Complement Activation in the Lysosomal Storage Disorders

Overview

The lysosomal storage disorders (LSDs) are monogenic disorders associated with inflammation affecting multiple organs, and early death. Few treatments are available that can modify the disease course, and there is an urgent need to identify new steps in pathogenesis that can be targeted therapeutically. The complement system is novel and highly plausible as a primary driver of inflammation and cellular injury in the LSDs. This study assesses the complement activation state in patients with Fabry disease (FD), Gaucher disease (GD) and Niemann-Pick disease, type C (NPC), with comparison to healthy controls. This has the potential for immense clinical benefit through targeted complement inhibition across the full spectrum of lysosomal storage disorders, in which key pathophysiological processes including the inflammatory response to lysosomally 'stored' materials are shared.

This is a single-centre, cross-sectional observational study in patients \>16 years of age diagnosed with FD, GD or NPC. The research hypotheses of this study are: 1. That complement is excessively activated, including at the specifically complement C5 level, in patients with the lysosomal storage disorders FD, GD and NPC. 2. That complement activation drives tissue injury in the LSDs via downstream effector mechanisms including membrane attach complex (MAC/C5b-9)-mediated cytotoxicity and C5aR-mediated inflammation. The study aims to show enhanced complement activation, including at the C5 level, in patients with FD, GD and NPC compared to healthy controls. The research assays for this study include the primary outcome measure of plasma soluble C5b-9 (sC6b-9) levels measured using ELISA. This assay measures the degree to which ongoing C5 activation Is occurring in vivo based on sensitive detection in plasma of the key activation product C5b-9. The assay would be expected to show elevated plasma sC5b-9 levels in patients with the glycosphingolipidoses compared to disease-free controls, as was previously demonstrated in patient cohorts of atypical haemolytic uraemia syndrome (aHUS) and C3 glomerulopathy (C3G). Additional complement activation products will be assessed as secondary endpoints including plasma C3a and C5a levels by ELISA, and intracellular leukocyte C5a concentration as a marker of systemic C5a generation and C5aR1 expression.

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