.lastname: Woodfine
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D000882:Haplorhini; D007249:Inflammation / Q000473:pathology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000009:adverse effects*; D018570:Risk Assessment; D013045:Species Specificity
chemical_list: D016376:Oligonucleotides, Antisense
keywords: amyloid; glomerulonephritis; hyaline glomerulopathy.; monkey pathology; mouse pathology; renal; safety assessment