Current and Investigational Therapeutics for Fabry Disease

Abstract

Fabry disease (FD) is an X-linked lysosomal storage disease caused by a deficiency in the lysosomal enzyme a-galactosidase (a-GAL). This in turn leads to the buildup of globotriaosylceramide, resulting classically in progressive kidney disease, peripheral neuropathy, early-onset cerebrovascular disease, gastrointestinal symptoms, hypertrophic cardiomyopathy, arrhythmias, corneal whorls, and angiokeratomas. The diagnosis of FD relies on identification of a low a-GAL enzyme activity, identification of a genetic mutation, or histologic evidence of disease. With more than 900 mutations identified, there is phenotypic variability deriving from both mutational effects as well as the effect of skewed X-inactivation in females. Treatment of this disease has relied on intravenous replacement of the deficient enzyme with agalsidase a or agalsidase b. However, treatment options for some patients with FD have recently expanded, with the approval of migalastat, an oral molecular chaperone. In addition to chaperone-based therapies, there are several additional therapies under development that could substantially reshape treatment options for patients with FD. Four approaches to gene therapy, through both ex vivo and in vivo methods, are under development. Another approach is through the administration of a-GAL mRNA to help stimulate production of a-GAL, which is another unique form of therapy. Finally, substrate reduction therapies act as inhibitors of glucosylceramide synthase, thus inhibiting the production of GB-3, promise another oral option to treat FD. This article will review the literature around current therapies as well as these newer therapeutics agents in the pipeline for FD.

Impact of COVID-19 pandemic on patients with Fabry disease: An Italian experience

“…To date, the treatment options for this genetic disease include intravenous (i.v.) infusion of enzyme replacement therapy (ERT) with agalsidase alfa or agalsidase beta every other week, and oral therapy with the pharmacological chaperone migalastat [ 3 ]. Moreover, clinical trials to evaluate the efficacy of pegunigalsidase alfa, a pegylated dimerized version of agalsidase alfa, infused at two different doses either every other week or monthly, are currently ongoing [ 3 ].…”

The rapidly evolving view of lysosomal storage diseases

“…For its effect on this early step of the glycosphingolipid biosynthetic pathway, Miglustat has also been proposed for the treatment of GM1 and GM2 gangliosidoses, with a slowed disease progression (Poswar et al , 2019; Fischetto et al , 2020), and is approved for the treatment Niemann‐Pick disease type, in which gangliosides GM2, GM3 gangliosides, and other glycosphingolipids play a role in the pathogenesis of neurological manifestations (Zervas et al , 2001). Other substrate‐reducing molecules are now in clinical development or approved for the treatment of Gaucher and Fabry disease, such as eliglustat tartrate, venglustat, and lucerastat (Felis et al , 2019; Poswar et al , 2019). This approach is attractive, as substrate‐reducing drugs are small molecules that reach therapeutic concentrations in tissues, including those that are difficult to reach by ERT, and can be taken orally, with minimal impact on patient quality of life.…”

Renal Manifestations of Fabry Disease: A Narrative Review

“… 54 Gene therapy and gene editing are also under development and may represent a promising safe alternative. 55 , 56 …”