Long-Term Effect of Antibodies against Infused Alpha-Galactosidase A in Fabry Disease on Plasma and Urinary (lyso)Gb3 Reduction and Treatment Outcome

Rombach, Saskia M.; Aerts, Johannes M. F. G.; Poorthuis, Ben J. H. M.; Groener, J.E.M.; Donker‐Koopman, Wilma E.; Hendriks, Erik; Mirzaian, Mina; Kuiper, Sijmen; Wijburg, Frits A.; Hollak, Carla E. M.; Linthorst, Gabor E.

doi:10.1371/journal.pone.0047805

Cited by 107 publications

(118 citation statements)

References 29 publications

(49 reference statements)

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“…Two recent studies demonstrated that antibody formation results in serum-mediated ERT inhibition, affecting the Gb3 clearance in ERT i+ men with FD. 4,7 However, the longterm effect of serum-mediated ERT inhibition on clinical outcome remains elusive. By establishing a similar approach for in vitro serum-inhibition measurement, defining ERT i+ as .50% ERT inhibition, we confirm previous data 4,7 and provide new evidence for an association between ERT inhibition and more severe end-organ manifestations.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to male patients with FD, the mean ERT inhibition did not differ significantly between women (P=0.1385; Figure 1B). To analyze whether ERT inhibition depends on the applied product and to confirm previous studies concerning the crossreactivity of antibodies, 4,7 inhibition assays were performed in a crossover design with agalsidase-a as well as agalsidase-b for male patients under ERT. Linear regression revealed that the value of mean ERT inhibition is product-independent, indicating no measurable specific inhibition for any product (r 2 =0.93; P,0.0001).…”

Section: Ert Inhibition Status In Patients With Fdmentioning

confidence: 94%

“…To analyze serum-mediated ERT inhibition as previously reported, 4,7 we tested sera of 168 patients with FD using an in vitro GLA inhibition assay. Patients had been consecutively recruited at the Fabry center of the University Hospital Muenster (IFAZ) between 2001 and 2014.…”

Section: Ert Inhibition Status In Patients With Fdmentioning

confidence: 99%

“…2,3 Recent studies suggested that infusion of recombinant enzyme may lead to formation of antibodies, resulting in short-term acute complications, 2 as well as deleterious long-term effects by therapy inhibition, resulting in severely decreased Gb3 and lyso-Gb3 depletion. [4][5][6][7] Reduced lyso-Gb3 clearance, as a marker of disease progression, may be accompanied by a deterioration of clinical manifestations and symptoms in affected patients. Until now, only indirect associations between ERT inhibition and end-organ manifestations have been shown, in that elevated lyso-Gb3 levels of inhibition-positive patients were associated with left ventricular mass (LV mass ) and the formation of whitematter lesions.…”

mentioning

confidence: 99%

“…Until now, only indirect associations between ERT inhibition and end-organ manifestations have been shown, in that elevated lyso-Gb3 levels of inhibition-positive patients were associated with left ventricular mass (LV mass ) and the formation of whitematter lesions. 7 In the current study, we analyzed 168 patients with FD (68 male) for serum-mediated ERT inhibition and addressed the impact of ERT inhibition in these patients' clinical outcome.…”

mentioning

confidence: 99%

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Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Lenders

Stypmann

Duning

et al. 2016

Journal of the American Society of Nephrology

104

113

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Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme replacement therapy (agalsidase). However, recent studies suggest an endogenous inhibition of agalsidase in patients with FD, as reported for other lysosomal storage diseases. To assess the clinical consequences of serum-mediated agalsidase inhibition in affected patients, we determined the agalsidase inhibition status of 168 patients (68 male) with FD and compared outcomes of inhibition-positive patients with those of inhibition-negative patients. The assessment included clinical events during time on agalsidase, determination of renal and cardiac function, and evaluation of FD-related symptoms. The frequency of serum-mediated agalsidase inhibition was 40% in agalsidase-treated males. Inhibition did not depend on the compound initially used (agalsidase-a or -b). Agalsidase inhibition was associated with higher lysoglobotriaosylceramide levels and worse disease severity scores in patients. Compared with agalsidase inhibition-negative men, agalsidase inhibition-positive men showed greater left ventricular mass (P=0.02) and substantially lower renal function (difference in eGFR of about -30 ml/min per 1.73 m 2 ; P=0.04), which was confirmed by a longitudinal 5-year retrospective analysis. Additionally, affected patients presented more often with FD-typical symptoms, such as diarrhea, fatigue, and neuropathic pain, among others. Therefore, patients with poor clinical outcome on agalsidase should be tested for agalsidase inhibition. Future studies are warranted to determine if affected patients with FD benefit from acute reduction of anti-agalsidase antibodies or long-term immune modulation therapies to suppress agalsidase inhibition and to identify mechanisms that minimize antibody generation against agalsidase.

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Section: Discussionmentioning

confidence: 99%

Section: Ert Inhibition Status In Patients With Fdmentioning

confidence: 94%

Section: Ert Inhibition Status In Patients With Fdmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Lenders

Stypmann

Duning

et al. 2016

Journal of the American Society of Nephrology

104

113

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Enzyme replacement therapy for Anderson-Fabry disease

Dib

Gomaa

Carvalho

et al. 2016

Cochrane Database of Systematic Reviews

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Trials comparing enzyme replacement therapy to placebo show significant improvement with enzyme replacement therapy in regard to microvascular endothelial deposits of globotriaosylceramide and in pain-related quality of life. There is, however, no evidence identifying if the alfa or beta form is superior or the optimal dose or frequency of enzyme replacement therapy. With regards to safety, adverse events (i.e., rigors, fever) were more significant in the agalsidase beta as compared to placebo. The long-term influence of enzyme replacement therapy on risk of morbidity and mortality related to Anderson-Fabry disease remains to be established. This review highlights the need for continued research into the use of enzyme replacement therapy for Anderson-Fabry disease.

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Lysosomal Storage Diseases. For Better or Worse: Adapting to Defective Lysosomal Glycosphingolipid Breakdown

Aerts

Ferraz

Mirzaian

et al. 2017

Encyclopedia of Life Sciences

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The cellular recycling of glycosphingolipids (GSLs) is mediated by specific lysosomal glycosidases. Inherited deficiencies in these enzymes cause lysosomal storage disorders. Some of the common disorders are Gaucher disease (GD) and Fabry disease (FD) resulting from the defects in lysosomal glucocerebrosidase (GBA) degrading glucosylceramide and α‐galactosidase A (GLA) degrading globotriaosylceramide. Here, GSL accumulation in tissues slows down with age despite ongoing lysosomal turnover of endogenous and endocytosed GSLs. Biochemical adaptations might explain this phenomenon. One crucial adaptation is the deacylation of accumulating GSLs in lysosomes by acid ceramidase. The soluble bases glucosylsphingosine in GD and globotriaosylsphingosine in FD are capable of leaving lysosomes and cells. In the case of GD, a further adaptation involves the cytosol‐faced enzyme GBA2. This enzyme allows extra‐lysosomal degradation of GlcCer while possibly generating glucosylated cholesterol. The beneficial and harmful effects of these adaptations are discussed. Key Concepts Glycosphingolipids (GSLs) are membrane constituents composed of a ceramide with one or more sugars. The simplest GSL is glucosylceramide (GlcCer). Ongoing recycling of GSLs in cells includes lysosomal degradation by the sequential action of glycosidases and acid ceramidase. Deficiency of lysosomal glycosidase leads to lysosomal storage diseases caused by accumulation of the corresponding substrate in lysosomes. The most common glycosphingolipidoses are Gaucher disease (GD) and Fabry disease (FD). GD is an autosomal recessive disorder caused by deficient activity of the lysosomal enzyme acid β‐glucosidase (glucocerebrosidase; GBA) resulting in lysosomal accumulation of GlcCer. FD is an X‐linked disorder caused by deficient activity of the lysosomal enzyme α‐galactosidase A (GLA) resulting in lysosomal accumulation of globotriaosylceramide (Gb3). Accumulation of storage lipids during GBA and GLA tends to slow down with age, likely partly due to poorly appreciated biochemical adaptations. Active conversion of accumulating GlcCer in lysosomes of GBA‐deficient cells is mediated by acid ceramidase, resulting in the formation of water‐soluble glucosylsphingosine (GlcSph). Likewise, globotriaosylsphingosine (lysoGb3) is formed from accumulating in lysosomes of GLA‐deficient cells. Elevated plasma GlcSph and lysoGb3 levels can be sensitively measured LC–MS and may assist in diagnosing and monitoring of the disease and response to treatment in GD and FD patients, respectively. Increased GlcSph level in GD patients acts as an autoantigen, causing ongoing B‐cell proliferation, leading to multiple myeloma. Increased lysoGb3 level in FD patients is thought to cause damage to nociceptive neurons and podocytes, thus contributing to pain and renal failure. In GD, the cytosol‐faced enzyme β‐glucosidase GBA2 allows degradation of GlcCer outside lysosomes. Through transglycosylation, GBA2 may generate glucosylcholesterol and ceramide from GlcCer and cholesterol. The toxic effects of secondary metabolites such as glycosphingoid bases (GlcSph in GD and lysoGb3 in FD) and glucosylated metabolites (GlcChol in GD) warrant further investigations.

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Long-Term Effect of Antibodies against Infused Alpha-Galactosidase A in Fabry Disease on Plasma and Urinary (lyso)Gb3 Reduction and Treatment Outcome

Cited by 107 publications

References 29 publications

Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Enzyme replacement therapy for Anderson-Fabry disease

Lysosomal Storage Diseases. For Better or Worse: Adapting to Defective Lysosomal Glycosphingolipid Breakdown

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