Lyso−Gb3is not a predictive biomarker of treatment response in migalastat-treated patients with migalastat-amenable variants

Abstract

Fabry disease (FD) is an X-linked disorder caused by mutations in GLA gene responsible for coding of the lysosomal enzyme alpha-galactosidase A(α-GAL). The resultant accumulation of globotriaosylceramide (Gb-3) leads to multisystemic disease including progressive chronic kidney disease, hypertrophic cardiomyopathy, stroke, angiokeratomas and corneal whorls. Current treatments include enzyme replacement therapy (ERT), along with recent advent of chaperone therapy. ERT has not shown to have dramatic improvement in outcomes for all organ systems, with benefit mostly seen in kidney disease and reduction in left ventricular hypertrophy. ERT, however, is associated with formation of anti-drug antibodies and requirement of long-term venous access, while chaperone therapy can only be used in amenable mutations. 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). This review encapsulates literature pertaining to current and investigational therapies for FD.