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헌터증후군의 효소대체요법에 사용되는 두 재조합 효소의 생화학적 및 물리화학적 비교
- Alternative Title
- A biochemical and physicochemical comparison of two recombinant enzymes used for enzyme replacement therapies of Hunter syndrome
- Author(s)
- Chung, Yo-Kyung
- Alternative Author(s)
- Yo-Kyung Chung
- Advisor
- 김용성
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2016-02
- Language
- eng
- Alternative Abstract
- Mucopolysaccharidosis II (MPS II, Hunter syndrome; OMIM 309900) is an X-linked lysosomal storage disease caused by the deficiency of the enzyme iduronate-2-sulfatase (IDS), leading to accumulation of glycosaminoglycans (GAGs). For enzyme replacement therapy (ERT) of Hunter syndrome, two recombinant enzymes, idursulfase (Elaprase®, Shire Human Genetic Therapies, Lexington, MA) and idursulfase beta (Hunterase®, Green Cross Corporation, Yongin, Korea), are currently available in Korea. The manufacturing process of idursulfase beta was developed for enzyme replacement therapy of Hunter syndrome. The structural and glycosylational differences of two recombinant enzymes were compared. The efficacy and safety of idursulfase beta were evaluated by phase I/II clinical trial. Urine GAGs were significantly reduced in the 0.5 mg/kg and 1.0 mg/kg idursulfase beta groups when compared to the 0.5 mg/kg idursulfase group. Changes in 6MWT (six-minute walk test) were significantly greater in the 0.5 mg/kg and 1.0 mg/kg idursulfase beta groups than in the 0.5 mg/kg idursulfase group. To investigate these clinical differences, the biochemical and physicochemical differences between idursulfase and idursulfase beta were compared. The formylglycine (FGly) content, specific enzyme activity, mannose-6-phosphate (M6P) content, sialic acid content, and in vitro cell uptake activity of normal human fibroblasts of these two enzymes were examined. The FGly content, which determines the enzyme activity, of idursulfase beta was significantly higher than that of idursulfase (79.4±0.9 vs. 68.1±2.2 %, P<0.001). In accordance with the FGly content, the specific enzyme activity of idursulfase beta was significantly higher than that of idursulfase (42.6±1.1 vs. 27.8±0.9 nmol/min/ug protein, P<0.001). The levels of M6P and sialic acid were not significantly different (2.4±0.1 vs 2.4±0.3 mol/mol protein for M6P and 12.3±0.7 vs. 12.4±0.4 mol/mol protein for sialic acid). However, the cellular uptake activity of the normal human fibroblasts in vitro showed a significant difference (Kuptake, 5.09±0.96 vs. 6.50±1.28 nM protein, P=0.017). In conclusion, idursulfase beta exhibited significantly higher specific enzyme activity than idursulfase, resulting from higher FGly content. These biochemical differences may be partly attributed to clinical efficacy. However, long-term clinical evaluations of Hunter syndrome patients treated with these two enzymes will be needed to demonstrate the clinical implications of significant difference of the enzyme activity and the FGly content.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Molecular Science and Technology > 4. Theses(Ph.D)
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