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ID 117739
Author
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
Content Type
Journal Article
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.
Journal Title
Molecular Therapy - Methods and Clinical Development
ISSN
23290501
Publisher
The American Society of Gene and Cell Therapy|Elsevier
Volume
25
Start Page
297
End Page
310
Published Date
2022-04-15
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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DOI (Published Version)
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language
eng
TextVersion
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departments
Bioscience and Bioindustry
Pharmaceutical Sciences
Oral Sciences