Effect of substrate reduction therapy with Eliglustat on red blood cell properties in type 1 Gaucher disease

Type 1 Gaucher disease (GD) is a lysosomal storage disorder characterized by splenomegaly, lipid-laden macrophage accumulation (Gaucher cells), and complex skeletal involvement, though its pathophysiology remains incompletely understood. We previously showed that red blood cells (RBC) from GD patients display abnormal membrane properties that may contribute to clinical manifestations. Current therapies for GD type 1 include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). Eliglustat (Cerdelga ® ), an SRT, effectively prevents GD symptoms, suggesting it could improve RBC parameters. We therefore investigated whether Eliglustat ameliorates RBC characteristics in GD type 1. We performed a comparative analysis of blood samples from treatment-naïve (UT, n = 11) and SRT-treated (SRT, n = 15) GD patients, and followed patients transitioning from ERT to SRT longitudinally ( n = 5). We assessed RBC membrane properties, semaphorin 7 A (Sema7A) expression, and glucosylsphingosine (Lyso-GB1) content. In parallel, we quantified plasma Lyso-GB1 and glucosylceramide (GlcCer) and soluble glycoprotein non-metastatic melanoma protein B (GPNMB), a macrophage activation marker relevant to GD. SRT improved key RBC parameters, notably Lyso-GB1 concentration ( p = 0.037) and Sema7A expression ( p = 0.0017), while also lowering plasma Lyso-GB1 ( p = 0.0417), GlcCer ( p = 0.0007) and GPNMB levels ( p = 0.0055). Furthermore, the longitudinal study revealed that SRT maintained blood counts, plasma markers, and RBC properties comparably to ERT. Treatment with eliglustat improves certain RBCs membrane abnormalities in type 1 GD, alongside its effects on plasma biomarkers. These results suggest that RBCs might be involved in some aspects of GD pathophysiology and highlight their potential relevance as mechanistic markers in patients undergoing SRT.