Complement Activation in the Lysosomal Storage Disorders
Complement Activation in the Lysosomal Storage Disorders
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.
Inclusion Criteria:

 -  All consenting patients with a prior diagnosis of FD, GD or NPC will be included in
 the study. Control participants will be healthy volunteers.

 Exclusion Criteria:

 -  Patients who are unable to provide consent or to perform a blood or urine test will be
 excluded.