Therapeutic Small Interfering RNA Targeting Complement C3 in a Mouse Model of C3 Glomerulopathy

• Published in: The Journal of immunology (1950) 2022-04, Vol.208 (7), p.1772-1781
• Main Authors: Zanchi, Cristina, Locatelli, Monica, Cerullo, Domenico, Aumiller, Verena, Corna, Daniela, Rottoli, Daniela, Eisermann, Mona, Donadelli, Roberta, Mousavi, Mansoureh, Noris, Marina, Remuzzi, Giuseppe, Benigni, Ariela, Zoja, Carlamaria
• Format: Article
• Language: English
• Subjects: Animals; Complement C3 - genetics; Complement C3 - metabolism; Complement Factor B - metabolism; Complement Factor H - genetics; Complement Pathway, Alternative - genetics; Glomerulonephritis, Membranoproliferative - pathology; Humans; Kidney Diseases; Mice; RNA, Small Interfering - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2100730

Alternative pathway complement dysregulation with abnormal glomerular C3 deposits and glomerular damage is a key mechanism of pathology in C3 glomerulopathy (C3G). No disease-specific treatments are currently available for C3G. Therapeutics inhibiting complement are emerging as a potential strategy for the treatment of C3G. In this study, we investigated the effects of -acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) targeting the C3 component of complement that inhibits liver C3 expression in the C3G model of mice with heterozygous deficiency of factor H ( mice). We showed a duration of action for GalNAc-conjugated C3 siRNA in reducing the liver C3 gene expression in mice that were dosed s.c. once a month for up to 7 mo. C3 siRNA limited fluid-phase alternative pathway activation, reducing circulating C3 fragmentation and activation of factor B. Treatment with GalNAc-conjugated C3 siRNA reduced glomerular C3d deposits in mice to levels similar to those of wild-type mice. Ultrastructural analysis further revealed the efficacy of the C3 siRNA in slowing the formation of mesangial and subendothelial electron-dense deposits. The present data indicate that RNA interference-mediated C3 silencing in the liver may be a relevant therapeutic strategy for treating patients with C3G associated with the haploinsufficiency of complement factor H.