Safety analysis of self-administered enzyme replacement therapy using data from the Fabry Outcome and Gaucher Outcome SurveysRevel-Vilk, Ramaswami, Pintos-Morell
et alOrphanet J Rare Dis (2025) 20 (1), 145
Abstract: Fabry disease and Gaucher disease are rare genetic disorders characterized by defective degradation of glycosphingolipids caused by enzymatic deficiencies in α-galactosidase A and β-glucocerebrosidase, respectively, and often require life-long treatment. Treatment options for these disorders include replacing the deficient enzymes via enzyme replacement therapy (ERT). Agalsidase alfa for Fabry disease and velaglucerase alfa for Gaucher disease are two ERT options with demonstrated efficacy, safety, and tolerability. ERT infusions administered by a health care provider (HCP) in the clinic/hospital, or at the patient's home are considered HCP-supported infusions. Self-administration of ERT (by patient, partner, relative, or caregiver) is optional in patients who tolerate the HCP-supported infusions at home and have a suitable home environment. This analysis explored the safety profiles of self-administered agalsidase alfa (202 patients) and velaglucerase alfa (30 patients) versus HCP-supported infusions using data from the Fabry Outcome Survey (FOS) and Gaucher Outcome Survey (GOS) registries.The frequency of infusion-related reactions (IRRs) adverse events (AEs) recorded in the two registries was lower in patients self-administering (FOS: 4.5%, GOS: 0%) versus patients receiving HCP-supported infusions (FOS: 13.6%, GOS: 1.6%). In the FOS registry, AE rates per 100 patient-years (100PY) of follow-up were similar between the self-administration (7.99) and HCP-supported infusion (6.78) groups. In patients self-administering agalsidase alfa, cardiac disorders were the most frequently reported AEs (19 [9.4%] patients) and serious AEs (12 [5.9%]) and gastrointestinal disorders were the most frequently reported IRRs (3 [1.5%]). In the GOS registry, AE rates per 100PY were similar between self-administration (4.97) and HCP-supported infusion (4.67) groups. In patients self-administering velaglucerase alfa, skin and subcutaneous disorders (4 [13.3%]) and infections and infestations (2 [6.7%]) were the most reported AEs and serious AEs, respectively, and no IRRs were reported.These findings suggest that self-administration of agalsidase alfa or velaglucerase alfa infusions are not associated with additional safety risks compared with HCP-supported infusions and are a suitable option for qualifying patients. Further research is warranted to support these findings and to explore further the long-term safety and efficacy of ERT self-administration. FOS trial registration: ClinicalTrials.gov, NCT03289065. Registered 01 April 2001, https://clinicaltrials.gov/study/NCT03289065 . GOS trial registration: ClinicalTrials.gov, NCT03291223. Registered 27 July 2010, https://classic.gov/ct2/show/NCT03291223 .© 2025. Takeda Pharmaceuticals International AG.
Cultured Macrophage Models for the Investigation of Lysosomal Glucocerebrosidase and Gaucher DiseaseLouwerse, Bila, van der Lienden
et alInt J Mol Sci (2025) 26 (6)
Abstract: Macrophages are specialised cells that degrade a range of substrates during their lifetime. In inherited lysosomal storage disorders, particularly the sphingolipidoses, macrophages transform into storage cells and contribute to pathology. An appropriate cultured macrophage model is desired for fundamental research and the assessment of considered therapeutic interventions. We compared commonly used macrophage cell lines, RAW264.7, J774A.1, and THP-1 cells, with human monocyte-derived macrophages (HMDMs) isolated from peripheral blood. Specific lysosomal glucosidases were analysed by enzymatic activity measurements and visualised with fluorescent activity-based probes. Special attention was given to lysosomal glucocerebrosidase (GBA1), the enzyme deficient in Gaucher disease in which lipid-laden macrophages are a hallmark. In macrophage cell lines and HMDMs, various (glyco)sphingolipids relevant to GBA1 activity were determined. Finally, the feasibility of inactivation of GBA1 with a cell-permeable suicide inhibitor was established, as well as the monitoring of uptake of therapeutic recombinant human GBA1. Major differences among various cell lines were noted in terms of morphology, lysosomal enzyme expression, and glycosphingolipid content. HMDMs appear to be the most suitable model for investigations into GBA1 and Gaucher disease. Moreover, they serve as a valuable model for mannose-receptor mediated uptake of therapeutic human GBA1, effectively mimicking enzyme replacement therapy for Gaucher disease.
Never-Treated, Non Splenectomised Patients With Gaucher Disease (The French GANT Study): The Prospective Follow-UpNasce, Nguyen, Belmatoug
et alJ Inherit Metab Dis (2025) 48 (2), e70026
Abstract: Treatment options for Type 1 Gaucher Disease (GD1) include enzyme replacement therapy and oral substrate reduction therapy. The criteria for treatment initiation vary across regions. Recent retrospective studies have highlighted the natural progression of never-treated GD1, suggesting that some patients remain asymptomatic or stable for extended periods. However, there is no data on long-term prospective follow-up. We conducted a prospective study following a cross-sectional analysis of 36 never-treated, non-splenectomised GD1 patients from the French Gaucher Disease Registry (FGDR). The objective was to describe the natural disease progression, tracking clinical, radiological, and biological characteristics over time. Thirty-six non-splenectomised and never-treated patients (19 women and 17 men) diagnosed with Gaucher Disease were prospectively followed for an additional median duration of 6.5 (5-8.3) years. Of the cohort, 17 remained untreated, 10 initiated treatment, and 7 were lost to follow-up. Although never-treated patients tended to be older at the time of first symptoms, diagnosis, and last follow-up compared to those who received treatment, the difference was not significant in this small cohort. At last follow-up, never-treated patients had no worsening of most of their symptoms. No significant changes were observed in platelets, chitotriosidase, and lyso-Gb1. In this prospective cohort, we highlight that patients with mild GD can remain untreated with no disease progression, offering insights into cost-effective management strategies. Identifying such patients is still challenging.© 2025 SSIEM.
Screening of intestinal protein signatures in pacific white-leg shrimp (Litopenaeus vannamei) with white feces syndrome by proteomeXv, Pang, Wang
et alFish Shellfish Immunol (2025) 161, 110257
Abstract: White feces syndrome (WFS) has been one of the emerging diseases causing instructive economic losses in the penaeid shrimp aquaculture industry, though the etiology of WFS remains unclear. In this research, we have collected intestinal samples from normal and diseased shrimp (Litopenaeus vannamei) from the natural shrimp cultivation farm for histological and proteomic analysis. The preliminary pathogen detection confirmed that WFS in this study was (Enterocytozoon hepatopenaei) EHP-WFS that was related to Vibrio spp. Moreover, the destructive damage of the intestine in WFS-diseased shrimp revealed by histological observation indicated a deficiency in digestive capacity, which might be closely related to WFS. Furthermore, we have characterized 86 and 165 differentially expressed proteins (DEPs) through a non-directional integrative analysis, which were significantly up-regulated and down-regulated, respectively. The down-regulation of various digestive enzymes in the WFS-diseased shrimp was consistent with the results of intestinal histology. DEPs were enriched in the lysosome and sphingolipid metabolism pathway, indicating that they were strongly associated with the occurrence of WFS (P < 0.05). Of this, the expression of down-regulated proteins in the lysosomal pathway was further validated by real-time quantitative polymerase chain reaction (RT-qPCR). Ultimately, crustin, lipase, and glucosylceramidase (GBA), which were significantly decreased in WFS-diseased shrimp, were screened as the predictive protein signatures for the diagnosis and prevention of WFS. Consequently, our results will provide a theoretical reference for the diagnosis of EHP-WFS by the protein aspect and crustin, lipase, and GBA may be predictive signatures that are suitable for EHP-WFS.Copyright © 2025. Published by Elsevier Ltd.
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