Therapeutic Small Interfering RNA Targeting Complement C3 in a Mouse Model of C3 Glomerulopathy
Cristina Zanchi1, Monica Locatelli1, Domenico Cerullo1
1Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Bergamo, Italy; and.
Insights
Complement dysregulation causes C3 glomerulopathy (C3G). This study shows that GalNAc-conjugated C3 siRNA effectively reduces C3 levels and glomerular deposits in a mouse model, offering a potential therapeutic strategy for C3G.
Area of Science:
- Nephrology
- Immunology
- Genetics
Background:
- C3 glomerulopathy (C3G) is characterized by complement alternative pathway dysregulation, leading to glomerular C3 deposition and damage.
- Currently, no specific treatments exist for C3G, highlighting the need for novel therapeutic approaches.
Purpose of the Study:
- To investigate the therapeutic potential of N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) targeting complement component C3 in a mouse model of C3G.
Main Methods:
- Utilized a mouse model with heterozygous deficiency of factor H (Cfh+/- mice) to mimic C3G.
- Administered GalNAc-conjugated C3 siRNA subcutaneously monthly for up to 7 months.
- Assessed C3 gene expression, complement activation markers (C3 fragmentation, factor B activation), and glomerular C3d deposits.
Main Results:
- Demonstrated a sustained reduction in liver C3 gene expression and circulating C3 fragments with monthly C3 siRNA administration.
- Observed a significant decrease in glomerular C3d deposits in treated mice, comparable to wild-type levels.
- Ultrastructural analysis confirmed reduced formation of electron-dense deposits in glomeruli.
Conclusions:
- RNA interference-mediated C3 silencing via liver-targeted GalNAc-conjugated siRNA is a promising therapeutic strategy for C3G.
- This approach effectively targets complement dysregulation in C3G associated with complement factor H deficiency.
Abstract:
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 N-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 (Cfh +/- mice). We showed a duration of action for GalNAc-conjugated C3 siRNA in reducing the liver C3 gene expression in Cfh +/- 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 Cfh +/- 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.
