Fabry Disease Therapy: State-of-the-Art and Current Challenges

• Main Authors: Olga Azevedo, Miguel Fernandes Gago, Gabriel Miltenberger-Miltenyi, Nuno Sousa, Damião Cunha
• Format: Article
• Language: English
• Published: MDPI AG 2021-12-01
• Series: International Journal of Molecular Sciences
• Subjects: fabry disease; enzyme replacement therapy; agalsidase alfa; agalsidase beta; migalastat; pegunigalsidase alfa
• Online Access: https://www.mdpi.com/1422-0067/22/1/206
• ISSN: 1661-6596; 1422-0067

Fabry disease (FD) is a lysosomal storage disorder caused by mutations of the <i>GLA</i> gene that lead to a deficiency of the enzymatic activity of α-galactosidase A. Available therapies for FD include enzyme replacement therapy (ERT) (agalsidase alfa and agalsidase beta) and the chaperone migalastat. Despite the large body of literature published about ERT over the years, many issues remain unresolved, such as the optimal dose, the best timing to start therapy, and the clinical impact of anti-drug antibodies. Migalastat was recently approved for FD patients with amenable <i>GLA</i> mutations; however, recent studies have raised concerns that “in vitro” amenability may not always reflect “in vivo” amenability, and some findings on real-life studies have contrasted with the results of the pivotal clinical trials. Moreover, both FD specific therapies present limitations, and the attempt to correct the enzymatic deficiency, either by enzyme exogenous administration or enzyme stabilization with a chaperone, has not shown to be able to fully revert FD pathology and clinical manifestations. Therefore, several new therapies are under research, including new forms of ERT, substrate reduction therapy, mRNA therapy, and gene therapy. In this review, we provide an overview of the state-of-the-art on the currently approved and emerging new therapies for adult patients with FD.