RARE DISEASE
C3 glomerulopathy
C3 glomerulopathy
C3 glomerulopathy
Synonyms: Non-Ig-mediated MPGN, Non-Ig-mediated membranoproliferative glomerulonephritis, Non-immunoglobulin-mediated MPGN, Non-immunoglobulin-mediated membranoproliferative glomerulonephritis
Synonyms: Non-Ig-mediated MPGN, Non-Ig-mediated membranoproliferative glomerulonephritis, Non-immunoglobulin-mediated MPGN, Non-immunoglobulin-mediated membranoproliferative glomerulonephritis
Synonyms: Non-Ig-mediated MPGN, Non-Ig-mediated membranoproliferative glomerulonephritis, Non-immunoglobulin-mediated MPGN, Non-immunoglobulin-mediated membranoproliferative glomerulonephritis
Drug discovery
14
drugs
With orphan designations
Overview
C3 glomerulopathy (C3G) is a rare complement dysregulation disorder driven by alternative pathway overactivation, characterized by C3 protein deposition in glomeruli. It encompasses dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), diagnosed via kidney biopsy. Chronic progression leads to kidney damage in ~50% of patients within 10 years, with high recurrence rates post-transplant. No disease-modifying therapies exist, necessitating supportive care and targeted clinical trials [1][3][9].
Therapies
First-line: ACE inhibitors/ARBs for proteinuria; renoprotective measures (SGLT2 inhibitors, dietary sodium/protein restriction) [2][3][13]
Immunomodulation: Mycophenolate mofetil + glucocorticoids for moderate-severe disease (36-65% remission rate) [2][8][17]
Emerging therapies: Anti-C5 (eculizumab), factor B inhibitors (iptacopan), C3-targeted drugs (pegcetacoplan) in late-stage trials [3][9][17]
Categories: rare genetic diseases, rare renal diseases, rare transplant-related disorders
Research Papers
587 drug discovery papers about C3 glomerulopathy, with 3 first-in-class and 43 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
587 drug discovery papers about C3 glomerulopathy, with 3 first-in-class and 43 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-09-25 | Complement diagnostics and therapeutics for the pediatric population: early successes and opportunities for further advancement.
Complement-mediated diseases are individually rare, often rapidly progressive, and historically associated with high rates of permanent organ injury or death but are now among the most therapeutically actionable conditions in pediatric nephrology, hematology, and rheumatology. As demonstrated by thrombotic microangiopathy, and hemolytic uremic syndrome in particular, diagnostic delay can contribute directly to irreversible kidney injury. Complement inhibition has substantially improved outcomes in these conditions that previously carried a substantial risk of end-stage kidney disease. This review addresses the complement system as a clinical and therapeutic framework for the practicing pediatric clinician. The pathophysiology of the major complement-mediated diseases affecting children is examined, with atypical hemolytic uremic syndrome and transplant-associated thrombotic microangiopathy as central disease models alongside paroxysmal nocturnal hemoglobinuria, C3 glomerulopathy, IgA nephropathy, and ANCA-associated vasculitis. Approved complement inhibitors are reviewed by mechanistic position in the cascade, with attention to the clinical implications of terminal versus proximal pathway inhibition. Laboratory diagnosis, monitoring, and assessment of complement blockade adequacy are addressed, including practical limitations of complement testing in clinical practice. Critical gaps are examined, including diagnostic delays, absent validated biomarkers, inadequate pediatric trial infrastructure, and conditions without targeted therapies. Emerging therapeutics, point-of-care diagnostics, and pediatric-specific considerations including transition of care and reproductive counseling complete the review. Complement therapeutics have meaningfully altered the trajectory of some of the most severe and inadequately treated pediatric diseases. This field continues to evolve rapidly, with expanding indications and novel agents, though drug development challenges, diagnostic and monitoring gaps, and equitable consideration of pediatric application of these novel agents remain essential priorities.
2026-09-11 | Complement in Kidney Disease: Core Curriculum 2026.
The complement cascade is part of the innate immune system, and it provides an important line of defense against infections. Inappropriate or excessive activation of this system, however, is also a driver of kidney inflammation in many diseases. Complement inhibitory drugs have now been approved by the US Food and Drug Administration for the treatment of 5 renal diseases: atypical hemolytic uremic syndrome, C3 glomerulopathy, immune-complex membranoproliferative glomerulonephritis, antineutrophil cytoplasmic antibody-associated vasculitis, and IgA nephropathy. Ongoing clinical trials are testing new anticomplement drugs and additional renal indications for complement inhibitors. Most immunosuppressive drugs do not directly block complement activation, and the use of complement inhibitors for renal indications is likely to expand in the coming years. Complement activation in renal diseases also generates plasma, urine, and tissue biomarkers, and laboratory evaluation of the complement system is an important part of the clinical work-up of patients with these inflammatory and autoimmune conditions. It is essential, therefore, that nephrologists are familiar with the available anticomplement drugs and with complement diagnostics.
2026-09-03 | Clinical improvement of acquired partial lipodystrophy in an adolescent with C3 glomerulopathy treated with pegcetacoplan.
C3 glomerulopathy and acquired partial lipodystrophy (APL) are rare disorders associated with dysregulation of the alternative complement pathway and occasionally coexist. We report a 14-year-old girl who developed nephritic-nephrotic syndrome due to C3 glomerulonephritis concomitant with APL. Despite treatment with mycophenolate mofetil and tacrolimus, kidney function deteriorated, proteinuria increased, and she developed marked faciotruncal lipoatrophy with a 10-kg weight loss. Pegcetacoplan, a C3/C3b inhibitor, was initiated. Five weeks later, serum C3 levels were normal. Creatinine clearance subsequently improved from 25 to 133 mL/min, while proteinuria progressively declined from 3.2 to 0.15 g/g. Within 40 weeks, the patient recovered her usual body weight with marked clinical improvement in subcutaneous fat distribution. This observation suggests that pegcetacoplan may represent a novel therapeutic option for APL.
2026-08-14 | Global research landscape of C3 glomerulopathy: A bibliometric analysis.
C3 glomerulopathy (C3G) is a rare, complement-mediated kidney disease with significant diagnostic and therapeutic challenges. Despite a growing number of publications, no study has comprehensively mapped the global research landscape. This bibliometric analysis aimed to evaluate publication trends, influential contributors, thematic evolution, and collaboration networks in C3G research from 1980 to 2025. A systematic bibliometric analysis was conducted using PubMed-indexed publications from 1980 - 2025 retrieved with predefined Boolean queries. Eligible articles included original research and reviews addressing the pathophysiology, diagnosis, and management of C3G. Bibliometric parameters were analyzed using the Bibliometrix package in R (v4.3) and VOSviewer (v1.6.20). Citation data were verified via Google Scholar. A total of 967 publications across 273 journals were identified. Research output increased exponentially after 2013, coinciding with the C3G Consensus Report and the rise of complement-targeted therapies. Pediatric Nephrology, Kidney International, and JASN were the leading publication venues. The United States, United Kingdom, and Italy were the most productive countries, with emerging contributions from China, India, and Türkiye. S. Sethi was the most prolific author (24 papers). Keyword co-occurrence and citation network analyses demonstrated a thematic shift from morphologic classification ("dense deposit disease") toward molecular and therapeutic paradigms ("complement inhibition," "iptacopan," "pegcetacoplan"). Collaboration networks remained modest and regionally clustered. Global research on C3G has evolved from descriptive pathology toward precision complement therapeutics. However, significant geographical disparities persist, emphasizing the need for stronger international collaboration and equitable access to emerging complement inhibitors.
2026-08-07 | Charting the Course of Recurrent C3 Glomerulopathy and Immune Complex–Mediated Membranoproliferative GN in Kidney Transplant Recipients
C3 glomerulopathy (C3G) comprises several closely related diseases associated with underlying complement dysregulation.Dense deposit disease is diagnosed by the finding of characteristic dense intramembranous electron deposits on electron microscopy.C3 GN is characterized by strong dominant C3 staining within the glomeruli, typically in association with subendothelial and/or mesangial electron dense deposits.In each of these diseases, patients may exhibit a pattern of injury ranging from membranoproliferative, mesangial proliferative, endocapillary proliferative, and crescentic.Other patients may exhibit codominant strong C3 and Ig staining, often with a membranoproliferative pattern of injury-these are considered an immune complex MPGN.Of this latter group, primary forms are considered part of the C3G disease spectrum.Common to all of these are the presence of abnormalities of complement dysregulation, often resulting in complement consumption in keeping with the definition of C3G as reported in the C3G consensus report in 2013. 1 Treatment options of C3G have been ineffective, with outcomes typically around 40% kidney failure over a median of 11 years of follow-up.2 However, recent pivotal trials of alternative pathway inhibitors of largely nontransplanted patients have met primary outcomes, 3,4 and the emergence of these now approved treatments in the clinic will hopefully improve outcomes and reduce the risk of kidney failure.However, for a significant cohort of patients with C3G, who are already at kidney failure there is the further burden of disease recurrence with rates as high as 89%, 5 which raises the important question of how best to use alternative pathway inhibitors in this group of patients.In this issue, Ruiz-Cabello et al. 6 report a retrospective study of a large international cohort of 134 patients who have recurrence of C3G or immune complex MPGN.A strength of this study is that biopsies were re-reviewed to help with accurate classification of disease, and those
small molecules
2026-09-08 | Complement targeting in autoimmune diseases.
Complement is a central effector of cell and tissue injury in hematological and autoimmune diseases, and recent intensive research brought new inhibitors to the clinic. This review summarizes complement-mediated mechanisms across hematological, systemic, and kidney-specific autoimmune diseases, appraises emerging biomarker strategies, and evaluates these therapies. For years, clinical complement inhibition was possible only at C5, first in paroxysmal nocturnal hemoglobinuria. The arsenal has now expanded to the initiation pathways: sutimlimab (anti-C1s) is effective in the hematological autoimmune condition cold agglutinin disease, pegcetacoplan (C3-inhibitor) in C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis, and oral iptacopan (Factor B-inhibitor) reduces proteinuria in immunoglobulin A nephropathy and C3 glomerulopathy. Nevertheless, challenges remain. Avacopan (C5aR1-inhibitor) faces proposed withdrawal after trial manipulation and hepatotoxicity, and although complement is central to systemic lupus erythematosus and contributes to membranous nephropathy, no effective strategy has yet emerged. Recognizing complement's role in the pathophysiology of hematological and autoimmune diseases has driven effective new therapies. Comprehensive profiling complement biomarkers, now feasible through complementomics in fluids and tissues, may reveal responsive endotypes and optimal cascade steps to target in diseases where complement is implicated but trials have not yet matched the right drug to the right patients.
2026-09-01 | Distinct Pharmacodynamic Complement Biomarker Signatures Define Iptacopan and Pegcetacoplan Treatment in C3 Glomerulopathy
Background C3 glomerulopathy (C3G) is driven by alternative pathway (AP) dysregulation. Iptacopan inhibits factor B, whereas pegcetacoplan inhibits C3/C3b, suggesting distinct pharmacodynamic (PD) biomarker profiles. Methods We conducted an exploratory, nonrandomized observational cohort study of patients with biopsy-confirmed C3G treated with iptacopan (n = 9) or pegcetacoplan (n = 9), using paired pretreatment and approximately 3-month post-treatment samples. Complement activity, protein levels, activation products, autoantibodies, and genetic findings were assessed. Profiles were classified as PD-concordant (PDC), largely PD-concordant (LPDC), or PD-discordant (PDD) using treatment-specific signatures. Results Both treatments suppressed AP activity and terminal pathway activation but produced distinct profiles. The expected PDC signature for iptacopan included increases in C3, factor B, C5, properdin, and CH50 and reductions in complement activation products (C3a, C3c, C3d, Bb, and sC5b-9). The expected pegcetacoplan signature included supranormal increases in C3, C3c, and properdin, reductions in C3a, C3d, Bb, and sC5b-9, and generally preserved or increased CH50. PDC profiles occurred in 6 of 9 patients in each cohort. LPDC profiles occurred in three iptacopan-treated patients, all nephritic factor-positive, and two pegcetacoplan-treated patients with nephritic factors or a likely pathogenic C3 variant. One patient with severe factor H deficiency showed a PDD profile during pegcetacoplan treatment and again in a descriptive post-transplant sample during subsequent iptacopan treatment. Conclusions Iptacopan and pegcetacoplan produce distinct, mechanism-specific PD signatures in C3G. Pathway-based biomarker assessment may distinguish expected treatment effects from incomplete or discordant biochemical control. These categories describe PD patterns rather than clinical efficacy and require validation against clinical outcomes.
2026-08-28 | SEISMIC: a multistakeholder summit addressing access issues in diagnosis and treatment of C3G nephropathy and IC-MPGN.
C3 glomerulopathy (C3G)-primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) is an ultrarare disease spectrum associated with a significant health burden and for which there is a huge unmet need for safe and effective treatment. The underlying pathophysiology is dysregulation and overactivation of the alternative complement pathway. Two new therapeutic agents, iptacoplan and pegcetacoplan, that target proximal steps in the cascade, have demonstrated to be effective and have been approved for use in patients with C3G alone and with C3G/IC-MPGN, respectively. A key challenge to the nephrology community is how to incorporate these disease-modifying drugs into clinical practice in a timely and equitable manner. This report summarizes the deliberations and recommendations that emerged from the Addressing Access Issues in Diagnosis and Treatment of C3G Nephropathy and IC-MPGN (SEISMIC) summit in July 2025. The meeting assembled a broad panel of experts and patients and addressed the following 3 aims: (i) define issues in proper and timely diagnosis of this complex disease spectrum, (ii) assess management strategies in light of the availability of this new class of therapeutic agents, and (iii) identify barriers to access to care and treatment with these new therapeutic agents and design strategies to surmount them.
2026-08-20 | Beyond Defense: Kidney Mysteries in Inborn Errors of Immunity
Inborn errors of immunity (IEI), formerly termed primary immunodeficiencies, are increasingly recognized as disorders of immune dysregulation rather than infection susceptibility alone. With over 500 validated genes in the 2024 International Union of Immunological Societies (IUIS) classification and approximately one-quarter of patients presenting without infection, autoimmunity, autoinflammation, lymphoproliferation, and malignancy are now core features. The kidney is affected across at least 22 IEI categories, yet renal involvement remains under-recognized. This review proposes a mechanistic framework for IEI-associated kidney disease, encompassing: complement dysregulation (C3 glomerulopathy, atypical hemolytic uremic syndrome from CFH/CFI/C3 variants); immune complex–mediated and monogenic lupus nephritis (C1q, C2, C4, DNASE1L3, and TREX1 defects); autoinflammatory and type I interferonopathy–driven nephropathy; infection-related glomerulonephritis (common variable immunodeficiency [CVID], chronic granulomatous disease); lymphoproliferative and immune-dysregulation syndromes causing interstitial nephritis (ALPS, CTLA-4 and LRBA deficiency); and syndromic IEI with intrinsic structural disease. We outline a stepwise diagnostic approach integrating clinical red flags, complement and immune profiling, kidney biopsy with immunofluorescence and electron microscopy, and genetic testing, emphasizing that genetic diagnosis should precede immunosuppression. The therapeutic landscape is shifting from empirical immunosuppression toward precision medicine, including complement inhibitors (iptacopan, pegcetacoplan, Food and Drug Administration–approved for C3 glomerulopathy in 2025), JAK inhibitors for interferonopathies, leniolisib for activated PI3Kδ syndrome, CTLA4-Ig agents, and curative hematopoietic stem cell transplantation and emerging gene therapy. An illustrative case from Europe’s largest kidney transplant center illustrates a girl with Schimke immuno-osseous dysplasia (SMARCAL1 mutation) presenting with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis who underwent kidney transplantation following bone marrow transplant. Recognizing IEI in unexplained nephropathy, combining biopsy with complement and genetic profiling, and early nephrology–immunology collaboration are key to improving renal outcomes and enabling potentially curative therapy.
2026-08-13 | Characterizing Properdin-Inhibited C3 Nephritic Factors in Patients with Complement-Mediated Kidney Diseases.
C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) are severe complement-mediated kidney diseases. In a substantial proportion of these patients, C3 nephritic factors (C3NeFs) are detected; these autoantibodies stabilize the complement alternative pathway (AP) C3 convertase. Previous studies have investigated and distinguished properdin-dependent and properdin-independent C3NeFs. In this study, we investigated a distinct subset of C3NeFs that are exclusively active in the absence of properdin: properdin-inhibited C3NeFs. A two-step hemolytic AP convertase activity assay was employed to examine convertase activity in patient serum in the presence versus absence of properdin using the properdin inhibitor Salp20. In 7/16 patients and 1/23 healthy controls, who showed no convertase stabilization in full serum, convertase stabilization was observed upon properdin inhibition, indicating properdin-inhibited C3NeF activity. Consistent findings were obtained when purified patient Igs were added to properdin-depleted serum. Moreover, in an ELISA-based C3bBb binding assay, 6/7 patients with properdin-inhibited C3NeFs showed increased convertase binding, which decreased upon addition of properdin. Complement levels in patients with properdin-inhibited C3NeFs were not significantly different from those in the C3NeF-negative group, and properdin levels were generally within the refence range. In conclusion, our results support the existence of properdin-inhibited C3NeFs, thereby further expanding the functional heterogeneity of these autoantibodies. Although their functional relevance under physiological conditions remains unclear, these findings may have important implications for complement-targeted therapies, particularly strategies aimed at properdin inhibition, as the presence of these C3NeFs may predispose to unintended effects.
oligonucleotides
2026-07-28 | Therapeutic Evaluation of a C3-Targeting Small Nucleic Acid Drug in a Spontaneous Humanized C3 Glomerulopathy Mouse Model 2256845
Abstract Introduction Complement component C3 is central to the activation of the alternative pathway (AP), and its dysregulation drives C3 glomerulopathy, a severe renal autoimmune disease that lacks effective therapies. Methods To enable translational studies, we established a humanized C3G model, B6-hC3 mC3 KO, which overexpresses human C3 while lacking the endogenous murine C3. These mice spontaneously develop progressive glomerulopathy resembling human C3G pathology. Small nucleic acid drugs were administered to mice to evaluate drug efficacy. Results The disease phenotype observed in humanized C3 transgenic mice appears to arise from a dysfunctional interaction between human C3 protein and murine complement proteins, resulting in uncontrolled AP activation. Subcutaneous administration of C3-targeting small nucleic acid drugs effectively reduced serum C3 and plasma C3a levels, and downregulated the ratio of Ba (the activated fragment of complement factor B, CFB) to CFB, indicating suppression of AP hyperactivation. After 6 weeks of treatment, renal histology showed markedly reduced deposition of hC3 and diminished inflammatory cell infiltration. Conclusion B6-hC3 mC3 KO mice reproduce key immunopathological features of C3G and serve as a powerful platform for mechanistic studies and preclinical evaluation of complement-targeted therapeutics. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)
2025-10-01 | Interim Phase 1 Study Results of ADX-038: A Novel siRNA Against Complement Factor B, and Next Steps in IgAN and C3 Glomerulopathy (C3G)
Background: ADX-038 is a siRNA that targets complement factor B (CFB) mRNA, being developed for diseases with dysregulation of the complement system. The effects of ADX-038 on CFB protein levels and on the complement alternative pathway (AP) and classical pathway (CP) activity in healthy volunteers is reported with the discussion of the Phase 2 study in IgAN and C3G. Methods: As of 2/2025, 41 healthy adults were randomized and administered one subcutaneous dose of ADX-038 n=31 or placebo n=10. ADX-038 doses ranged from 0.4 to 6 mg/kg (actual doses 25 to 360 mg). Circulating CFB protein levels, and AP and CP activity were measured. Clinical safety was based on adverse events (AEs) and monitoring of clinical lab tests, physical exams (PE). Results: Dose-dependent reductions in CFB protein levels and inhibition of AP activity were observed, Figures 1 and 2. A single 4 mg/kg ADX-038 dose suppressed AP activity by 99% from baseline through 3M. As expected, CP activity was unchanged. Treatment was well-tolerated. The most common AE was upper respiratory tract infection, similar to placebo. There were no encapsulated bacterial infections nor clinically relevant changes in clinical lab tests, PE or vital signs. The Phase 2 study will dose IgAN and C3G patients Q3M with ADX-038. The primary objective of the study is to assess the tolerability of ADX-038, with the secondary objective of changes to proteinuria. Conclusion: A single dose of ADX-038 effectively silenced CFB gene expression, resulting in selective and near-complete suppression of complement AP activity. The durable on-target PD effects support its potential as an effective therapeutic agent for kidney diseases with a convenient (Q3M) subcutaneous dosing schedule. Based on these results, a Phase 2 study has been initiated to assess the safety and efficacy of ADX-038 in patients with complement mediated kidney diseases (eg. IgAN and C3G). Funding: Commercial Support - Adarx pharmaceuticals
2025-10-01 | Safety and Pharmacodynamics of SGB-9768, an siRNA Targeting Complement C3 in Healthy Volunteers
Background: SGB-9768, a GalNAc-conjugated siRNA, inhibits hepatic complement C3 production in Heathy volunteers, warrants further investigation in its potential to treat complement-related kidney diseases. Methods: Two phase 1, randomized, double-blind, placebo-controlled trials (SGB-9768-001, NZ; SGB-9768-002, China) evaluated the safety, pharmacokinetics, and pharmacodynamics of single subcutaneous doses of SGB-9768 in healthy volunteers. Results: Study 001 enrolled 29 participants (mostly Caucasian) receiving 25–400 mg of SGB-9768 (4:2 active to placebo). Study 002 enrolled 37 participants (all Chinese) with doses of 50–600 mg (3:2 active to placebo at 50 mg, 6:2 at higher doses). All participants received vaccinations (meningococcal vaccine and pneumococcal vaccine) before dosing and prophylactic antibiotics throughout the study. SGB-9768 demonstrated a favorable safety and tolerability profile, with no significant infections, including no cases involving encapsulated organisms. There were no dose limiting toxicity or treatment-related serious adverse events (AE) or discontinuations due to AEs. Treatment-related AE reported in ≥10% of participants was injection site reaction. PD data (Figure 1) showed dose-dependent serum C3 reductions of 52–85% (Study 001, 25–400mg) and 75–93% (Study 002, 50-600 mg) at 1 month, sustained at 52–84% and 69–92% at 3 months. Alternative pathway activity (Wieslab® AP) decreased by 43–99% (Study 001) and 66–100% (Study 002) at 1 month, sustained at 59–99% and 59–100% at 3 months. Classical pathway activity (Wieslab® CP) reductions ranged from 12–56% at 1 month. Conclusion: SGB-9768 was safe, with sustained, dose-dependent reductions in C3 and complement activity, supporting development for kidney diseases like IgA nephropathy and C3 glomerulopathy. Funding: Commercial Support - Suzhou Sanegene Bio Inc.Figure 1. Measures of serum complement C3 level (a), Wieslab® AP (b), Wieslab® CP (c) in healthy volunteers.
2025-04-21 | Abstract 6848: Development of a humanized C3 mouse model for preclinical evaluation of therapeutics in C3 glomerulopathy
Abstract C3 glomerulopathy (C3G) is a rare and progressive kidney disease, encompassing C3 glomerulonephritis and dense deposit disease, both driven by dysregulation of the alternative pathway of complement activation. Approximately 50% of patients progress to end-stage kidney disease (ESKD) within 10 years, with limited treatment options currently available. To address this unmet need, we developed a novel humanized C3 (hC3) mouse model that exhibits a pronounced C3G-like phenotype, characterized by early progression to ESKD and increased mortality. Compared to wild-type mice, hC3 mice display significantly reduced circulating C3 levels, alongside liver and kidney dysfunction confirmed by biochemical and pathological analyses. These mice also demonstrate reduced body weight, elevated morbidity early in life, and a shortened lifespan of approximately 5-6 months. To evaluate potential therapies, we treated hC3 mice with the small interfering RNA drug ARO-C3 at high and low doses. ARO-C3 treatment led to a reduction in serum hC3 levels as early as one week post-administration, with a single dose maintaining suppression for at least five weeks. Importantly, ARO-C3 treatment significantly prolonged survival and improved liver and kidney function, as demonstrated by molecular and histopathological analyses. This hC3 mouse model provides a robust platform for studying complement-mediated diseases such as C3G and for preclinical evaluation of novel therapeutic strategies targeting the complement system. Citation Format: Andrei Golovko, Shuang Li, Xiaolei Qiu, Yi Li, Ruilin Sun. Development of a humanized C3 mouse model for preclinical evaluation of therapeutics in C3 glomerulopathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6848.
2024-03-13 | Efficacy of GalNAc C3 siRNAs in factor H-deficient mice with C3 glomerulopathy.
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.
proteins
2026-07-08 | Dataset related to article "Moss-derived recombinant Factor H, CPV-104, effectively antagonizes alternative pathway C3/C5 convertases stabilization by NeFs from patients with primary C3 glomerulopathy
This dataset contains the raw experimental data supporting the article "Moss-derived recombinant Factor H, CPV-104, effectively antagonizes alternative pathway C3/C5 convertases stabilization by NeFs from patients with primary C3 glomerulopathy", published in Frontiers in Immunology, 2026. The dataset includes the following files: Western blot raw data (Figure 1, Supplementary Figure S1, and Supplementary Table S1). Western blot raw data (Figure 2, Supplementary Figure S2, and Supplementary Table S2). ELISA C3a raw data (Figures 3A, 4A, and 4B). ELISA C3a raw data (sCR1 experiments). ELISA Ba raw data (Figures 3B, 4C, and 4D). The files contain the original experimental data underlying the figures and supplementary material reported in the associated publication.
2026-07-01 | Moss-derived recombinant Factor H, CPV-104, effectively antagonizes alternative pathway C3/C5 convertases stabilization by NeFs from patients with primary C3 glomerulopathy
Background C3 glomerulopathy (C3G) is a rare kidney disease caused by uncontrolled activation of the complement alternative pathway (AP), frequently driven by nephritic factors (NeFs) that stabilize the AP C3 and C5 convertases. NeFs are detected in up to 80% of patients and exhibit heterogeneous stabilizing activity, contributing to variable degrees of complement dysregulation. Current complement−targeted therapies reduce complement activation but may compromise immune surveillance by blocking key components of the pathway. Supplementation with the physiological AP regulator factor H (FH) represents an alternative strategy aimed at restoring complement homeostasis while preserving essential immune functions. CPV−104 is a fully functional recombinant human FH produced in moss, with optimized glycosylation and improved pharmacokinetics, offering a promising therapeutic approach for C3G. Objectives and Methods We evaluated the ability of CPV−104 to antagonize NeF−mediated stabilization of the AP C3 convertase (C3bBb) in eight C3G patients enrolled in the Italian MPGN/C3G Registry. Patients were classified as C3NeF+ or C5NeF+ based on properdin dependence in convertase stabilization assays. NeF activity was analyzed using solid−phase assays in which C3bBb decay and formation were assessed in the presence of CPV−104 or serum−derived FH (sd−FH). The impact of CPV−104 ex vivo was tested in fluid−phase assays using patient sera, with Ba (convertase formation) and C3a (convertase activity) measured by ELISA. Results CPV−104 accelerated decay of NeF−stabilized C3bBb with efficacy comparable to sd−FH. Convertases stabilized by six of eight NeFs were fully dissociated by CPV−104, while two highly potent C3NeFs were partially antagonized. When added during convertase assembly, CPV−104 significantly reduced C3bBb formation in all patients and showed a stronger inhibitory effect than sd−FH. In fluid−phase assays, using patient sera, CPV−104 markedly decreased Ba and C3a generation, with mean inhibition of 68.9% and 51.8%, respectively, and consistently outperformed sd−FH across patient samples. Conclusions CPV−104 effectively limits both stabilization and formation of AP C3 convertases in NeF−positive C3G, demonstrating superior functional activity compared with sd−FH. By restoring physiological AP regulation rather than broadly inhibiting complement activation, CPV−104 represents a promising and potentially safer therapeutic strategy for NeF−driven C3G and warrants further clinical investigation.
2026-03-11 | A novel fusion protein reduces kidney complement in experimental C3 glomerulopathy.
Complement activation contributes to kidney damage in many types of glomerulonephritis and complement inhibition therapy is approved for IgA nephropathy and C3 glomerulopathy. However, inhibition is not specific to the kidney resulting in unnecessary systemic complement inhibition and increased infection risk. To develop an effective inhibitor of glomerular complement we combined complement factor H-related protein 5 (FHR51-9), which binds to glomerular complement C3, with the complement regulatory domains of the key negative regulator of C3 activation complement factor H (FH1-5). One week after adeno-associated virus (AAV) mediated expression of the FHR51-9FH1-5 fusion protein in factor H (FH)-deficient mice, glomerular C3b/iC3b/C3c was significantly reduced and properdin resolved completely compared to controls. There was no change to circulating C3 levels and FHR51-9FH1-5 was detected in glomeruli in association with C3d. Six and twenty weeks after AAV8-FHR51-9FH1-5 treatment in hFH-FHR5mut mice (a mouse model of CFHR5 nephropathy) glomerular C3b/iC3b/C3c, C3d, and C5 were significantly reduced and properdin resolved completely compared to controls. Pre-administration of AAV-FHR51-9FH1-5 also ameliorated abnormal glomerular C3b/iC3b/C3c, C3d, C5, and properdin in a triggered CFHR5 nephropathy model. In vitro FHR51-9FH1-5 showed dose-dependent binding to surface-immobilized C3, C3b, iC3b, and C3d; factor I cofactor activity; and reduced C3a generation in an alternative pathway convertase assay. Taken together, the FHR51-9FH1-5 protein reduced glomerular C3 in experimental models of C3 glomerulopathy driven by either FH deficiency or mutated FHR5. These preclinical data indicate that FHR51-9FH1-5 protein represents a novel treatment strategy for complement-mediated kidney disease.
2026-02-18 | Thrombospondin-1 as inhibitor of the alternative complement pathway in antineutrophil cytoplasmic antibodyassociated vasculitis
Thrombospondin-1 (TSP-1) is a matricellular glycoprotein involved in tissue remodeling, inflammation, angiogenesis, and cell signaling. Previous studies have demonstrated interactions between TSP-1 and complement Factor H (FH), the principal regulator of the alternative complement pathway (AP). In addition, complement-regulatory properties have been shown before for TSP-5, another member of the thrombospondin family. Based on these findings, the aim of this thesis was to investigate the potential regulatory role of TSP-1 within the AP. A novel function of TSP-1 as an endogenous inhibitor of the AP was identified, and its involvement in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) was investigated. The complement regulatory properties of TSP-1 were characterized through a combination of biochemical studies, in vitro functional assays, ex vivo assays using patient-derived material as well as in vivo disease models. TSP-1 was found to bind multiple components of the complement cascade, including C3, C5, Factor B (FB), FH, and C8. Functionally, the cleavage of C3 and C5 by their respective convertases was inhibited by TSP-1. In addition, TSP-1 blocked the cleavage of FB by Factor D (FD) as well as the formation of the membrane attack complex (MAC). Although binding to FH was confirmed, no interference with its cofactor or decay-accelerating activities was detected. These findings suggest that TSP-1 exerts complement regulation through a distinct mechanism independent of its interaction with FH. The physiological relevance of TSP-1-mediated complement inhibition was further assessed ex vivo using serum from patients with atypical hemolytic uremic syndrome and erythrocytes from patients with paroxysmal nocturnal hemoglobinuria. Pathological C3 deposition and hemolysis were significantly inhibited by TSP-1. On endothelial cells, TSP-1 knockdown led to increased complement deposition and cell activation, confirming a direct regulatory function. Finally, TSP-1 could normalize serum C3 levels and reduce glomerular C3 deposition in a mouse model of C3 glomerulopathy, confirming the functional importance of TSP 1 in regulating complement activity. Another key focus of this thesis was AAV, a disease marked by excessive neutrophil extracellular trap (NET) formation due to AP overactivation. Prominent TSP-1 staining in glomeruli of AAV patients suggested a regulatory role of TSP-1 in this disease. Further functional assays using microfluidic systems showed that TSP-1 inhibits NETosis through complement-dependent mechanisms. The role of TSP-1 was further investigated using a mouse model for AAV. In this model, TSP-1-deficient mice exhibited more severe kidney injury compared to wild-type controls. This was associated with increased glomerular complement deposition and elevated levels of citrullinated histone, a marker for NETosis. In conclusion, this thesis demonstrates a novel and functionally distinct inhibitory role of TSP 1 in the alternative complement pathway and provides new insights into the interaction between endothelium, the immune and complement system. Although TSP-1 does not seem to be a major regulator of complement under resting conditions, its local release from endothelial cells and platelets during inflammation is capable of restricting complement activity. TSP 1 may thus represent a promising new target and biomarker in complement-mediated diseases.
2026-01-16 | Treatment of atypical hemolytic uremic syndrome and C3 glomerulopathy in mice by hepatic expression of factor D.
Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are diseases driven by dysregulation of the alternative pathway (AP) complement. Current treatments of these diseases involve the use of frequent and often large doses of monoclonal antibodies, peptide inhibitors, or chemical inhibitors of complement proteins, with various limitations. In this study, we describe ectopic expression of factor D (FD) in the liver as a potential novel therapy for these indications. Unlike most plasma complement proteins, which are synthesized in the liver, FD, a serine protease in the AP, is synthesized primarily in fat tissues. Newly synthesized FD is released largely as an inactive proenzyme that requires activation by mannose-binding lectin-associated serine protease 3 (MASP3) to form the mature enzyme. We found serendipitously that ectopic expression of mature FD, but not pro-FD, in the mouse liver led to C3-dependent depletion of plasma factor B (FB) and abolished AP complement activity. Coexpression of C3, FB, and mature FD in cultured Hepa1-6 cells caused intracellular FB activation and consumption, probably within the secretory vesicles where all 3 proteins may colocalize. Hepatic FD-mediated local FB activation and depletion effectively prevented disease development in murine models of aHUS and C3G. Our results suggest that segregated tissue production of FD, FB, and C3, as well as FD regulation by MASP3, is necessary to prevent in situ FB activation and depletion. Ectopic expression of mature FD in the liver is an effective way to inhibit FB expression and AP complement activity, with potential therapeutic applications in diseases such as aHUS and C3G.
other
2025-12-10 | Kidney damage in patients with multiple myeloma associated with light chain deposition disease and C3 glomerulopathy
Background. Kidney dysfunction is a common manifestation of multiple myeloma (MM). Kidney damage in MM is most often associated with cast nephropathy; however, rarer forms such as light chain deposition disease (LCDD) and C3 glomerulopathy (C3 GP) also occur. According to several studies, patients with these forms of kidney damage more frequently develop end-stage renal disease and have a worse prognosis for kidney function recovery. Aim. To evaluate the efficacy of induction therapy with targeted drugs followed by consolidation with high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with MM and nephropathy associated with LCDD and C3 GP. Materials and methods. Medical data from 3 patients with MM and nephropathy caused by LCDD (2 cases) and C3 GP (1 case) who received induction therapy followed by auto-HSCT were retrospectively analyzed. Results. At disease onset, impaired kidney function with reduced glomerular filtration rate was detected in all 3 patients; 1 case presented with anuria. All patients received renal replacement therapy. After induction, complete hematologic response was achieved in 2 patients and very good partial response in 1 patient with MM and C3 GP. Renal replacement therapy was discontinued in 2 out of 3 cases. On the 100th day after auto-HSCT, hematologic complete response persisted in 2 patients with LCDD; in the C3 GP case, the response deepened to stringent complete response. All patients achieved renal response, with no need for renal replacement therapy. During long-term follow-up (23–82 months), 1 patient maintained the achieved response, while 2 patients relapsed at 2.5 and 2 years post-auto-HSCT, respectively. Conclusion. Multiple myeloma patients with LCDD- or C3 GP-associated nephropathy exhibit severe kidney dysfunction, often requiring renal replacement therapy, necessitating thorough evaluation in the absence of typical cast nephropathy features. Comprehensive therapy including auto-HSCT in young, fit MM patients with LCDD- or C3 GP-associated nephropathy enables deep hematologic response and improves renal function.
2025-10-01 | Single-Dose Adeno-Associated Virus Gene Therapy for C3 Glomerulopathy in an Avatar Mouse Model of Human Complement-Mediated Kidney Disease
Background: Complement 3 glomerulopathy (C3G) is a rare complement-mediated kidney disease caused by uncontrolled activation of the complement alternative pathway associated with factor H (CFH) mutations. About half of the patients with C3G will eventually develop kidney failure because no effective treatment is currently available. The aim of this study was to evaluate the therapeutic potential of a liver-directed Adeno-Associated Virus (AAV) therapy to treat a mouse CFH mutant model with C3 glomerulopathy. Methods: C3G mouse model was established with a patient-derived specific point mutation W1180R in the CFH gene. An AAV2 vector that contains the human CFH sequence with a liver specific promoter (AAV-hCFH) was generated and packaged into a liver tropic capsid AAV8 and was administered intravenously into susceptible CFH mutant mice. Four and eight weeks after treatment, hepatic vector transduction was assessed by testing the vector copy number (VCN). The therapeutic outcome was evaluated by kidney function, proteinuria, serum CFH levels and C3 deposition in kidney. Results: CFH homozygous (CfhW1180R/W1180R) mice showed spontaneous deposition of glomerular C3, absent circulating CFH and progressive renal injury with age as compared to heterozygous (CfhW1180R/WT) mice and wild type mice. A single intravenous dose of AAV-hCFH (5x1011 vector genome per mouse) was successfully transduced and retained in liver with a high level of VCN and functional CFH expression, increased serum CFH and reduced serum C3 levels as compared with untreated mutant mice. CfhW1180R/W1180R mice treated with the AAV-hCFH demonstrated improved kidney function with lower serum creatinine (42±2.3 vs 28±2.8µmol/L, p<0.05), less proteinuria (5.2±0.8 vs 2.5±0.4mg/16h, p<0.001), less kidney injury (5.4±0.4 vs 3.6±0.6, p<0.01) and reduced C3 deposition as compared to untreated CfhW1180R/W1180R mice. Conclusion: Human CFH was successfully delivered to the liver of CFH mutant mice using AAV. hCFH was expressed in the mouse liver and was therapeutic with reduction in kidney injury in mutant mice compared with untreated mutant mice. Funding: Government Support – Non-U.S.
2025-07-28 | Guarding glomeruli from immune injury
C3 glomerulopathy (C3G), which includes C3 glomerulonephritis and dense deposit disease, is a severe renal disease caused by dysregulation of the complement system. In a study published in this issue of Molecular Therapy, Cfh−/− mice, which are an established model of C3G, were administered systemic adeno-associated virus (AAV8) containing truncated constructs of the human complement factor H (hCFH) gene to transduce hepatocytes.1 Increased CFH expression in the liver of Cfh−/− mice restored the alternative complement pathway and significantly reduced or eliminated histological and ultrastructural features of the disease.
2025-07-01 | AAV-mHDM-FH: Safety and expression profile in two murine models of hyper-complement activation
C3 glomerulopathy (C3G) and atypical haemolytic uraemic syndrome (aHUS) are rare kidney disorders characterized by the dysregulation of the alternative pathway (AP). Unlike aHUS, current treatment options for C3G are limited. Factor H (FH) plays a key role in regulating the AP, and mice lacking FH develop a disease similar to C3G. We previously developed mouse homodimeric minimal FH (mHDM-FH) as a gene therapy using an adeno-associated virus (AAV) vector incorporating a liver-specific promoter to rebalance the AP activation. We previously noted that a single dose of AAV-mHDM-FH (1 × 10 11 ) restored complement regulation in Cfh −/− mice by 21 days post inoculation, however this was associated with a strong anti-HDM-FH response, which was markedly reduced in Cfh +/− mice. In the current study, we focussed on long-term evaluation of AAV-mHDM-FH in both Cfh +/− mice and C3 N/N mice (the C3 D1115N gain-of-function mouse model of aHUS). At six months post-inoculation, C3 N/N mice treated with AAV-mHDM-FH showed significantly improved survival compared to AAV-GFP controls. However, the therapeutic effect was partially limited due to reduced binding affinity of mHDM-FH to the mutant C3 D1115N protein. These findings indicate that while AAV-mHDM-FH retains some functionality in C3 mutation-driven disease, its efficacy may not match therapies targeting the terminal complement pathway. In Cfh +/− mice, no signs of disease or safety concerns were observed over the six-month period. Importantly, increased serum levels of both C3 and FH were detected, suggesting improved control of the amplification loop in these mice. AAV transgene expression remained detectable in the liver at six months, an encouraging result for long-term efficacy. Across both experimental time points, anti-AAV antibody responses were detected in Cfh +/− mice. These responses peaked at 21 days post-inoculation but were present at relatively low levels after 6 months. This pattern aligns with observations in patients receiving AAV-based gene therapies. Despite the presence of anti-AAV antibodies, the 6 month data showed transgene expression and no safety concerns, leaving the extent to which these antibodies impact therapeutic efficacy still uncertain. Looking ahead, we aim to enhance long-term vector expression by exploring the use of alternative promoters tailored to different cellular targets. References: 1. Yang Y, Denton H, Davis O R, Smith-Jackson K, Kerr H, Herbert A P, Barlow P N, Pickering M C and Marchbank K J An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy J Am Soc Nephrol 2018 29(6):1649–1661.
2025-04-26 | Truncated complement factor H Y402 gene therapy rescues C3 glomerulonephritis.
There are no effective therapies for patients with dry age-related macular degeneration (AMD) or C3 glomerulonephritis (C3G). Unfortunately, past efforts to treat C3G using exogenous human complement factor H (CFH) found limited success due to immune rejection of a foreign protein response. AMD research has also faced myriad challenges, including the absence of an ideal therapeutic target and difficulties with treatment delivery in certain preclinical models. In pursuit of an AMD therapy to overcome these obstacles, we ultimately capitalized on parallels in complement dysregulation between AMD and C3G. Here, we investigate the potential for CFH supplementation as a strategy to rescue C3G. Our findings demonstrate restored inhibition of complement's alternative pathway and long-term reversal of disease without immune rejection using adeno-associated virus (AAV)-mediated delivery of truncated CFH (tCFH) in a Cfh-/- mouse model of C3G. We tested three different tCFH vectors and found significant differences in their relative transduction efficiency and therapeutic efficacy. These discoveries motivate the development of AAV-mediated tCFH replacement therapy for patients with C3G while simultaneously demonstrating proof of concept for AAV-mediated tCFH gene augmentation therapy for patients with AMD.
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2026-09-25 | Complement diagnostics and therapeutics for the pediatric population: early successes and opportunities for further advancement.
Complement-mediated diseases are individually rare, often rapidly progressive, and historically associated with high rates of permanent organ injury or death but are now among the most therapeutically actionable conditions in pediatric nephrology, hematology, and rheumatology. As demonstrated by thrombotic microangiopathy, and hemolytic uremic syndrome in particular, diagnostic delay can contribute directly to irreversible kidney injury. Complement inhibition has substantially improved outcomes in these conditions that previously carried a substantial risk of end-stage kidney disease. This review addresses the complement system as a clinical and therapeutic framework for the practicing pediatric clinician. The pathophysiology of the major complement-mediated diseases affecting children is examined, with atypical hemolytic uremic syndrome and transplant-associated thrombotic microangiopathy as central disease models alongside paroxysmal nocturnal hemoglobinuria, C3 glomerulopathy, IgA nephropathy, and ANCA-associated vasculitis. Approved complement inhibitors are reviewed by mechanistic position in the cascade, with attention to the clinical implications of terminal versus proximal pathway inhibition. Laboratory diagnosis, monitoring, and assessment of complement blockade adequacy are addressed, including practical limitations of complement testing in clinical practice. Critical gaps are examined, including diagnostic delays, absent validated biomarkers, inadequate pediatric trial infrastructure, and conditions without targeted therapies. Emerging therapeutics, point-of-care diagnostics, and pediatric-specific considerations including transition of care and reproductive counseling complete the review. Complement therapeutics have meaningfully altered the trajectory of some of the most severe and inadequately treated pediatric diseases. This field continues to evolve rapidly, with expanding indications and novel agents, though drug development challenges, diagnostic and monitoring gaps, and equitable consideration of pediatric application of these novel agents remain essential priorities.
2026-09-11 | Complement in Kidney Disease: Core Curriculum 2026.
The complement cascade is part of the innate immune system, and it provides an important line of defense against infections. Inappropriate or excessive activation of this system, however, is also a driver of kidney inflammation in many diseases. Complement inhibitory drugs have now been approved by the US Food and Drug Administration for the treatment of 5 renal diseases: atypical hemolytic uremic syndrome, C3 glomerulopathy, immune-complex membranoproliferative glomerulonephritis, antineutrophil cytoplasmic antibody-associated vasculitis, and IgA nephropathy. Ongoing clinical trials are testing new anticomplement drugs and additional renal indications for complement inhibitors. Most immunosuppressive drugs do not directly block complement activation, and the use of complement inhibitors for renal indications is likely to expand in the coming years. Complement activation in renal diseases also generates plasma, urine, and tissue biomarkers, and laboratory evaluation of the complement system is an important part of the clinical work-up of patients with these inflammatory and autoimmune conditions. It is essential, therefore, that nephrologists are familiar with the available anticomplement drugs and with complement diagnostics.
2026-09-03 | Clinical improvement of acquired partial lipodystrophy in an adolescent with C3 glomerulopathy treated with pegcetacoplan.
C3 glomerulopathy and acquired partial lipodystrophy (APL) are rare disorders associated with dysregulation of the alternative complement pathway and occasionally coexist. We report a 14-year-old girl who developed nephritic-nephrotic syndrome due to C3 glomerulonephritis concomitant with APL. Despite treatment with mycophenolate mofetil and tacrolimus, kidney function deteriorated, proteinuria increased, and she developed marked faciotruncal lipoatrophy with a 10-kg weight loss. Pegcetacoplan, a C3/C3b inhibitor, was initiated. Five weeks later, serum C3 levels were normal. Creatinine clearance subsequently improved from 25 to 133 mL/min, while proteinuria progressively declined from 3.2 to 0.15 g/g. Within 40 weeks, the patient recovered her usual body weight with marked clinical improvement in subcutaneous fat distribution. This observation suggests that pegcetacoplan may represent a novel therapeutic option for APL.
2026-08-14 | Global research landscape of C3 glomerulopathy: A bibliometric analysis.
C3 glomerulopathy (C3G) is a rare, complement-mediated kidney disease with significant diagnostic and therapeutic challenges. Despite a growing number of publications, no study has comprehensively mapped the global research landscape. This bibliometric analysis aimed to evaluate publication trends, influential contributors, thematic evolution, and collaboration networks in C3G research from 1980 to 2025. A systematic bibliometric analysis was conducted using PubMed-indexed publications from 1980 - 2025 retrieved with predefined Boolean queries. Eligible articles included original research and reviews addressing the pathophysiology, diagnosis, and management of C3G. Bibliometric parameters were analyzed using the Bibliometrix package in R (v4.3) and VOSviewer (v1.6.20). Citation data were verified via Google Scholar. A total of 967 publications across 273 journals were identified. Research output increased exponentially after 2013, coinciding with the C3G Consensus Report and the rise of complement-targeted therapies. Pediatric Nephrology, Kidney International, and JASN were the leading publication venues. The United States, United Kingdom, and Italy were the most productive countries, with emerging contributions from China, India, and Türkiye. S. Sethi was the most prolific author (24 papers). Keyword co-occurrence and citation network analyses demonstrated a thematic shift from morphologic classification ("dense deposit disease") toward molecular and therapeutic paradigms ("complement inhibition," "iptacopan," "pegcetacoplan"). Collaboration networks remained modest and regionally clustered. Global research on C3G has evolved from descriptive pathology toward precision complement therapeutics. However, significant geographical disparities persist, emphasizing the need for stronger international collaboration and equitable access to emerging complement inhibitors.
2026-08-07 | Charting the Course of Recurrent C3 Glomerulopathy and Immune Complex–Mediated Membranoproliferative GN in Kidney Transplant Recipients
C3 glomerulopathy (C3G) comprises several closely related diseases associated with underlying complement dysregulation.Dense deposit disease is diagnosed by the finding of characteristic dense intramembranous electron deposits on electron microscopy.C3 GN is characterized by strong dominant C3 staining within the glomeruli, typically in association with subendothelial and/or mesangial electron dense deposits.In each of these diseases, patients may exhibit a pattern of injury ranging from membranoproliferative, mesangial proliferative, endocapillary proliferative, and crescentic.Other patients may exhibit codominant strong C3 and Ig staining, often with a membranoproliferative pattern of injury-these are considered an immune complex MPGN.Of this latter group, primary forms are considered part of the C3G disease spectrum.Common to all of these are the presence of abnormalities of complement dysregulation, often resulting in complement consumption in keeping with the definition of C3G as reported in the C3G consensus report in 2013. 1 Treatment options of C3G have been ineffective, with outcomes typically around 40% kidney failure over a median of 11 years of follow-up.2 However, recent pivotal trials of alternative pathway inhibitors of largely nontransplanted patients have met primary outcomes, 3,4 and the emergence of these now approved treatments in the clinic will hopefully improve outcomes and reduce the risk of kidney failure.However, for a significant cohort of patients with C3G, who are already at kidney failure there is the further burden of disease recurrence with rates as high as 89%, 5 which raises the important question of how best to use alternative pathway inhibitors in this group of patients.In this issue, Ruiz-Cabello et al. 6 report a retrospective study of a large international cohort of 134 patients who have recurrence of C3G or immune complex MPGN.A strength of this study is that biopsies were re-reviewed to help with accurate classification of disease, and those
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2026-09-08 | Complement targeting in autoimmune diseases.
Complement is a central effector of cell and tissue injury in hematological and autoimmune diseases, and recent intensive research brought new inhibitors to the clinic. This review summarizes complement-mediated mechanisms across hematological, systemic, and kidney-specific autoimmune diseases, appraises emerging biomarker strategies, and evaluates these therapies. For years, clinical complement inhibition was possible only at C5, first in paroxysmal nocturnal hemoglobinuria. The arsenal has now expanded to the initiation pathways: sutimlimab (anti-C1s) is effective in the hematological autoimmune condition cold agglutinin disease, pegcetacoplan (C3-inhibitor) in C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis, and oral iptacopan (Factor B-inhibitor) reduces proteinuria in immunoglobulin A nephropathy and C3 glomerulopathy. Nevertheless, challenges remain. Avacopan (C5aR1-inhibitor) faces proposed withdrawal after trial manipulation and hepatotoxicity, and although complement is central to systemic lupus erythematosus and contributes to membranous nephropathy, no effective strategy has yet emerged. Recognizing complement's role in the pathophysiology of hematological and autoimmune diseases has driven effective new therapies. Comprehensive profiling complement biomarkers, now feasible through complementomics in fluids and tissues, may reveal responsive endotypes and optimal cascade steps to target in diseases where complement is implicated but trials have not yet matched the right drug to the right patients.
2026-09-01 | Distinct Pharmacodynamic Complement Biomarker Signatures Define Iptacopan and Pegcetacoplan Treatment in C3 Glomerulopathy
Background C3 glomerulopathy (C3G) is driven by alternative pathway (AP) dysregulation. Iptacopan inhibits factor B, whereas pegcetacoplan inhibits C3/C3b, suggesting distinct pharmacodynamic (PD) biomarker profiles. Methods We conducted an exploratory, nonrandomized observational cohort study of patients with biopsy-confirmed C3G treated with iptacopan (n = 9) or pegcetacoplan (n = 9), using paired pretreatment and approximately 3-month post-treatment samples. Complement activity, protein levels, activation products, autoantibodies, and genetic findings were assessed. Profiles were classified as PD-concordant (PDC), largely PD-concordant (LPDC), or PD-discordant (PDD) using treatment-specific signatures. Results Both treatments suppressed AP activity and terminal pathway activation but produced distinct profiles. The expected PDC signature for iptacopan included increases in C3, factor B, C5, properdin, and CH50 and reductions in complement activation products (C3a, C3c, C3d, Bb, and sC5b-9). The expected pegcetacoplan signature included supranormal increases in C3, C3c, and properdin, reductions in C3a, C3d, Bb, and sC5b-9, and generally preserved or increased CH50. PDC profiles occurred in 6 of 9 patients in each cohort. LPDC profiles occurred in three iptacopan-treated patients, all nephritic factor-positive, and two pegcetacoplan-treated patients with nephritic factors or a likely pathogenic C3 variant. One patient with severe factor H deficiency showed a PDD profile during pegcetacoplan treatment and again in a descriptive post-transplant sample during subsequent iptacopan treatment. Conclusions Iptacopan and pegcetacoplan produce distinct, mechanism-specific PD signatures in C3G. Pathway-based biomarker assessment may distinguish expected treatment effects from incomplete or discordant biochemical control. These categories describe PD patterns rather than clinical efficacy and require validation against clinical outcomes.
2026-08-28 | SEISMIC: a multistakeholder summit addressing access issues in diagnosis and treatment of C3G nephropathy and IC-MPGN.
C3 glomerulopathy (C3G)-primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) is an ultrarare disease spectrum associated with a significant health burden and for which there is a huge unmet need for safe and effective treatment. The underlying pathophysiology is dysregulation and overactivation of the alternative complement pathway. Two new therapeutic agents, iptacoplan and pegcetacoplan, that target proximal steps in the cascade, have demonstrated to be effective and have been approved for use in patients with C3G alone and with C3G/IC-MPGN, respectively. A key challenge to the nephrology community is how to incorporate these disease-modifying drugs into clinical practice in a timely and equitable manner. This report summarizes the deliberations and recommendations that emerged from the Addressing Access Issues in Diagnosis and Treatment of C3G Nephropathy and IC-MPGN (SEISMIC) summit in July 2025. The meeting assembled a broad panel of experts and patients and addressed the following 3 aims: (i) define issues in proper and timely diagnosis of this complex disease spectrum, (ii) assess management strategies in light of the availability of this new class of therapeutic agents, and (iii) identify barriers to access to care and treatment with these new therapeutic agents and design strategies to surmount them.
2026-08-20 | Beyond Defense: Kidney Mysteries in Inborn Errors of Immunity
Inborn errors of immunity (IEI), formerly termed primary immunodeficiencies, are increasingly recognized as disorders of immune dysregulation rather than infection susceptibility alone. With over 500 validated genes in the 2024 International Union of Immunological Societies (IUIS) classification and approximately one-quarter of patients presenting without infection, autoimmunity, autoinflammation, lymphoproliferation, and malignancy are now core features. The kidney is affected across at least 22 IEI categories, yet renal involvement remains under-recognized. This review proposes a mechanistic framework for IEI-associated kidney disease, encompassing: complement dysregulation (C3 glomerulopathy, atypical hemolytic uremic syndrome from CFH/CFI/C3 variants); immune complex–mediated and monogenic lupus nephritis (C1q, C2, C4, DNASE1L3, and TREX1 defects); autoinflammatory and type I interferonopathy–driven nephropathy; infection-related glomerulonephritis (common variable immunodeficiency [CVID], chronic granulomatous disease); lymphoproliferative and immune-dysregulation syndromes causing interstitial nephritis (ALPS, CTLA-4 and LRBA deficiency); and syndromic IEI with intrinsic structural disease. We outline a stepwise diagnostic approach integrating clinical red flags, complement and immune profiling, kidney biopsy with immunofluorescence and electron microscopy, and genetic testing, emphasizing that genetic diagnosis should precede immunosuppression. The therapeutic landscape is shifting from empirical immunosuppression toward precision medicine, including complement inhibitors (iptacopan, pegcetacoplan, Food and Drug Administration–approved for C3 glomerulopathy in 2025), JAK inhibitors for interferonopathies, leniolisib for activated PI3Kδ syndrome, CTLA4-Ig agents, and curative hematopoietic stem cell transplantation and emerging gene therapy. An illustrative case from Europe’s largest kidney transplant center illustrates a girl with Schimke immuno-osseous dysplasia (SMARCAL1 mutation) presenting with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis who underwent kidney transplantation following bone marrow transplant. Recognizing IEI in unexplained nephropathy, combining biopsy with complement and genetic profiling, and early nephrology–immunology collaboration are key to improving renal outcomes and enabling potentially curative therapy.
2026-08-13 | Characterizing Properdin-Inhibited C3 Nephritic Factors in Patients with Complement-Mediated Kidney Diseases.
C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) are severe complement-mediated kidney diseases. In a substantial proportion of these patients, C3 nephritic factors (C3NeFs) are detected; these autoantibodies stabilize the complement alternative pathway (AP) C3 convertase. Previous studies have investigated and distinguished properdin-dependent and properdin-independent C3NeFs. In this study, we investigated a distinct subset of C3NeFs that are exclusively active in the absence of properdin: properdin-inhibited C3NeFs. A two-step hemolytic AP convertase activity assay was employed to examine convertase activity in patient serum in the presence versus absence of properdin using the properdin inhibitor Salp20. In 7/16 patients and 1/23 healthy controls, who showed no convertase stabilization in full serum, convertase stabilization was observed upon properdin inhibition, indicating properdin-inhibited C3NeF activity. Consistent findings were obtained when purified patient Igs were added to properdin-depleted serum. Moreover, in an ELISA-based C3bBb binding assay, 6/7 patients with properdin-inhibited C3NeFs showed increased convertase binding, which decreased upon addition of properdin. Complement levels in patients with properdin-inhibited C3NeFs were not significantly different from those in the C3NeF-negative group, and properdin levels were generally within the refence range. In conclusion, our results support the existence of properdin-inhibited C3NeFs, thereby further expanding the functional heterogeneity of these autoantibodies. Although their functional relevance under physiological conditions remains unclear, these findings may have important implications for complement-targeted therapies, particularly strategies aimed at properdin inhibition, as the presence of these C3NeFs may predispose to unintended effects.
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2026-07-28 | Therapeutic Evaluation of a C3-Targeting Small Nucleic Acid Drug in a Spontaneous Humanized C3 Glomerulopathy Mouse Model 2256845
Abstract Introduction Complement component C3 is central to the activation of the alternative pathway (AP), and its dysregulation drives C3 glomerulopathy, a severe renal autoimmune disease that lacks effective therapies. Methods To enable translational studies, we established a humanized C3G model, B6-hC3 mC3 KO, which overexpresses human C3 while lacking the endogenous murine C3. These mice spontaneously develop progressive glomerulopathy resembling human C3G pathology. Small nucleic acid drugs were administered to mice to evaluate drug efficacy. Results The disease phenotype observed in humanized C3 transgenic mice appears to arise from a dysfunctional interaction between human C3 protein and murine complement proteins, resulting in uncontrolled AP activation. Subcutaneous administration of C3-targeting small nucleic acid drugs effectively reduced serum C3 and plasma C3a levels, and downregulated the ratio of Ba (the activated fragment of complement factor B, CFB) to CFB, indicating suppression of AP hyperactivation. After 6 weeks of treatment, renal histology showed markedly reduced deposition of hC3 and diminished inflammatory cell infiltration. Conclusion B6-hC3 mC3 KO mice reproduce key immunopathological features of C3G and serve as a powerful platform for mechanistic studies and preclinical evaluation of complement-targeted therapeutics. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)
2025-10-01 | Interim Phase 1 Study Results of ADX-038: A Novel siRNA Against Complement Factor B, and Next Steps in IgAN and C3 Glomerulopathy (C3G)
Background: ADX-038 is a siRNA that targets complement factor B (CFB) mRNA, being developed for diseases with dysregulation of the complement system. The effects of ADX-038 on CFB protein levels and on the complement alternative pathway (AP) and classical pathway (CP) activity in healthy volunteers is reported with the discussion of the Phase 2 study in IgAN and C3G. Methods: As of 2/2025, 41 healthy adults were randomized and administered one subcutaneous dose of ADX-038 n=31 or placebo n=10. ADX-038 doses ranged from 0.4 to 6 mg/kg (actual doses 25 to 360 mg). Circulating CFB protein levels, and AP and CP activity were measured. Clinical safety was based on adverse events (AEs) and monitoring of clinical lab tests, physical exams (PE). Results: Dose-dependent reductions in CFB protein levels and inhibition of AP activity were observed, Figures 1 and 2. A single 4 mg/kg ADX-038 dose suppressed AP activity by 99% from baseline through 3M. As expected, CP activity was unchanged. Treatment was well-tolerated. The most common AE was upper respiratory tract infection, similar to placebo. There were no encapsulated bacterial infections nor clinically relevant changes in clinical lab tests, PE or vital signs. The Phase 2 study will dose IgAN and C3G patients Q3M with ADX-038. The primary objective of the study is to assess the tolerability of ADX-038, with the secondary objective of changes to proteinuria. Conclusion: A single dose of ADX-038 effectively silenced CFB gene expression, resulting in selective and near-complete suppression of complement AP activity. The durable on-target PD effects support its potential as an effective therapeutic agent for kidney diseases with a convenient (Q3M) subcutaneous dosing schedule. Based on these results, a Phase 2 study has been initiated to assess the safety and efficacy of ADX-038 in patients with complement mediated kidney diseases (eg. IgAN and C3G). Funding: Commercial Support - Adarx pharmaceuticals
2025-10-01 | Safety and Pharmacodynamics of SGB-9768, an siRNA Targeting Complement C3 in Healthy Volunteers
Background: SGB-9768, a GalNAc-conjugated siRNA, inhibits hepatic complement C3 production in Heathy volunteers, warrants further investigation in its potential to treat complement-related kidney diseases. Methods: Two phase 1, randomized, double-blind, placebo-controlled trials (SGB-9768-001, NZ; SGB-9768-002, China) evaluated the safety, pharmacokinetics, and pharmacodynamics of single subcutaneous doses of SGB-9768 in healthy volunteers. Results: Study 001 enrolled 29 participants (mostly Caucasian) receiving 25–400 mg of SGB-9768 (4:2 active to placebo). Study 002 enrolled 37 participants (all Chinese) with doses of 50–600 mg (3:2 active to placebo at 50 mg, 6:2 at higher doses). All participants received vaccinations (meningococcal vaccine and pneumococcal vaccine) before dosing and prophylactic antibiotics throughout the study. SGB-9768 demonstrated a favorable safety and tolerability profile, with no significant infections, including no cases involving encapsulated organisms. There were no dose limiting toxicity or treatment-related serious adverse events (AE) or discontinuations due to AEs. Treatment-related AE reported in ≥10% of participants was injection site reaction. PD data (Figure 1) showed dose-dependent serum C3 reductions of 52–85% (Study 001, 25–400mg) and 75–93% (Study 002, 50-600 mg) at 1 month, sustained at 52–84% and 69–92% at 3 months. Alternative pathway activity (Wieslab® AP) decreased by 43–99% (Study 001) and 66–100% (Study 002) at 1 month, sustained at 59–99% and 59–100% at 3 months. Classical pathway activity (Wieslab® CP) reductions ranged from 12–56% at 1 month. Conclusion: SGB-9768 was safe, with sustained, dose-dependent reductions in C3 and complement activity, supporting development for kidney diseases like IgA nephropathy and C3 glomerulopathy. Funding: Commercial Support - Suzhou Sanegene Bio Inc.Figure 1. Measures of serum complement C3 level (a), Wieslab® AP (b), Wieslab® CP (c) in healthy volunteers.
2025-04-21 | Abstract 6848: Development of a humanized C3 mouse model for preclinical evaluation of therapeutics in C3 glomerulopathy
Abstract C3 glomerulopathy (C3G) is a rare and progressive kidney disease, encompassing C3 glomerulonephritis and dense deposit disease, both driven by dysregulation of the alternative pathway of complement activation. Approximately 50% of patients progress to end-stage kidney disease (ESKD) within 10 years, with limited treatment options currently available. To address this unmet need, we developed a novel humanized C3 (hC3) mouse model that exhibits a pronounced C3G-like phenotype, characterized by early progression to ESKD and increased mortality. Compared to wild-type mice, hC3 mice display significantly reduced circulating C3 levels, alongside liver and kidney dysfunction confirmed by biochemical and pathological analyses. These mice also demonstrate reduced body weight, elevated morbidity early in life, and a shortened lifespan of approximately 5-6 months. To evaluate potential therapies, we treated hC3 mice with the small interfering RNA drug ARO-C3 at high and low doses. ARO-C3 treatment led to a reduction in serum hC3 levels as early as one week post-administration, with a single dose maintaining suppression for at least five weeks. Importantly, ARO-C3 treatment significantly prolonged survival and improved liver and kidney function, as demonstrated by molecular and histopathological analyses. This hC3 mouse model provides a robust platform for studying complement-mediated diseases such as C3G and for preclinical evaluation of novel therapeutic strategies targeting the complement system. Citation Format: Andrei Golovko, Shuang Li, Xiaolei Qiu, Yi Li, Ruilin Sun. Development of a humanized C3 mouse model for preclinical evaluation of therapeutics in C3 glomerulopathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6848.
2024-03-13 | Efficacy of GalNAc C3 siRNAs in factor H-deficient mice with C3 glomerulopathy.
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.
proteins
2026-07-08 | Dataset related to article "Moss-derived recombinant Factor H, CPV-104, effectively antagonizes alternative pathway C3/C5 convertases stabilization by NeFs from patients with primary C3 glomerulopathy
This dataset contains the raw experimental data supporting the article "Moss-derived recombinant Factor H, CPV-104, effectively antagonizes alternative pathway C3/C5 convertases stabilization by NeFs from patients with primary C3 glomerulopathy", published in Frontiers in Immunology, 2026. The dataset includes the following files: Western blot raw data (Figure 1, Supplementary Figure S1, and Supplementary Table S1). Western blot raw data (Figure 2, Supplementary Figure S2, and Supplementary Table S2). ELISA C3a raw data (Figures 3A, 4A, and 4B). ELISA C3a raw data (sCR1 experiments). ELISA Ba raw data (Figures 3B, 4C, and 4D). The files contain the original experimental data underlying the figures and supplementary material reported in the associated publication.
2026-07-01 | Moss-derived recombinant Factor H, CPV-104, effectively antagonizes alternative pathway C3/C5 convertases stabilization by NeFs from patients with primary C3 glomerulopathy
Background C3 glomerulopathy (C3G) is a rare kidney disease caused by uncontrolled activation of the complement alternative pathway (AP), frequently driven by nephritic factors (NeFs) that stabilize the AP C3 and C5 convertases. NeFs are detected in up to 80% of patients and exhibit heterogeneous stabilizing activity, contributing to variable degrees of complement dysregulation. Current complement−targeted therapies reduce complement activation but may compromise immune surveillance by blocking key components of the pathway. Supplementation with the physiological AP regulator factor H (FH) represents an alternative strategy aimed at restoring complement homeostasis while preserving essential immune functions. CPV−104 is a fully functional recombinant human FH produced in moss, with optimized glycosylation and improved pharmacokinetics, offering a promising therapeutic approach for C3G. Objectives and Methods We evaluated the ability of CPV−104 to antagonize NeF−mediated stabilization of the AP C3 convertase (C3bBb) in eight C3G patients enrolled in the Italian MPGN/C3G Registry. Patients were classified as C3NeF+ or C5NeF+ based on properdin dependence in convertase stabilization assays. NeF activity was analyzed using solid−phase assays in which C3bBb decay and formation were assessed in the presence of CPV−104 or serum−derived FH (sd−FH). The impact of CPV−104 ex vivo was tested in fluid−phase assays using patient sera, with Ba (convertase formation) and C3a (convertase activity) measured by ELISA. Results CPV−104 accelerated decay of NeF−stabilized C3bBb with efficacy comparable to sd−FH. Convertases stabilized by six of eight NeFs were fully dissociated by CPV−104, while two highly potent C3NeFs were partially antagonized. When added during convertase assembly, CPV−104 significantly reduced C3bBb formation in all patients and showed a stronger inhibitory effect than sd−FH. In fluid−phase assays, using patient sera, CPV−104 markedly decreased Ba and C3a generation, with mean inhibition of 68.9% and 51.8%, respectively, and consistently outperformed sd−FH across patient samples. Conclusions CPV−104 effectively limits both stabilization and formation of AP C3 convertases in NeF−positive C3G, demonstrating superior functional activity compared with sd−FH. By restoring physiological AP regulation rather than broadly inhibiting complement activation, CPV−104 represents a promising and potentially safer therapeutic strategy for NeF−driven C3G and warrants further clinical investigation.
2026-03-11 | A novel fusion protein reduces kidney complement in experimental C3 glomerulopathy.
Complement activation contributes to kidney damage in many types of glomerulonephritis and complement inhibition therapy is approved for IgA nephropathy and C3 glomerulopathy. However, inhibition is not specific to the kidney resulting in unnecessary systemic complement inhibition and increased infection risk. To develop an effective inhibitor of glomerular complement we combined complement factor H-related protein 5 (FHR51-9), which binds to glomerular complement C3, with the complement regulatory domains of the key negative regulator of C3 activation complement factor H (FH1-5). One week after adeno-associated virus (AAV) mediated expression of the FHR51-9FH1-5 fusion protein in factor H (FH)-deficient mice, glomerular C3b/iC3b/C3c was significantly reduced and properdin resolved completely compared to controls. There was no change to circulating C3 levels and FHR51-9FH1-5 was detected in glomeruli in association with C3d. Six and twenty weeks after AAV8-FHR51-9FH1-5 treatment in hFH-FHR5mut mice (a mouse model of CFHR5 nephropathy) glomerular C3b/iC3b/C3c, C3d, and C5 were significantly reduced and properdin resolved completely compared to controls. Pre-administration of AAV-FHR51-9FH1-5 also ameliorated abnormal glomerular C3b/iC3b/C3c, C3d, C5, and properdin in a triggered CFHR5 nephropathy model. In vitro FHR51-9FH1-5 showed dose-dependent binding to surface-immobilized C3, C3b, iC3b, and C3d; factor I cofactor activity; and reduced C3a generation in an alternative pathway convertase assay. Taken together, the FHR51-9FH1-5 protein reduced glomerular C3 in experimental models of C3 glomerulopathy driven by either FH deficiency or mutated FHR5. These preclinical data indicate that FHR51-9FH1-5 protein represents a novel treatment strategy for complement-mediated kidney disease.
2026-02-18 | Thrombospondin-1 as inhibitor of the alternative complement pathway in antineutrophil cytoplasmic antibodyassociated vasculitis
Thrombospondin-1 (TSP-1) is a matricellular glycoprotein involved in tissue remodeling, inflammation, angiogenesis, and cell signaling. Previous studies have demonstrated interactions between TSP-1 and complement Factor H (FH), the principal regulator of the alternative complement pathway (AP). In addition, complement-regulatory properties have been shown before for TSP-5, another member of the thrombospondin family. Based on these findings, the aim of this thesis was to investigate the potential regulatory role of TSP-1 within the AP. A novel function of TSP-1 as an endogenous inhibitor of the AP was identified, and its involvement in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) was investigated. The complement regulatory properties of TSP-1 were characterized through a combination of biochemical studies, in vitro functional assays, ex vivo assays using patient-derived material as well as in vivo disease models. TSP-1 was found to bind multiple components of the complement cascade, including C3, C5, Factor B (FB), FH, and C8. Functionally, the cleavage of C3 and C5 by their respective convertases was inhibited by TSP-1. In addition, TSP-1 blocked the cleavage of FB by Factor D (FD) as well as the formation of the membrane attack complex (MAC). Although binding to FH was confirmed, no interference with its cofactor or decay-accelerating activities was detected. These findings suggest that TSP-1 exerts complement regulation through a distinct mechanism independent of its interaction with FH. The physiological relevance of TSP-1-mediated complement inhibition was further assessed ex vivo using serum from patients with atypical hemolytic uremic syndrome and erythrocytes from patients with paroxysmal nocturnal hemoglobinuria. Pathological C3 deposition and hemolysis were significantly inhibited by TSP-1. On endothelial cells, TSP-1 knockdown led to increased complement deposition and cell activation, confirming a direct regulatory function. Finally, TSP-1 could normalize serum C3 levels and reduce glomerular C3 deposition in a mouse model of C3 glomerulopathy, confirming the functional importance of TSP 1 in regulating complement activity. Another key focus of this thesis was AAV, a disease marked by excessive neutrophil extracellular trap (NET) formation due to AP overactivation. Prominent TSP-1 staining in glomeruli of AAV patients suggested a regulatory role of TSP-1 in this disease. Further functional assays using microfluidic systems showed that TSP-1 inhibits NETosis through complement-dependent mechanisms. The role of TSP-1 was further investigated using a mouse model for AAV. In this model, TSP-1-deficient mice exhibited more severe kidney injury compared to wild-type controls. This was associated with increased glomerular complement deposition and elevated levels of citrullinated histone, a marker for NETosis. In conclusion, this thesis demonstrates a novel and functionally distinct inhibitory role of TSP 1 in the alternative complement pathway and provides new insights into the interaction between endothelium, the immune and complement system. Although TSP-1 does not seem to be a major regulator of complement under resting conditions, its local release from endothelial cells and platelets during inflammation is capable of restricting complement activity. TSP 1 may thus represent a promising new target and biomarker in complement-mediated diseases.
2026-01-16 | Treatment of atypical hemolytic uremic syndrome and C3 glomerulopathy in mice by hepatic expression of factor D.
Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are diseases driven by dysregulation of the alternative pathway (AP) complement. Current treatments of these diseases involve the use of frequent and often large doses of monoclonal antibodies, peptide inhibitors, or chemical inhibitors of complement proteins, with various limitations. In this study, we describe ectopic expression of factor D (FD) in the liver as a potential novel therapy for these indications. Unlike most plasma complement proteins, which are synthesized in the liver, FD, a serine protease in the AP, is synthesized primarily in fat tissues. Newly synthesized FD is released largely as an inactive proenzyme that requires activation by mannose-binding lectin-associated serine protease 3 (MASP3) to form the mature enzyme. We found serendipitously that ectopic expression of mature FD, but not pro-FD, in the mouse liver led to C3-dependent depletion of plasma factor B (FB) and abolished AP complement activity. Coexpression of C3, FB, and mature FD in cultured Hepa1-6 cells caused intracellular FB activation and consumption, probably within the secretory vesicles where all 3 proteins may colocalize. Hepatic FD-mediated local FB activation and depletion effectively prevented disease development in murine models of aHUS and C3G. Our results suggest that segregated tissue production of FD, FB, and C3, as well as FD regulation by MASP3, is necessary to prevent in situ FB activation and depletion. Ectopic expression of mature FD in the liver is an effective way to inhibit FB expression and AP complement activity, with potential therapeutic applications in diseases such as aHUS and C3G.
other
2025-12-10 | Kidney damage in patients with multiple myeloma associated with light chain deposition disease and C3 glomerulopathy
Background. Kidney dysfunction is a common manifestation of multiple myeloma (MM). Kidney damage in MM is most often associated with cast nephropathy; however, rarer forms such as light chain deposition disease (LCDD) and C3 glomerulopathy (C3 GP) also occur. According to several studies, patients with these forms of kidney damage more frequently develop end-stage renal disease and have a worse prognosis for kidney function recovery. Aim. To evaluate the efficacy of induction therapy with targeted drugs followed by consolidation with high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with MM and nephropathy associated with LCDD and C3 GP. Materials and methods. Medical data from 3 patients with MM and nephropathy caused by LCDD (2 cases) and C3 GP (1 case) who received induction therapy followed by auto-HSCT were retrospectively analyzed. Results. At disease onset, impaired kidney function with reduced glomerular filtration rate was detected in all 3 patients; 1 case presented with anuria. All patients received renal replacement therapy. After induction, complete hematologic response was achieved in 2 patients and very good partial response in 1 patient with MM and C3 GP. Renal replacement therapy was discontinued in 2 out of 3 cases. On the 100th day after auto-HSCT, hematologic complete response persisted in 2 patients with LCDD; in the C3 GP case, the response deepened to stringent complete response. All patients achieved renal response, with no need for renal replacement therapy. During long-term follow-up (23–82 months), 1 patient maintained the achieved response, while 2 patients relapsed at 2.5 and 2 years post-auto-HSCT, respectively. Conclusion. Multiple myeloma patients with LCDD- or C3 GP-associated nephropathy exhibit severe kidney dysfunction, often requiring renal replacement therapy, necessitating thorough evaluation in the absence of typical cast nephropathy features. Comprehensive therapy including auto-HSCT in young, fit MM patients with LCDD- or C3 GP-associated nephropathy enables deep hematologic response and improves renal function.
2025-10-01 | Single-Dose Adeno-Associated Virus Gene Therapy for C3 Glomerulopathy in an Avatar Mouse Model of Human Complement-Mediated Kidney Disease
Background: Complement 3 glomerulopathy (C3G) is a rare complement-mediated kidney disease caused by uncontrolled activation of the complement alternative pathway associated with factor H (CFH) mutations. About half of the patients with C3G will eventually develop kidney failure because no effective treatment is currently available. The aim of this study was to evaluate the therapeutic potential of a liver-directed Adeno-Associated Virus (AAV) therapy to treat a mouse CFH mutant model with C3 glomerulopathy. Methods: C3G mouse model was established with a patient-derived specific point mutation W1180R in the CFH gene. An AAV2 vector that contains the human CFH sequence with a liver specific promoter (AAV-hCFH) was generated and packaged into a liver tropic capsid AAV8 and was administered intravenously into susceptible CFH mutant mice. Four and eight weeks after treatment, hepatic vector transduction was assessed by testing the vector copy number (VCN). The therapeutic outcome was evaluated by kidney function, proteinuria, serum CFH levels and C3 deposition in kidney. Results: CFH homozygous (CfhW1180R/W1180R) mice showed spontaneous deposition of glomerular C3, absent circulating CFH and progressive renal injury with age as compared to heterozygous (CfhW1180R/WT) mice and wild type mice. A single intravenous dose of AAV-hCFH (5x1011 vector genome per mouse) was successfully transduced and retained in liver with a high level of VCN and functional CFH expression, increased serum CFH and reduced serum C3 levels as compared with untreated mutant mice. CfhW1180R/W1180R mice treated with the AAV-hCFH demonstrated improved kidney function with lower serum creatinine (42±2.3 vs 28±2.8µmol/L, p<0.05), less proteinuria (5.2±0.8 vs 2.5±0.4mg/16h, p<0.001), less kidney injury (5.4±0.4 vs 3.6±0.6, p<0.01) and reduced C3 deposition as compared to untreated CfhW1180R/W1180R mice. Conclusion: Human CFH was successfully delivered to the liver of CFH mutant mice using AAV. hCFH was expressed in the mouse liver and was therapeutic with reduction in kidney injury in mutant mice compared with untreated mutant mice. Funding: Government Support – Non-U.S.
2025-07-28 | Guarding glomeruli from immune injury
C3 glomerulopathy (C3G), which includes C3 glomerulonephritis and dense deposit disease, is a severe renal disease caused by dysregulation of the complement system. In a study published in this issue of Molecular Therapy, Cfh−/− mice, which are an established model of C3G, were administered systemic adeno-associated virus (AAV8) containing truncated constructs of the human complement factor H (hCFH) gene to transduce hepatocytes.1 Increased CFH expression in the liver of Cfh−/− mice restored the alternative complement pathway and significantly reduced or eliminated histological and ultrastructural features of the disease.
2025-07-01 | AAV-mHDM-FH: Safety and expression profile in two murine models of hyper-complement activation
C3 glomerulopathy (C3G) and atypical haemolytic uraemic syndrome (aHUS) are rare kidney disorders characterized by the dysregulation of the alternative pathway (AP). Unlike aHUS, current treatment options for C3G are limited. Factor H (FH) plays a key role in regulating the AP, and mice lacking FH develop a disease similar to C3G. We previously developed mouse homodimeric minimal FH (mHDM-FH) as a gene therapy using an adeno-associated virus (AAV) vector incorporating a liver-specific promoter to rebalance the AP activation. We previously noted that a single dose of AAV-mHDM-FH (1 × 10 11 ) restored complement regulation in Cfh −/− mice by 21 days post inoculation, however this was associated with a strong anti-HDM-FH response, which was markedly reduced in Cfh +/− mice. In the current study, we focussed on long-term evaluation of AAV-mHDM-FH in both Cfh +/− mice and C3 N/N mice (the C3 D1115N gain-of-function mouse model of aHUS). At six months post-inoculation, C3 N/N mice treated with AAV-mHDM-FH showed significantly improved survival compared to AAV-GFP controls. However, the therapeutic effect was partially limited due to reduced binding affinity of mHDM-FH to the mutant C3 D1115N protein. These findings indicate that while AAV-mHDM-FH retains some functionality in C3 mutation-driven disease, its efficacy may not match therapies targeting the terminal complement pathway. In Cfh +/− mice, no signs of disease or safety concerns were observed over the six-month period. Importantly, increased serum levels of both C3 and FH were detected, suggesting improved control of the amplification loop in these mice. AAV transgene expression remained detectable in the liver at six months, an encouraging result for long-term efficacy. Across both experimental time points, anti-AAV antibody responses were detected in Cfh +/− mice. These responses peaked at 21 days post-inoculation but were present at relatively low levels after 6 months. This pattern aligns with observations in patients receiving AAV-based gene therapies. Despite the presence of anti-AAV antibodies, the 6 month data showed transgene expression and no safety concerns, leaving the extent to which these antibodies impact therapeutic efficacy still uncertain. Looking ahead, we aim to enhance long-term vector expression by exploring the use of alternative promoters tailored to different cellular targets. References: 1. Yang Y, Denton H, Davis O R, Smith-Jackson K, Kerr H, Herbert A P, Barlow P N, Pickering M C and Marchbank K J An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy J Am Soc Nephrol 2018 29(6):1649–1661.
2025-04-26 | Truncated complement factor H Y402 gene therapy rescues C3 glomerulonephritis.
There are no effective therapies for patients with dry age-related macular degeneration (AMD) or C3 glomerulonephritis (C3G). Unfortunately, past efforts to treat C3G using exogenous human complement factor H (CFH) found limited success due to immune rejection of a foreign protein response. AMD research has also faced myriad challenges, including the absence of an ideal therapeutic target and difficulties with treatment delivery in certain preclinical models. In pursuit of an AMD therapy to overcome these obstacles, we ultimately capitalized on parallels in complement dysregulation between AMD and C3G. Here, we investigate the potential for CFH supplementation as a strategy to rescue C3G. Our findings demonstrate restored inhibition of complement's alternative pathway and long-term reversal of disease without immune rejection using adeno-associated virus (AAV)-mediated delivery of truncated CFH (tCFH) in a Cfh-/- mouse model of C3G. We tested three different tCFH vectors and found significant differences in their relative transduction efficiency and therapeutic efficacy. These discoveries motivate the development of AAV-mediated tCFH replacement therapy for patients with C3G while simultaneously demonstrating proof of concept for AAV-mediated tCFH gene augmentation therapy for patients with AMD.
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Drug Discovery Landscape
14 orphan drug designations for C3 glomerulopathy, including 4 approved therapies.
14 orphan drug designations for C3 glomerulopathy, including 4 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
chemically synthesized double-stranded oligonucleotide directed against C3 messenger RNA | oligonucleotides | FDA | Sanegene Bio USA Inc. | |
Complement factor H, human, recombinant | proteins | EMA | Greenovation Biotech GmbH | |
synthetic double-strand small interfering ribonucleic acid (siRNA) oligonucleotide drug directed against C3 messenger RNA | RNAs | FDA | — | Silence Therapeutics plc |
Pegcetacoplan [ASPAVELI] | peptides | EMA | Approved | Swedish Orphan Biovitrum AB (publ) |
iptacopan [Fabhalta] | small molecules | FDA | Approved | Novartis Pharmaceuticals Corporation |
Poly(oxy-1,2-ethanediyl), alpha-hydro-omega-hydroxy-,15,15'-diester with N-acetyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-alpha-aspartyl-L-tryptophylglycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-L-threonyl-2-[2-(2-aminoethoxy)ethoxy]acetyl-N6-carboxy-L-lysinamide cyclic (2.fwdarw.12)-(disulfide); where two identical synthetic peptide domains are covalently linked at the ends of the polyethylene glycol chain | peptides | EMA | Swedish Orphan Biovitrum AB (publ) | |
pegcetacoplan [Empaveli] | peptides | FDA | Approved | Apellis Pharmaceuticals, Inc., a wholly owned subsidiary of Biogen, MA, Inc. |
(4-{(2S,4S)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl}benzoic acid-hydrogen chloride(1/1)) [FABHALTA] | small molecules | EMA | Approved | Novartis Europharm Limited |
Danicopan | small molecules | EMA | Alexion Europe | |
(2S,4R)-1-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide | small molecules | FDA | Alexion Pharmaceuticals, Inc | |
Avacopan | small molecules | EMA | Chemocentryx Ireland Limited | |
avacopan | small molecules | FDA | ChemoCentryx, Inc. | |
S3,S13-cyclo(D-tyrolsyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-aspartyl-L-tryptophyl-N-methyl-L-glycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-N-methyl-L-isoleucinamide) | peptides | EMA | Amyndas Pharmaceuticals S.A. | |
S3,S13-cyclo(D-tyrolsyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-aspartyl-L-tryptophyl-N-methyl-L-glycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-N-methyl-L-isoleucinamide | peptides | FDA | Amyndas Pharmaceuticals S.A |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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