Differences in cleavage of globotriaosylceramide and its derivatives accumulated in organs of young Fabry mice following enzyme replacement therapy

Kodama, Takashi; Tsukimura, Takahiro; Kawashima, Ichiro; Sato, Atsuko; Sakuraba, Hitoshi; Togawa, Tadayasu

doi:10.1016/j.ymgme.2016.10.003

Cited by 9 publications

(7 citation statements)

References 27 publications

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“…While enzyme activities are lower in the heart than in the kidney after sc injection (11% vs. 21%, Figure S1), the corresponding Gb3 reduction is more efficient in this organ (33% vs. 8%, Figure S4). This observation is in line with reports by others indicating that Gb3 clearance is least effective in the kidneys of Fabry mice 23,24 …”

Section: Discussionsupporting

confidence: 93%

“…This observation is in line with reports by others indicating that Gb3 clearance is least effective in the kidneys of Fabry mice. 23,24 Use of higher dose could increase moss-aGal's bioavailability (Figure S1). Results from the initial efficacy study show dose dependency; with the strongest Gb3 reduction obtained for 10 mg/kg (Figure S3), consistent with the highest enzyme activities for this dose.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of efficacy between subcutaneous and intravenous application of moss‐aGal in the mouse model of Fabry disease

Dabrowska‐Schlepp,

Busch,

Shen

et al. 2023

JIMD Reports

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Fabry disease (FD, OMIM 301500) is a rare X‐linked inherited lysosomal storage disorder associated with reduced activities of α‐galactosidase A (aGal, EC 3.2.1.22). The current standard of care for FD is based on enzyme replacement therapy (ERT), in which a recombinantly produced version of αGal is intravenously (iv) applied to Fabry patients in biweekly intervals. Though the iv application is clinically efficacious, periodical infusions are inconvenient, time‐ and resource‐consuming and they negatively impact the patients’ quality of life. Subcutaneous (sc) injection, in contrast, is an established route of administration for treatment of chronic conditions. It opens the beneficial option of self‐administration, thereby improving patients’ quality of life and at the same time reducing treatment costs. We have previously shown that Moss‐α‐Galactosidase (moss‐aGal), recombinantly produced in the moss Physcomitrium patens, is efficient in degrading accumulated Gb3 in target organs of murine model of FD and in the phase I clinical study, we obtained first efficacy evidence in human patients following single iv infusion. Here, we tested the efficacy of subcutaneous administration of moss‐aGal and compared it with the results observed following iv infusion in Fabry mice. The obtained findings demonstrate that subcutaneously applied moss‐aGal is correctly transported to target organs and efficacious in degrading Gb3 deposits there and thus suggest the possibility of using this route of administration for therapy of Fabry disease.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Comparison of efficacy between subcutaneous and intravenous application of moss‐aGal in the mouse model of Fabry disease

Dabrowska‐Schlepp,

Busch,

Shen

et al. 2023

JIMD Reports

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“…The presence of Gb3 analogs containing lyso-Gb3 analogs has been suggested in Gla knockout mouse organs (28,29) and the plasma of patients with Fabry disease (19), but this is the first experimental data demonstrating the presence of Gb3 analogs in mouse organs. LC-MS/MS has been widely used to determine Gb3 content in the plasma of patients with Fabry disease (13) and in mouse organs (31,32), and it can detect selected Gb3 isoforms but not Gb3 analogs. In this study, Gb3 analogs constituted <2% of the standard Gb3 from Matreya LLC; however, significant amounts of Gb3 analogs were observed in the heart, kidneys, and liver (approximately 12, 30, and 16%, respectively) of our mouse model (Table 1).…”

Section: Deacylation Of Gb3 From Different Organs Of Gla Tm Tg(cag-a4mentioning

confidence: 99%

Determination of globotriaosylceramide analogs in the organs of a mouse model of Fabry disease

Ishii

Taguchi

Okino

et al. 2020

Journal of Biological Chemistry

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Fabry disease is a heritable lipid disorder caused by the low activity of α-galactosidase A and characterized by the systemic accumulation of globotriaosylceramide (Gb3). Recent studies have reported a structural heterogeneity of Gb3 in Fabry disease, including Gb3 isoforms with different fatty acids and Gb3 analogs with modifications on the sphingosine moiety. However, Gb3 assays are often performed only on the selected Gb3 isoforms. To precisely determine the total Gb3 concentration, here we established two methods for determining both Gb3 isoforms and analogs. One was the deacylation method, involving Gb3 treatment with sphingolipid ceramide N-deacylase, followed by an assay of the deacylated products, globotriaosylsphingosine (lyso-Gb3) and its analogs, by ultra-performance LC coupled to tandem MS (UPLC-MS/MS). The other method was a direct assay established in the present study for 37 Gb3 isoforms and analogs/isoforms by UPLC-MS/MS. Gb3s from the organs of symptomatic animals of a Fabry disease mouse model were mainly Gb3 isoforms and two Gb3 analogs, such as Gb3(+18) containing the lyso-Gb3(+18) moiety and Gb3(−2) containing the lyso-Gb3(−2) moiety. The total concentrations and Gb3 analog distributions determined by the two methods were comparable. Gb3(+18) levels were high in the kidneys (24% of total Gb3) and the liver (13%), and we observed Gb3(−2) in the heart (10%) and the kidneys (5%). These results indicate organ-specific expression of Gb3 analogs, insights that may lead to a deeper understanding of the pathophysiology of Fabry disease.

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“…The contents of Gb3 and Lyso-Gb3 in organs and tissues were determined by LC and MS/MS, as described previously [ 30 ]. Briefly, for extraction of Gb3 and Lys-Gb3 from organs and tissues, a 10 μL aliquot of a homogenate was mixed with a 70 μL aliquot of chloroform:methanol (1:2), and then a 10 μL aliquot of 5 μg/mL Gb3 (C17:0) (Gb3 IS) and a 10 μL aliquot of 500 nmol/L stable isotope-labelled Lyso-Gb3 (Lyso-Gb3 IS) were added as the internal standards.…”

Section: Methodsmentioning

confidence: 99%

Does administration of hydroxychloroquine/amiodarone accelerate accumulation of globotriaosylceramide and globotriaosylsphingosine in Fabry mice?

Tsukimura

Shiga

Saito

et al. 2021

Molecular Genetics and Metabolism Reports

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Drug-induced lysosomal storage disease (DILSD) caused by cationic amphiphilic drugs (CADs), which exhibits toxic manifestations and pathological findings mimicking Fabry disease (α-galactosidase A deficiency), has attracted the interests of clinicians and pathologists. Although the affected region is lysosomes in both the diseases, DILSD is characterized by intralysosomal accumulation of phospholipids and Fabry disease that of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). However, it is unknown whether administration of CADs affects the catabolism of Gb3 and Lyso-Gb3 in Fabry disease. In this study, we independently administered hydroxychloroquine/amiodarone to wild-type and Fabry mice and examined the effects of the drugs on the enzyme activity and substrates accumulated in organs and tissues. The results revealed that the administration of the drugs induced accumulation of phosphatidylcholine in both the wild-type and Fabry mice. However, reduction of α-galactosidase A activity in the organs and tissues of the wild-type mice was not found, and the storage of Gb3 and Lyso-Gb3 was not accelerated by these drugs in the Fabry mice. This suggests that hydroxychloroquine/amiodarone do not have any significant impact on the catabolism of Gb3 and Lyso-Gb3 in organs and tissues of both wild-type and Fabry mice.

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Differences in cleavage of globotriaosylceramide and its derivatives accumulated in organs of young Fabry mice following enzyme replacement therapy

Cited by 9 publications

References 27 publications

Comparison of efficacy between subcutaneous and intravenous application of moss‐aGal in the mouse model of Fabry disease

Comparison of efficacy between subcutaneous and intravenous application of moss‐aGal in the mouse model of Fabry disease

Determination of globotriaosylceramide analogs in the organs of a mouse model of Fabry disease

Does administration of hydroxychloroquine/amiodarone accelerate accumulation of globotriaosylceramide and globotriaosylsphingosine in Fabry mice?

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