Systemic complement activation levels in Stargardt disease

Abstract

Purpose Preclinical research provides evidence for the complement system as a potential common pathway in Stargardt disease (STGD1) and age-related macular degeneration (AMD) leading to retinal pigment epithelium (RPE) loss. However, systemic complement activation has not yet been assessed in STGD1 patients. We conducted a cross-sectional case-control study to assess systemic complement activation in STGD1 patients and its association with disease severity. Methods Systemic concentrations of complement component C3 and its degradation product C3d were compared between 80 STGD1 patients and 80 controls that were frequency matched for age and sex. The C3d/C3 ratio was used as parameter of systemic complement activation. Within the STGD1 cohort, we additionally examined the association between the C3d/C3 ratio, demographic and behavioural factors (age, sex, smoking and BMI), and measures of disease severity (age at onset, visual acuity, and area of atrophy). Results The C3d/C3 ratio did not significantly differ between patients (mean C3d/C3 ratio 3.5±1.4) and controls (mean C3d/C3 ratio 3.6±1.0), mean difference -0.156 (p = 0.804, independent samples t-test). The overall effect size was 8% (95% confidence interval, 3–15%). Elevated C3d/C3 ratios (>8.1) were found in three patients who all had a concomitant inflammatory condition at the time of blood draw. Within the patient cohort, C3 levels were associated with sex (mean difference -134, p = 0.001, independent samples t-test) and BMI (correlation coefficient 0.463, p<0.001, Spearman’s Correlation). Conclusions Systemic complement levels were not elevated in STGD1 patients compared to age and sex matched controls and was not associated with STGD1 severity. Considering the continued absent proof of a systemic contribution of the complement system to RPE loss in STGD1 patients, we hypothesize that complement activation in STGD1 is more likely a local process. In light of upcoming complement-targeted therapies, further studies are needed that measure complement levels in the eye of STGD1 patients.

Polyunsaturated Lipids in the Light-Exposed and Prooxidant Retinal Environment

“…Furthermore, complement activation occurred in an acellular system containing human serum plus A2E oxidised [ 85 ], providing support to the notion that lipofuscin component A2E may contribute to low-grade inflammation by activating the complement system and explaining the increased AMD risk associated with gene variants affecting the control of alternative complement pathway (discussed in [ 86 ]). A recent study investigated the relevance of complement alternative pathway activation in patients with Stargardt disease caused by ABCA4 mutations (STGD1) but did not find a difference between patients and matched controls [ 87 ]. The adverse finding may indicate that in STGD1 patients, RPE cell demise may occur either without complement activation or complement activation may occur locally and could not be assessed at the systemic level in patients.…”

The Next Generation of Molecular and Cellular Therapeutics for Inherited Retinal Disease

“…The complement pathway, an essential part of the innate immune system, has been suggested as a potential common pathway between Stargardt disease and AMD [67,68]. Avacincaptad pegol (Zimura, Iveric Bio), which targets complement factor C5, was shown to be effective in reducing the progression of GA secondary to AMD in a Phase 2/3 trial (GATHER1, NCT02686658).…”