Nisticò Robert, Pisani Antonio
Dipartimento di Biologia, Università di Roma "Tor Vergata"; European Brain Research Institute (EBRI) "Rita Levi-Montalcini" Foundation, Roma.
Cattedra di Nefrologia, Dipartimento di Sanità Pubblica, Università Federico II, Napoli.
Recenti Prog Med. 2021 Oct;112(10):75e-84e. doi: 10.1701/3679.36652.
Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from the deficiency of the hydrolytic enzyme α-galactosidase A (α-Gal A), with consequent accumulation of globotrioasoylceramide in cells and tissues of the body, resulting in a multi-system pathology. Classically affected hemizygous males may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), and cerebrovascular (transient ischemic attacks, strokes) signs of the disease, while heterozygous females have symptoms ranging from very mild to severe. End-stage renal disease and cardiovascular or cerebrovascular complications limit life-expectancy of untreated patients. Demonstration of α-Gal A deficiency is the definitive method for the diagnosis of hemizygous males, while it's often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. The treatment options for FD are enzyme replacement therapy (ERT), and the oral pharmacological chaperone migalastat. Two different products, agalsidase alfa and agalsidase beta, have been commercially available in Europe for 20 years and they are both indicated for long-term ERT. In fact, clinical trials, observational studies and registry data have provided abundant evidence for the safety and efficacy of ERT in improving symptoms and disease progression. Agalsidase alpha and beta are two almost identical recombinant proteins although they are used clinically with a different dosage regimen. In this chapter we aim to clarify the differences between the two ERTs and how these can affect the pharmacokinetic/pharmacodynamic (PK/PD) characteristics and ultimately the risk/benefit profile. The chaperone migalastat, available in Europe since 2016, is the only oral treatment for FD, and acts stabilizing specific mutant forms of α-Gal, defined "amenable" to migalastat. A multitude of therapies are now under investigation in various phases of clinical trials. These include pegylated form of α-Gal (pegunigalsidase alpha), gene therapy (both in-vivo and ex-vivo methods), mRNA therapy (inducing production of α-Gal) and substrate reduction therapy (inhibitors of glucosylceramide synthase leading to reduction of Gb-3).
法布里病(FD)是一种X连锁溶酶体贮积症,因水解酶α-半乳糖苷酶A(α-Gal A)缺乏所致,导致体内细胞和组织中球三己糖酰基鞘脂蓄积,进而引发多系统病变。典型的受累半合子男性可能会出现该疾病所有的特征性神经(疼痛)、皮肤(血管角质瘤)、肾脏(蛋白尿、肾衰竭)、心血管(心肌病、心律失常)和脑血管(短暂性脑缺血发作、中风)症状,而杂合子女性的症状则从非常轻微到严重不等。终末期肾病以及心血管或脑血管并发症会限制未治疗患者的预期寿命。α-Gal A缺乏的检测是诊断半合子男性的确诊方法,而对于女性,由于随机的X染色体失活,该检测结果往往不确定,因此女性必须进行分子检测(基因分型)。FD的治疗选择包括酶替代疗法(ERT)和口服药理伴侣米加司他。两种不同的产品,阿加糖酶α和阿加糖酶β,已在欧洲上市20年,二者均适用于长期ERT。事实上,临床试验、观察性研究和登记数据已提供了大量证据,证明ERT在改善症状和疾病进展方面的安全性和有效性。阿加糖酶α和β是两种几乎相同的重组蛋白,尽管它们在临床使用时剂量方案不同。在本章中,我们旨在阐明这两种ERT之间的差异,以及这些差异如何影响药代动力学/药效学(PK/PD)特征,并最终影响风险/获益情况。自2016年起在欧洲上市的伴侣米加司他是FD的唯一口服治疗药物,其作用是稳定特定的α-Gal突变形式,即对米加司他“适用”的形式。目前多种疗法正处于不同阶段的临床试验研究中。这些疗法包括聚乙二醇化形式的α-Gal(聚乙二醇化阿加糖酶α)、基因疗法(体内和体外方法)、mRNA疗法(诱导α-Gal产生)和底物减少疗法(葡糖神经酰胺合酶抑制剂,导致Gb-3减少)。