PDF(Pubmed)
Abstract：
Despite the implementation of lifesaving newborn screening programs and a galactose-restricted diet, many patients with classic galactosemia develop long-term debilitating neurological deficits and primary ovarian insufficiency. Previously, we showed that the administration of human GALT mRNA predominantly expressed in the GalT gene-trapped mouse liver augmented the expression of hepatic GALT activity, which decreased not only galactose-1 phosphate (gal-1P) in the liver but also peripheral tissues. Since each peripheral tissue requires distinct methods to examine the biomarker and/or GALT effect, this highlights the necessity for alternative strategies to evaluate the overall impact of therapies. In this study, we established that whole-body galactose oxidation (WBGO) as a robust, noninvasive, and specific method to assess the in vivo pharmacokinetic and pharmacodynamic parameters of two experimental gene-based therapies that aimed to restore GALT activity in a mouse model of galactosemia. Although our results illustrated the long-lasting efficacy of AAVrh10-mediated GALT gene transfer, we found that GALT mRNA therapy that targets the liver predominantly is sufficient to sustain WBGO. The latter could have important implications in the design of novel targeted therapy to ensure optimal efficacy and safety.
摘要：
尽管实施了拯救生命的新生儿筛查计划和半乳糖限制饮食，许多经典半乳糖血症患者会出现长期衰弱的神经功能缺损和原发性卵巢功能不全。以前,我们表明，主要在GalT基因捕获的小鼠肝脏中表达的人GALTmRNA的给药增加了肝脏GALT活性的表达，不仅减少了肝脏中的半乳糖-1磷酸（gal-1P），而且减少了外周组织。由于每个外周组织需要不同的方法来检查生物标志物和/或GALT效应，这凸显了采用替代策略评估治疗总体影响的必要性.在这项研究中,我们确定全身半乳糖氧化（WBGO）是一种强大的，非侵入性，以及评估旨在恢复半乳糖血症小鼠模型中GALT活性的两种基于基因的实验性疗法的体内药代动力学和药效学参数的具体方法。尽管我们的结果说明了AAVrh10介导的GALT基因转移的长期疗效，我们发现主要针对肝脏的GALTmRNA治疗足以维持WBGO。后者可能在设计新型靶向治疗以确保最佳疗效和安全性方面具有重要意义。
