Early biochemical effects of velmanase alfa in a 7‐month‐old infant with alpha‐mannosidosis

Santoro, Lucia; Zampini, Lucia; Padella, Lucia; Monachesi, Chiara; Zampieri, Stefania; Dardis, Andrea; Cordiali, Rosanna; Galeazzi, Tiziana; Catassi, Carlo

doi:10.1002/jmd2.12144

Cited by 7 publications

(12 citation statements)

References 14 publications

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“…Man2GlcNAc trisaccharide was identified as the most abundant structure in all AM samples in accordance with literature data [19]. Previous studies have linked the ManOS levels to AM severity [12] and treatment response either by HSCT [35] or ERT [13]. During Phase I-II of clinical testing of rhLAMAN, Borgwardt et al [31] observed an over-all 54.1% decrease in urinary ManOS in 10 patients over 12 months.…”

Section: Evaluation Of Ert Efficacysupporting

confidence: 82%

“…During Phase I-II of clinical testing of rhLAMAN, Borgwardt et al [31] observed an over-all 54.1% decrease in urinary ManOS in 10 patients over 12 months. Santoro et al [13] reported a 67% decrease in urinary ManOS in a 7-month-old infant after two months of ERT. In our work, we observed an 88.6% decrease in total urinary ManOS after four months of ERT.…”

Section: Evaluation Of Ert Efficacymentioning

confidence: 98%

“…4). However, the absolute quantification of urinary ManOS by LC-MS/MS is problematic due to a lack of external and internal standards and, in the case of HPLC-FLD, the need for labeling and SPE, which can cause the loss of analytes [13]. Nevertheless, monitoring of ERT efficacy based on the determination of ManOS levels is a unique approach provid-ing complementary information, as usually only the clinical parameters and unspecific improvement of a patient's subjective condition are monitored.…”

Section: Comparison Of Nmr and Hplcmentioning

confidence: 99%

“…Diagnosis of AM is based on measuring αmannosidase activity in leukocytes or fibroblasts using colorimetry or fluorimetry [10]. Methods detecting urinary oligosaccharides, such as NMR spectroscopy [11], highperformance liquid chromatography (HPLC) [12], thin layer chromatography (TLC), and mass spectrometry (MS) [13] are only suggestive; the diagnosis should be confirmed by gene sequencing [10]. However, these methods may be utilized to monitor disease progression and therapy effectiveness by estimation of ManOS levels, since it was found that the excretion of urinary oligosaccharides is linked to a patient's general endurance, disease severity, and response to treatment [12,13].…”

Section: Introductionmentioning

confidence: 99%

“…Methods detecting urinary oligosaccharides, such as NMR spectroscopy [11], highperformance liquid chromatography (HPLC) [12], thin layer chromatography (TLC), and mass spectrometry (MS) [13] are only suggestive; the diagnosis should be confirmed by gene sequencing [10]. However, these methods may be utilized to monitor disease progression and therapy effectiveness by estimation of ManOS levels, since it was found that the excretion of urinary oligosaccharides is linked to a patient's general endurance, disease severity, and response to treatment [12,13]. Additionally, instrumental methods are a suitable alternative to a traditional TLC screening method due to their superior sensitivity, resolution, and automation.…”

Section: Introductionmentioning

confidence: 99%

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The Application of HPLC-FLD and NMR in the Monitoring of Therapy Efficacy in Alpha-Mannosidosis

Krchňák

Kodríková

Matulovà

et al. 2023

Front. Biosci. (Landmark Ed)

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Background: Alpha-mannosidosis is a rare lysosomal storage disorder, caused by decreased activity of α-D-mannosidase. This enzyme is involved in the hydrolysis of mannosidic linkages in N-linked oligosaccharides. Due to the mannosidase defect, undigested mannoserich oligosaccharides (Man2GlcNAc -Man9GlcNAc) accumulating in cells are excreted in large quantities in urine. Methods: In this work, we determined the levels of urinary mannose-rich oligosaccharides in a patient subjected to novel enzyme replacement therapy. Urinary oligosaccharides were extracted using solid phase extraction (SPE), labeled by fluorescent tag 2-aminobenzamide, and quantified by high-performance liquid chromatography (HPLC) with fluorescence detector (FLD). The identity of peaks was determined by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI-TOF/TOF) mass spectrometry. In addition, the levels of urinary mannose-rich oligosaccharides were also quantified by 1 H nuclear magnetic resonance (NMR) spectroscopy. The data were analyzed using one-tailed paired t-test and Pearson's correlation tests. Results: Compared to levels before the administration of therapy, an approximately two-folds decrease in total mannose-rich oligosaccharides after one month of treatment was observed by NMR and HPLC. After four months, an approximately ten-folds significant decrease in total urinary mannose-rich oligosaccharides was detected, suggesting therapy effectiveness. A significant decrease in the levels of oligosaccharides with 7-9 mannose units was detected by HPLC. Conclusions: The application of both HPLC-FLD and NMR in quantification of oligosaccharide biomarkers is a suitable approach for monitoring of therapy efficacy in alpha-mannosidosis patients.

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Section: Evaluation Of Ert Efficacysupporting

confidence: 82%

Section: Evaluation Of Ert Efficacymentioning

confidence: 98%

Section: Comparison Of Nmr and Hplcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Application of HPLC-FLD and NMR in the Monitoring of Therapy Efficacy in Alpha-Mannosidosis

Krchňák

Kodríková

Matulovà

et al. 2023

Front. Biosci. (Landmark Ed)

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First experience of combined enzyme replacement therapy and hematopoietic stem cell transplantation in alpha‐mannosidosis

Santoro

Monachesi

Zampini

et al. 2023

American J of Med Genetics Pt A

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We describe the first case of bridge therapy in alpha‐mannosidosis (AM) in an infant diagnosed at only 5 months of life who underwent enzyme replacement therapy (ERT) in the pre‐ and peri‐transplant phases. Eight ERT infusions were administered before hematopoietic stem cell transplantation (HSCT) and continued for additional 90 days until complete engraftment. The clinical and laboratory data after 3 years post‐HSCT show that the early combined intervention may reduce the disease progression and the urine and plasma content of mannosyl‐oligosaccharides (OS) monitored by liquid chromatography tandem mass spectrometry (LC–MS/MS). This report highlights that early diagnosis and prompt initiation of such treatments in AM are the best chance to minimize the progression of symptoms.

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Long‐term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha‐mannosidosis: A phase 2, open label, multicenter study

Guffon

Konstantopoulou

Hennermann

et al. 2023

J of Inher Metab Disea

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Alpha‐mannosidosis (AM) is a rare, autosomal recessive, lysosomal storage disorder caused by alpha‐mannosidase deficiency that leads to the accumulation of mannose‐rich oligosaccharides. AM symptoms and severity vary among individuals; consequently, AM is often not diagnosed until late childhood. Velmanase alfa (VA), a recombinant human lysosomal alpha‐mannosidase product, is the first enzyme replacement therapy indicated to treat non‐neurological symptoms of AM in Europe. Previous studies suggested that early VA treatment in children may produce greater clinical benefit over the disease course than starting treatment in adolescents or adults; however, long‐term studies in children are limited, and very few studies include children under 6 years of age. The present phase 2, multicenter, open‐label study evaluated the safety and efficacy of long‐term VA treatment in children under 6 years of age with AM. Five children (three males) received VA weekly for ≥24 months, and all children completed the study. Four children experienced adverse drug reactions (16 events) and two experienced infusion‐related reactions (12 events). Most (99.5%) adverse events were mild or moderate, and none caused study discontinuation. Four children developed antidrug antibodies (three were neutralizing). After VA treatment, all children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreases), hearing, immunological profile, and quality of life, suggesting a beneficial effect of early treatment. Although the small study size limits conclusions, these results suggest that long‐term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to patients with AM under 6 years of age.

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Early biochemical effects of velmanase alfa in a 7‐month‐old infant with alpha‐mannosidosis

Cited by 7 publications

References 14 publications

The Application of HPLC-FLD and NMR in the Monitoring of Therapy Efficacy in Alpha-Mannosidosis

The Application of HPLC-FLD and NMR in the Monitoring of Therapy Efficacy in Alpha-Mannosidosis

First experience of combined enzyme replacement therapy and hematopoietic stem cell transplantation in alpha‐mannosidosis

Long‐term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha‐mannosidosis: A phase 2, open label, multicenter study

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