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Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model

Mucopolysaccharidosis IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Conventional enzyme replacement therapy (ERT) is approved for MPS IVA. However, the fact that the infused enzyme cannot penetrate avascular lesions in cartilage le...

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Autores principales: Sawamoto, Kazuki, Tomatsu, Shunji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747109/
https://www.ncbi.nlm.nih.gov/pubmed/31450640
http://dx.doi.org/10.3390/ijms20174139
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author Sawamoto, Kazuki
Tomatsu, Shunji
author_facet Sawamoto, Kazuki
Tomatsu, Shunji
author_sort Sawamoto, Kazuki
collection PubMed
description Mucopolysaccharidosis IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Conventional enzyme replacement therapy (ERT) is approved for MPS IVA. However, the fact that the infused enzyme cannot penetrate avascular lesions in cartilage leads to minimal impact on the bone lesion. Moreover, short half-life, high cost, instability, and narrow optimal pH range remain unmet challenges in ERT. Thermostable keratanase, endo-β-N-acetylglucosaminidase, has a unique character of a wide optimal pH range of pH 5.0–7.0. We hypothesized that this endoglycosidase degrades keratan sulfate (KS) polymer in circulating blood and, therefore, ameliorates the accumulation of KS in multiple tissues. We propose a novel approach, Substrate Degradation Enzyme Therapy (SDET), to treat bone lesion of MPS IVA. We assessed the effect of thermostable keratanase on blood KS level and bone pathology using Galns knock-out MPS IVA mice. After a single administration of 2 U/kg (= 0.2 mg/kg) of the enzyme at 8 weeks of age via intravenous injection, the level of serum KS was significantly decreased to normal range level, and this suppression was maintained for at least 4 weeks. We administered 2 U/kg of the enzyme to MPS IVA mice every fourth week for 12 weeks (total of 3 times) at newborns or 8 weeks of age. After a third injection, serum mono-sulfated KS levels were kept low for 4 weeks, similar to that in control mice, and at 12 weeks, bone pathology was markedly improved when SDET started at newborns, compared with untreated MPS IVA mice. Overall, thermostable keratanase reduces the level of KS in blood and provides a positive impact on cartilage lesions, demonstrating that SDET is a novel therapeutic approach to MPS IVA.
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spelling pubmed-67471092019-09-27 Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model Sawamoto, Kazuki Tomatsu, Shunji Int J Mol Sci Article Mucopolysaccharidosis IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Conventional enzyme replacement therapy (ERT) is approved for MPS IVA. However, the fact that the infused enzyme cannot penetrate avascular lesions in cartilage leads to minimal impact on the bone lesion. Moreover, short half-life, high cost, instability, and narrow optimal pH range remain unmet challenges in ERT. Thermostable keratanase, endo-β-N-acetylglucosaminidase, has a unique character of a wide optimal pH range of pH 5.0–7.0. We hypothesized that this endoglycosidase degrades keratan sulfate (KS) polymer in circulating blood and, therefore, ameliorates the accumulation of KS in multiple tissues. We propose a novel approach, Substrate Degradation Enzyme Therapy (SDET), to treat bone lesion of MPS IVA. We assessed the effect of thermostable keratanase on blood KS level and bone pathology using Galns knock-out MPS IVA mice. After a single administration of 2 U/kg (= 0.2 mg/kg) of the enzyme at 8 weeks of age via intravenous injection, the level of serum KS was significantly decreased to normal range level, and this suppression was maintained for at least 4 weeks. We administered 2 U/kg of the enzyme to MPS IVA mice every fourth week for 12 weeks (total of 3 times) at newborns or 8 weeks of age. After a third injection, serum mono-sulfated KS levels were kept low for 4 weeks, similar to that in control mice, and at 12 weeks, bone pathology was markedly improved when SDET started at newborns, compared with untreated MPS IVA mice. Overall, thermostable keratanase reduces the level of KS in blood and provides a positive impact on cartilage lesions, demonstrating that SDET is a novel therapeutic approach to MPS IVA. MDPI 2019-08-24 /pmc/articles/PMC6747109/ /pubmed/31450640 http://dx.doi.org/10.3390/ijms20174139 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sawamoto, Kazuki
Tomatsu, Shunji
Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model
title Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model
title_full Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model
title_fullStr Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model
title_full_unstemmed Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model
title_short Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model
title_sort development of substrate degradation enzyme therapy for mucopolysaccharidosis iva murine model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747109/
https://www.ncbi.nlm.nih.gov/pubmed/31450640
http://dx.doi.org/10.3390/ijms20174139
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