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Efficacy of GalNAc C3 siRNAs in factor H-deficient mice with C3 glomerulopathy
Cristina Zanchi1, Monica Locatelli1, Domenico Cerullo1
1Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
Insights
This study shows SLN501, a novel therapy, effectively reduces complement C3 production in mice with severe C3 glomerulopathy (C3G). This offers a promising treatment strategy for C3G patients by targeting liver C3 synthesis.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Complement alternative pathway (AP) dysregulation causes C3 glomerulopathy (C3G), a kidney disease with no current treatments.
- C3G is characterized by C3 deposition in the glomeruli, leading to kidney damage.
- Targeting complement C3 is a potential therapeutic strategy for C3G.
Purpose of the Study:
- To evaluate the efficacy of SLN501, an optimized siRNA targeting liver C3 synthesis, in a mouse model of severe C3G.
- To assess SLN501's impact on AP dysregulation, glomerular C3 deposition, and renal pathology in mice with complete factor H deficiency.
Main Methods:
- Utilized a mouse model with complete factor H deficiency (Cfh-/- mice) exhibiting a severe C3G phenotype.
- Administered SLN501, a small interfering RNA designed to inhibit liver C3 synthesis.
- Assessed liver C3 production, AP dysregulation markers, glomerular C3d deposits, and ultrastructural changes.
Main Results:
- SLN501 effectively suppressed liver C3 synthesis in C3G mice.
- SLN501 treatment limited AP dysregulation and reduced glomerular C3d deposits.
- SLN501 prevented the development of ultrastructural alterations associated with C3G.
Conclusions:
- siRNA-mediated liver C3 gene silencing, exemplified by SLN501, is a viable therapeutic approach for C3G.
- This strategy shows promise for treating C3G patients with factor H deficiency, both partial and complete.
- SLN501 demonstrates potential as a targeted therapy for rare renal disorders driven by complement dysregulation.
Abstract:
Complement alternative pathway (AP) dysregulation drives C3 glomerulopathy (C3G), a rare renal disorder characterized by glomerular C3 deposition and glomerular damage, for which no effective treatments are available. Blockade of complement C3 is emerging as a viable therapeutic option. In an earlier study we showed that SLN500, a small interfering RNA targeting liver C3 synthesis, was able to limit AP dysregulation and glomerular C3d deposits in mice with partial factor H (FH) deficiency (Cfh+/- mice). Here, we assessed the pharmacological effects of SLN501 - an optimized SLN500 version - in mice with complete FH deficiency (Cfh-/- mice) that exhibit a more severe C3G phenotype. SLN501 effectively prevented liver C3 synthesis, thus limiting AP dysregulation, glomerular C3d deposits and the development of ultrastructural alterations. These data provide firm evidence of the use of siRNA-mediated liver C3 gene silencing as a potential therapy for treating C3G patients with either partial or complete FH loss of function.
