ID | 117739 |
Author |
Horii, Yuto
Tokushima University
Iniwa, Toshiki
Tokushima University
Onitsuka, Masayoshi
Tokushima University
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Tsukimoto, Jun
Tokushima University
Tanaka, Yuki
Tokushima University
Ike, Hironobu
Tokushima University
Fukushi, Yuri
Tokushima University
Ando, Haruna
Tokushima University
Takeuchi, Yoshie
Tokushima University
Nishioka, So-ichiro
Tokushima University
Yamazaki, Naoshi
Tokushima University
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Takiguchi, Yoshiharu
Tokushima University
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Ishimaru, Naozumi
Tokushima University
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Itoh, Kohji
Tokushima University
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Content Type |
Journal Article
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Description | Galactosialidosis (GS) is a lysosomal cathepsin A (CTSA) deficiency. It associates with a simultaneous decrease of neuraminidase 1 (NEU1) activity and sialylglycan storage. Central nervous system (CNS) symptoms reduce the quality of life of juvenile/adult-type GS patients, but there is no effective therapy. Here, we established a novel GS model mouse carrying homozygotic Ctsa IVS6+1g→a mutation causing partial exon 6 skipping with concomitant deficiency of Ctsa/Neu1. The GS mice developed juvenile/adult GS-like symptoms, such as gargoyle-like face, edema, proctoprosia due to sialylglycan accumulation, and neurovisceral inflammation, including activated microglia/macrophage appearance and increase of inflammatory chemokines. We produced human CTSA precursor proteins (proCTSA), a homodimer carrying terminal mannose 6-phosphate (M6P)-type N-glycans. The CHO-derived proCTSA was taken up by GS patient-derived fibroblasts via M6P receptors and delivered to lysosomes. Catalytically active mature CTSA showed a shorter half-life due to intralysosomal proteolytic degradation. Following single i.c.v. administration, proCTSA was widely distributed, restored the Neu1 activity, and reduced the sialylglycans accumulated in brain regions. Moreover, proCTSA suppressed neuroinflammation associated with reduction of activated microglia/macrophage and up-regulated Mip1α. The results show therapeutic effects of intracerebrospinal enzyme replacement utilizing CHO-derived proCTSA and suggest suppression of CNS symptoms.
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Journal Title |
Molecular Therapy - Methods and Clinical Development
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ISSN | 23290501
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Publisher | The American Society of Gene and Cell Therapy|Elsevier
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Volume | 25
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Start Page | 297
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End Page | 310
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Published Date | 2022-04-15
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Rights | This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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EDB ID | |
DOI (Published Version) | |
URL ( Publisher's Version ) | |
FullText File | |
language |
eng
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TextVersion |
Publisher
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departments |
Bioscience and Bioindustry
Pharmaceutical Sciences
Oral Sciences
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