Search

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.

Chaperone therapy was introduced first as a new molecular therapeutic approach to lysosomal diseases. In a recent article, I reviewed the development of chaperone therapy mainly for lysosomal diseases. Then, more data have been collected particularly on non-lysosomal protein misfolding diseases. In this short review, I propose the concept of chaperone therapy to be classified into two different therapeutic approaches, for pH-dependent lysosomal, and pH-independent non-lysosomal protein misfolding diseases. The concept of lysosomal chaperone therapy is well established, but the non-lysosomal chaperone therapy is heterogeneous and to be investigated further for various individual diseases. As a whole, these two-types of new molecular therapeutic approaches will make an impact on the treatment of a wide range of pathological conditions caused by protein misfolding, not necessarily lysosomal but also many non-lysosomal diseases caused by gene mutations, metabolic diseases, malignancy, infectious diseases, and aging. The concept will open a completely new aspect of protein therapy in future., Competing Interests: Declaration of Competing Interest The autho declares no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

In lysosomal diseases, enzyme deficiency is caused by misfolding of mutant enzyme protein with abnormal steric structure that is expressed by gene mutation. Chaperone therapy is a new molecular therapeutic approach primarily for lysosomal diseases. The misfolded mutant enzyme is digested rapidly or aggregated to induce endoplasmic reticulum stress. As a result, the catalytic activity is lost. The following sequence of events results in chaperone therapy to achieve correction of molecular pathology. An orally administered low molecular competitive inhibitor (chaperone) is absorbed into the bloodstream and reaches the target cells and tissues. The mutant enzyme is stabilized by the chaperone and subjected to normal enzyme proteinfolding (proteostasis). The first chaperone drug was developed for Fabry disease and is currently available in medical practice. At present three types of chaperones are available: competitive chaperone with enzyme inhibitory bioactivity (exogenous), non-competitive (or allosteric) chaperone without inhibitory bioactivity (exogenous), and molecular chaperone (heat shock protein; endogenous). The third endogenous chaperone would be directed to overexpression or activated by an exogenous low-molecular inducer. This new molecular therapeutic approach, utilizing the three types of chaperone, is expected to apply to a variety of diseases, genetic or non-genetic, and neurological or non-neurological, in addition to lysosomal diseases., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Fabry disease is caused by α-galactosidase A deficiency. Substrates of this lysosomal enzyme accumulate, resulting in cellular dysfunction. Patients experience neuropathic pain, kidney failure, heart disease, and strokes., Scope of Review: The clinical picture and molecular features of Fabry disease are described, along with updates on disease mechanisms, animal models, and therapies., Major Conclusions: How the accumulation of α-galactosidase A substrates, mainly glycosphingolipids, leads to organ damage is incompletely understood. Enzyme replacement and chaperone therapies are clinically available to patients, while substrate reduction, mRNA-based, and gene therapies are on the horizon. Animal models exist to optimize these therapies and elucidate disease mechanisms for novel treatments., General Significance: Recent newborn screening studies demonstrate that Fabry disease is the most common lysosomal storage disease. As many countries now include Fabry disease in their screening panels, the number of identified patients is expected to increase significantly. Better knowledge of disease pathogenesis is needed to improve treatment options., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Fabry disease (FD) is an X-linked lysosomal storage disease caused by a deficiency in the lysosomal enzyme α-galactosidase (α-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 α-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 α or agalsidase β. 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 α-GAL mRNA to help stimulate production of α-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., (© 2019 International Society of Nephrology. Published by Elsevier Inc.)

Anderson-Fabry disease (AFD) is a rare X-linked inherited metabolic disorder which results in a deficiency or absence of the enzyme α-galactosidase A, leading to the accumulation of glycosphingolipids in various cells and organs including the heart. Cardiac involvement is common and results in increased myocardial inflammation, left ventricular hypertrophy (LVH), and myocardial fibrosis. Echocardiography and cardiovascular magnetic resonance (CMR) offer distinctive and often complementary use to assist in the diagnosis and monitoring pharmacologic therapy in AFD, including detection of the AFD cardiac phenotype, differentiation from other forms of LVH, and patient selection for therapeutic intervention. Advanced cardiac imaging holds promise in subclinical detection of AFD-related abnormalities as well as disease staging and prognostication., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)