New drugs available for Fabry disease.

Abstract

Background: Fabry disease (FD) is an X-linked genetic condition caused by variants in the GLA gene, leading to a deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) and the accumulation of complex glycosphingolipids such as globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). The systemic disorder primarily affects the cardiovascular, renal, and nervous systems, resulting in decreased life expectancy. The timing of treatment initiation and optimal dosing play crucial roles in improving outcomes and quality of life (QoL) in Fabry patients. Available FD treatments include enzyme replacement therapy (ERT) with agalsidase alfa, aglasidase beta, and pegunigalsidase alfa, as well as oral chaperone therapy with migalastat, which can all stabilize or reduce the disease burden.

Summary: This review focuses exclusively on newly available drugs and future therapeutic approaches for treating FD, including migalastat, pegunigalsidase alfa, substrate reduction therapy (SRT), and gene therapy. Migalastat provides benefits such as oral administration and non-immunogenicity; however, it is only appropriate for patients with "amenable" GLA variants. The recently approved pegunigalsidase alfa is a pegylated form of α-Gal A manufactured in plant cell cultures, with apparent reduced immune response and prolonged circulating half-life. SRT (venglustat, lucerastat) reduces Gb3 synthesis, helping to normalize metabolic processes while offering certain advantages such as oral administration, non-immunogenic properties, and the possible crossing of the blood-brain barrier. Clinical trials in human and animal model studies are currently investigating ex-vivo and in-vivo gene therapy techniques, showing positive early outcomes. Messages: The ongoing development of novel treatments for Fabry disease suggests that patients will soon have access to a wider array of therapies, enabling more individualized care approaches. Although a definitive FD cure hasn't been achieved and the expense of combining therapies remains challenging, new therapeutic options such as gene and mRNA-based treatments show promise, though more research is needed.