| Summary: | 碩士 === 國立陽明大學 === 臨床醫學研究所 === 106 === Fabry disease (FD) is an X-linked lysosome storage disease (LSD) due to the mutation of α-galactosidase A (GLA) gene. GLA participates in the metabolism of glycosphingolipids and is responsible for the breakdown of globotriaosylceramide (Gb3). The impairment or dysfunction of GLA will leads to the accumulation of Gb3 in lysosomes and induce cell damage, which will cause life-threatening disease, including kidney failure, heart disease, and neurological disorder.
Enzyme replacement therapy (ERT) is currently the primary treatment of FD and the strategy is based on the intravenous administration of manufactured human α-GLA. Although ERT is effective on treating FD, the cost is very high and the infused enzyme tended to be unstable in patients body, resulting in a short circulating half-life. The development of a new therapy strategy is strongly in need. ACK170, a specific small molecule, have been proved that when co-formulated with ERT could significantly stabilize enzyme activity and effectively enhance the pharmacological ability in cell culture study. In order to demonstrate that ACK170 could serve as powerful adjuvant for treating FD, we proposed to investigate and verify the ability of ACK170 in stabilizing and prolonging the effect of ERT in an in vivo Fabry mice model.
In this study, we will first determine the half-life of GLA enzyme activity in each organ after ERT. Next, the toxicology test of ACK170 will be performed for choosing the appropriate dose to co-formulate with ERT in Fabry mice model. Meanwhile, the enzyme activity, biochemistry data and tissue biopsy slice will be collected for further analysis. We had found that there is significant difference of enzyme activity in heart, liver and kidney comparing the treatment of ERT alone and co-treatment of ACK170 with ERT after one week. These further conformed that ACK170 does have the ability to enhance and prolong the effect of ERT.
Taken together, these data suggested that the intravenous administration of ERT co-formulated with ACK170 may provide a new therapeutic strategy for Fabry disease and is worse for further investigation and development.
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