Identification of a novel therapeutic target underlying atypical manifestation of Gaucher disease

Abstract

Dear Editor,In the present study, we delineate the molecular pathways underlying atypical progressions of Gaucher disease (GD) that lead to unresponsiveness to enzyme replacement therapy (ERT). Specifically, we observed the accumulation of dense substrates (e.g., glucosylsphingosine [Lyso-Gb1]), which was associated with alterations in complement activity, autophagy metabolism, macrophage polarization and TGF-β signaling and subsequent endothelialto-mesenchymal transition (EndMT) and fibrosis. We also describe the potential therapeutic role of ambroxol, a chemical chaperone in GD, and highlight the need for a multi-functional therapeutic approach in managing GD cases with atypical progression.GD is caused by the deficiency of glucocerebrosidase (GCase) encoded by the glucocerebrosidase1 gene, which leads to the accumulation of glucosylceramide and Lyso-Gb1 in the lysosome. Specifically, Lyso-Gb1 plays important pathogenic roles in GD such as inflammation, impairment of cytoplasmic division, alteration of immune regulation and neurotoxicity. 1-3 GD can be categorized according to the degree of neurologic involvement: non-neuropathic (GD1), acute neuronopathic (GD2) and chronic neuronopathic (GD3). Since the advent of ERT, the clinical outcomes of patients with GD have improved remarkably; however, despite ERT, most GD2/3 patients as well as some GD1 patients show atypical manifestations such as lymphadenopathy, multiple myeloma, lymphoma, neurological deterioration and increases in Lyso-Gb1 levels. 4 The molecular mechanism underlying atypical responses to ERT is poorly understood.We evaluated the histological features of lymph nodes from three patients with GD, including submandibular lymph node from Pt1 (GD1, G85E/F252I), stomach lymph node from Pt2 (GD1, R87W/R296Q) and mesenteric lymph node from Pt3 (GD3, L483P/L483P) (Table S1). Despite 5 years of ERT, Pt3 died from progressiveThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Exploring Pro-Inflammatory Immunological Mediators: Unraveling the Mechanisms of Neuroinflammation in Lysosomal Storage Diseases

“…These events have been linked to the development of severe and chronic brain inflammation, resulting in the loss of neurons and early death [ 78 , 92 , 93 , 95 , 96 , 97 , 98 , 99 , 100 ]. Recent studies using induced pluripotent stem cell (iPSC)-derived mϕs and lymph nodes from patients with type 2 and type 3 Gaucher diseases have demonstrated that the C5a-C5aR1 axis triggers the induction of TNFα and TGFβ signaling [ 101 , 102 ]. The observed events, such as the induction of TNFα and TGFβ signaling triggered by the C5a-C5aR1 axis, have the potential to cause significant harm to patients with neuronopathic Gaucher disease.…”

A Brazilian Rare-Disease Center’s Experience with Glucosylsphingosine (lyso-Gb1) in Patients with Gaucher Disease: Exploring a Novel Correlation with IgG Levels in Plasma and a Biomarker Measurement in CSF

“…Even though GD1 is considered non-neuropathic, it has been shown that these patients are in a higher risk of developing Parkinson’s disease (PD) [ 3 , 4 ]. GD treatment includes enzyme-replacement therapy (ERT) and substrate-reduction therapy (SRT) that offers a significant improvement for most clinical parameters, with the exception of neurological impairment [ 5 ].…”

“…Over the years, lyso-Gb1 has demonstrated its accessibility in clinical samples, quantifiability in an easy and reliable manner, and significant value both as a diagnostic tool and as an indicator of responses to therapeutic interventions [ 1 , 9 ]. Despite enzyme-replacement therapy (ERT), most GD2/3 patients, as well as some GD1 patients, have atypical manifestations such as lymphadenopathy, multiple myeloma, lymphoma, and neurotoxicity [ 1 , 5 , 10 ].…”

A 10‐year follow‐up of high‐dose ambroxol treatment combined with enzyme replacement therapy for neuropathic Gaucher disease

“…Previous studies have revealed that atypical cells in patients with GD activate the classical pathway of complement, and ambroxol helps prevent endothelial-to-mesenchymal transition by stabilizing TGF-β signaling. 6 Ongoing real-world trials with high-dose ambroxol in GD, considering different types and treatment states, show no severe adverse events. Patients, even those with poor response to ERT, show improved symptoms and halted neurological decline with ambroxol treatment.…”