Abstract：
Fabry disease is an X-linked multisystemic disorder caused by the impairment of lysosomal α-Galactosidase A, which leads to the progressive accumulation of glycosphingolipids and to defective lysosomal metabolism. Currently, Fabry disease is treated by enzyme replacement therapy or the orally administrated pharmacological chaperone Migalastat. Both therapeutic strategies present limitations, since enzyme replacement therapy has shown low half-life and bioavailability, while Migalastat is only approved for patients with specific mutations. The aim of this work was to assess the efficacy of PBX galactose analogues to stabilize α-Galactosidase A and therefore evaluate their potential use in Fabry patients with mutations that are not amenable to the treatment with Migalastat. We demonstrated that PBX compounds are safe and effective concerning stabilization of α-Galactosidase A in relevant cellular models of the disease, as assessed by enzymatic activity measurements, molecular modelling, and cell viability assays. This experimental evidence suggests that PBX compounds are promising candidates for the treatment of Fabry disease caused by mutations which affect the folding of α-Galactosidase A, even for GLA variants that are not amenable to the treatment with Migalastat.
摘要：
Fabry病是由溶酶体α-半乳糖苷酶A受损引起的X连锁多系统疾病，这导致鞘糖脂的逐步积累和溶酶体代谢缺陷。目前,法布里病通过酶替代疗法或口服给予的药物伴侣Migalastat来治疗。两种治疗策略都存在局限性，由于酶替代疗法显示出低半衰期和生物利用度，而Migalastat仅被批准用于具有特定突变的患者。这项工作的目的是评估PBX半乳糖类似物稳定α-半乳糖苷酶A的功效，因此评估其在具有不适合Migalastat治疗的突变的Fabry患者中的潜在用途。我们证明了PBX化合物在相关细胞模型中对α-半乳糖苷酶A的稳定是安全有效的。通过酶活性测量评估，分子建模，和细胞活力测定。该实验证据表明，PBX化合物是治疗由影响α-半乳糖苷酶A折叠的突变引起的法布里病的有希望的候选化合物，即使对于不适合Migalastat治疗的GLA变体。
