ID | 117739 |
著者 |
Horii, Yuto
Tokushima University
Iniwa, Toshiki
Tokushima University
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
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資料タイプ |
学術雑誌論文
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抄録 | 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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掲載誌名 |
Molecular Therapy - Methods and Clinical Development
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ISSN | 23290501
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出版者 | The American Society of Gene and Cell Therapy|Elsevier
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巻 | 25
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開始ページ | 297
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終了ページ | 310
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発行日 | 2022-04-15
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権利情報 | 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 | |
出版社版DOI | |
出版社版URL | |
フルテキストファイル | |
言語 |
eng
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著者版フラグ |
出版社版
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部局 |
生物資源系
薬学系
歯学系
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