Genetic variants associated with Fabry disease progression despite enzyme replacement therapy.

Francesca Scionti,Francesca Falvo,Angela Nicoletti,Katia Roppa,Giuseppe Agapito,Mariamena Arbitrio,Maria Teresa Di Martino,Antonio Pisani,Simona Sestito,Licia Pensabene,Eleonora Riccio,Pietro Hiram Guzzi,Daniela Concolino

doi:10.18632/oncotarget.22505

Francesca Scionti, Francesca Falvo + Show 11 more

Open Access

https://doi.org/10.18632/oncotarget.22505

Copy DOI

Abstract

Enzyme replacement therapy (ERT) has been widely used for the treatment of Fabry disease, a rare X-linked recessive disorder due to absent or reduced activity of lysosomal enzyme α-galactosidase A. It is still unclear why some patients under ERT show disease progression typically with renal, cardiovascular and cerebrovascular dysfunctions. Here, we investigated the involvement of drug absorption, distribution, metabolism, and excretion gene variants in response variability to ERT, genotyping 37 patients with the Affymetrix Drug Metabolizing Enzyme and Transporters (DMET) Plus microarray. We found three single nucleotide polymorphisms in human alcohol dehydrogenase (ADH)4 gene (rs1126670, rs1126671, rs2032349) and one in ADH5 gene (rs2602836) associated with disease progression (p < 0.05). Our data provide a basic tool for identification of patient with ERT non-response risk that may represent a framework for personalized treatment of this rare disease.

Highlights

Fabry disease (FD, OMIM #301500) is a rare X-linked recessive disorder characterized by the absence or reduced activity of α-galactosidase A (α-GalA)
We investigated whether, in addition to α-GalA, genetic variants in genes encoding drug absorption, distribution, metabolism, and excretion (ADME) proteins exert some effect on response variability to Enzyme replacement therapy (ERT) in a group of 37 FD patients
When we evaluated Mains Severity Score Index (MSSI) score for single clinical parameters, we observed a significant difference between the two groups in cardiovascular baseline MSSI score (p = 0.001), after Bonferroni correction (p = 0.006)

Summary

Introduction

Fabry disease (FD, OMIM #301500) is a rare X-linked recessive disorder characterized by the absence or reduced activity of α-galactosidase A (α-GalA). This enzyme deficiency leads to deposition of globotriaosylceramide (Gb3) in body fluids and in the vascular endothelium of many organs [1]. Enzyme replacement therapy (ERT) with recombinant α-GalA has been widely used for the treatment of FD patients. Clinical trials using agalsidase alfa (Replagal® Shire HGT) and agalsidase beta (Fabrazyme® Genzyme Corp) have shown that ERT is safe and well tolerated and is able to remove Gb3 inclusions from smooth muscle, epithelial cells, myocardium and kidney [7,8,9,10,11,12]

Methods

Results

Conclusion