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Fabry disease (FD) is an X‐linked disease characterized by an accumulation of glycosphingolipids, notably of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) leading to renal failure, cardiomyopathy, and cerebral strokes. Inflammatory processes are involved in the pathophysiology. We investigated the immunological phenotype of peripheral blood mononuclear cells in Fabry patients depending on the clinical phenotype, treatment, Gb3, and lysoGb3 levels and the presence of anti‐drug antibodies (ADA). Leucocytes from 41 male patients and 20 controls were analyzed with mass cytometry using both unsupervised and supervised algorithms. FD patients had an increased expression of CD27 and CD28 in memory CD45‐ and CD45 + CCR7‐CD4 T cells (respectively p < 0.014 and p < 0.02). Percentage of CD45RA‐CCR7‐CD27 + CD28+ cells in CD4 T cells was correlated with plasma lysoGb3 (r = 0.60; p = 0.0036) and phenotype (p < 0.003). The correlation between Gb3 and CD27 in CD4 T cells almost reached significance (r = 0.33; p = 0.058). There was no immune profile associated with the presence of ADA. Treatment with agalsidase beta was associated with an increased proportion of Natural Killer cells. These findings provide valuable insights for understanding FD, linking Gb3 accumulation to inflammation, and proposing new prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Moss‐aGalactosidase A (moss‐aGal) is a moss‐derived version of human α‐galactosidase developed for enzyme replacement therapy in patients with Fabry disease. It exhibits a homogenous N‐glycosylation profile with >90% mannose‐terminated glycans. In contrast to mammalian cell produced α‐galactosidase, moss‐aGal does not rely on mannose‐6‐phosphate receptor mediated endocytosis but targets the mannose receptor for tissue uptake. We conducted a phase 1 clinical trial with moss‐aGal in six patients with confirmed diagnosis of Fabry disease during a 28‐day schedule. All patients received a single dose of 0.2 mg/kg moss‐aGal by i.v.‐infusion. Primary endpoints of the trial were safety and pharmacokinetics; secondary endpoints were pharmacodynamics by analyzing urine and plasma Gb3 and lyso‐Gb3 concentrations. In all patients, the administered single dose was well tolerated. No safety issues were observed. Pharmacokinetic data revealed a stable nonlinear profile with a short plasma half‐life of moss‐aGal of 14 minutes. After one single dose of moss‐aGal, urinary Gb3 concentrations decreased up to 23% 7 days and up to 60% 28 days post‐dose. Plasma concentrations of lyso‐Gb3 decreased by 3.8% and of Gb3 by 11% 28 days post‐dose. These data reveal that a single dose of moss‐aGal was safe, well tolerated, and led to a prolonged reduction of Gb3 excretion. As previously shown, moss‐aGal is taken up via the mannose receptor, which is expressed on macrophages but also on endothelial and kidney cells. Thus, these data indicate that moss‐aGal may target kidney cells. After these promising results, phase 2/3 clinical trials are in preparation. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Fabry disease is an X-linked lysosomal storage disorder related to α-galactosidase A deficiency. • Two enzyme replacement therapies were approved by the European Medicines Agency in 2001: agalsidase-alfa and agalsidase-beta. • Patients with Fabry disease and treated with agalsidase-alfa or -beta can develop antibodies against the protein infused. • IgG antibodies against agalsidase-alfa and IgG and IgE antibodies against agalsidase-beta were previously described. WHAT THIS STUDY ADDS • Despite two successive treatments with agalsidase in our patient, kidney function declined. • Cross-reactivity between the two enzymes could be demonstrated. • Negative IgE antibodies and skin tests results do not necessarily equate with safety and the ability to continue with enzyme replacement therapies. AIMS To report a severe adverse event related to enzyme replacement therapy with agalsidase in an hemizygous male patient treated for Fabry disease. METHODS Retrospective analysis of clinical, radiological and biochemical data in a patient who suffered adverse events related to both agalsidase alfa and agalsidase beta treatments. RESULTS A hemizygous male patient was first treated for Fabry disease with agalsidase alfa. After more than 1 year of therapy, infusion-related symptoms necessitated systemic steroids and antihistaminic therapy. Decline in kidney function prompted a switch for agalsidase beta. Anaphylactoid shock occurred after the second infusion. No serum IgE antibodies were disclosed. Skin-test reactivity to agalsidase beta was negative. Following a published rechallenge infusion protocol, agalsidase beta was reintroduced, leading to a second anaphylactoid shock episode. Enzyme replacement therapy was stopped and the patient was treated with symptomatic therapy only. This case was referred to the pharmacovigilance department. CONCLUSION The negativity of immunological tests (specific anti-agalsidase IgE antibodies and skin tests) does not rule out the risk of repeated anaphylactoid shock following agalsidase infusion. [ABSTRACT FROM AUTHOR]