Therapeutic Potential of Intracerebroventricular Replacement of Modified Human β-Hexosaminidase B for GM2 Gangliosidosis

被引:42
作者
Matsuoka, Kazuhiko [1 ,2 ]
Tamura, Tomomi [1 ]
Tsuji, Daisuke [1 ,2 ]
Dohzono, Yukie [1 ]
Kitakaze, Keisuke [1 ]
Ohno, Kazuki [3 ]
Saito, Seiji [4 ]
Sakuraba, Hitoshi [2 ,5 ]
Itoh, Kohji [1 ,2 ]
机构
[1] Univ Tokushima, Grad Sch Pharmaceut Sci, Dept Med Biotechnol, Inst Med Res, Tokushima 7708505, Japan
[2] Natl Inst Biomed Innovat NIBIO, Osaka, Japan
[3] NPO Promot Res Intellectual Property Tokyo, Tokyo, Japan
[4] Univ Tokyo, Grad Sch Agr & Life Sci, Tokyo, Japan
[5] Meiji Pharmaceut Univ, Dept Analyt Biochem, Tokyo, Japan
关键词
ACID ALPHA-GLUCOSIDASE; TAY-SACHS-DISEASE; SANDHOFF-DISEASE; NEUTRALIZING ANTIBODIES; MUCOPOLYSACCHARIDOSIS-I; ENZYME THERAPY; MOUSE MODEL; SUBUNIT; EFFICACY; GENE;
D O I
10.1038/mt.2011.27
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
To develop a novel enzyme replacement therapy for neurodegenerative Tay-Sachs disease (TSD) and Sandhoff disease (SD), which are caused by deficiency of beta-hexosaminidase (Hex) A, we designed a genetically engineered HEXB encoding the chimeric human beta-subunit containing partial amino acid sequence of the a-subunit by structure-based homology modeling. We succeeded in producing the modified HexB by a Chinese hamster ovary (CHO) cell line stably expressing the chimeric HEXB, which can degrade artificial anionic substrates and GM2 ganglioside in vitro, and also retain the wild-type (WT) HexB-like thermostability in the presence of plasma. The modified HexB was efficiently incorporated via cation-independent mannose 6-phosphate receptor into fibroblasts derived from Tay-Sachs patients, and reduced the GM2 ganglioside accumulated in the cultured cells. Furthermore, intracerebroventricular administration of the modified HexB to Sandhoff mode mice restored the Hex activity in the brains, and reduced the GM2 ganglioside storage in the parenchyma. These results suggest that the intracerebroventricular enzyme replacement therapy involving the modified HexB should be more effective for Tay-Sachs and Sandhoff than that utilizing the HexA, especially as a low-antigenic enzyme replacement therapy for Tay-Sachs patients who have endogenous WT HexB.
引用
收藏
页码:1017 / 1024
页数:8
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