Anti-histone therapy for vascular necrosis in severe glomerulonephritis
US9580495B2 · kind B2 · utility
Assignee
Inventors
Key dates
| Filing date | Jun 23, 2015 |
| Grant date | Feb 28, 2017 |
| Priority date | — |
| Expiry date | Jun 23, 2035 |
Classification
- Technology area (CPC C)Chemistry; Metallurgy
- CPC primaryC07K2319/00
- WIPO fieldPharmaceuticals
- WIPO sectorChemistry
Abstract
Severe glomerulonephritis involves cell necrosis as well as NETosis, programmed neutrophil death leading to expulsion of nuclear chromatin and neutrophil extracellular traps (NETs). Histones released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells. This was prevented by histone-neutralizing agents anti-histone IgG, activated protein C and heparin. Histone toxicity on glomeruli was TLR2/4-dependent. Anti-GBM glomerulonephritis involved NET formation and vascular necrosis. Pre-emptive anti-histone IgG administration significantly reduced all aspects of glomerulonephritis, including vascular necrosis, podocyte loss, albuminuria, cytokine induction, recruitment and activation of glomerular leukocytes and glomerular crescent formation. Subjects with established glomerulonephritis treated with anti-histone IgG, recombinant activated protein C, or heparin all abrogated severe glomerulonephritis suggesting that histone-mediated glomerular pathology is a subsequent, not initial event in necrotizing glomerulonephritis. Neutralizing extracellular histones is therapeutic in severe experimental glomerulonephritis.
Source: USPTO / EPO open patent data. Objective bibliographic and citation counts.