論文

査読有り 筆頭著者 国際誌
2016年5月2日

Protease-resistant modified human β-hexosaminidase B ameliorates symptoms in GM2 gangliosidosis model

Journal of Clinical Investigation
  • Kitakaze K
  • Mizutani Y
  • Sugiyama E
  • Tasaki C
  • Tsuji D
  • Maita N
  • Hirokawa T
  • Asanuma D
  • Kamiya M
  • Sato K
  • Setou M
  • Urano Y
  • Togawa T
  • Otaka A
  • Sakuraba H
  • Itoh K
  • 全て表示

126
5
開始ページ
1691
終了ページ
1703
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1172/JCI85300
出版者・発行元
AMER SOC CLINICAL INVESTIGATION INC

GM2 gangliosidoses, including Tay-Sachs and Sandhoff diseases, are neurodegenerative lysosomal storage diseases that are caused by deficiency of β-hexosaminidase A, which comprises an αβ heterodimer. There are no effective treatments for these diseases; however, various strategies aimed at restoring β-hexosaminidase A have been explored. Here, we produced a modified human hexosaminidase subunit β (HexB), which we have termed mod2B, composed of homodimeric β subunits that contain amino acid sequences from the α subunit that confer GM2 ganglioside–degrading activity and protease resistance. We also developed fluorescent probes that allow visualization of endocytosis of mod2B via mannose 6-phosphate receptors and delivery of mod2B to lysosomes in GM2 gangliosidosis models. In addition, we applied imaging mass spectrometry to monitor efficacy of this approach in Sandhoff disease model mice. Following i.c.v. administration, mod2B was widely distributed and reduced accumulation of GM2, asialo-GM2, and bis(monoacylglycero)phosphate in brain regions including the hypothalamus, hippocampus, and cerebellum. Moreover, mod2B administration markedly improved motor dysfunction and a prolonged lifespan in Sandhoff disease mice. Together, the results of our study indicate that mod2B has potential for intracerebrospinal fluid enzyme replacement therapy and should be further explored as a gene therapy for GM2 gangliosidoses.

リンク情報
DOI
https://doi.org/10.1172/JCI85300
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/27018595
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855921
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000375182100011&DestApp=WOS_CPL
Scopus
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84988531071&origin=inward
Scopus Citedby
https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=84988531071&origin=inward
ID情報
  • DOI : 10.1172/JCI85300
  • ISSN : 0021-9738
  • eISSN : 1558-8238
  • PubMed ID : 27018595
  • PubMed Central 記事ID : PMC4855921
  • SCOPUS ID : 84988531071
  • Web of Science ID : WOS:000375182100011

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