期刊
ISCIENCE
卷 24, 期 3, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.isci.2021.102154
关键词
-
资金
- Swedish Foundation for Strategic Research (SSF) [ID16-0036]
- Swedish Innovation Agency Vinnova [2019-00103, 2017-02105]
- Vinnova [2019-00103, 2017-02105] Funding Source: Vinnova
- Swedish Foundation for Strategic Research (SSF) [ID16-0036] Funding Source: Swedish Foundation for Strategic Research (SSF)
Ancestral sequence reconstruction can enhance the activity of iduronate-2-sulfatase, potentially improving treatment outcomes for Hunter syndrome. Ancestral variants showed up to 2-fold higher activity than human IDS in vitro and could offer a more effective therapeutic effect, reducing treatment burden.
We show the successful application of ancestral sequence reconstruction to enhance the activity of iduronate-2-sulfatase (IDS), thereby increasing its therapeutic potential for the treatment of Hunter syndrome-a lysosomal storage disease caused by impaired function of IDS. Current treatment, enzyme replacement therapy with recombinant human IDS, does not alleviate all symptoms, and an unmet medical need remains. We reconstructed putative ancestral sequences of mammalian IDS and compared them with extant IDS. Some ancestral variants displayed up to 2-fold higher activity than human IDS in in vitro assays and cleared more substrate in ex vivo experiments in patient fibroblasts. This could potentially allow for lower dosage or enhanced therapeutic effect in enzyme replacement therapy, thereby improving treatment outcomes and cost efficiency, as well as reducing treatment burden. In summary, we showed that ancestral sequence reconstruction can be applied to lysosomal enzymes that function in concert with modern enzymes and receptors in cells.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据