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Infiltrative Cardiomyopathies
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Arthur Qi, Quynh Nguyen, Haran Yogasundaram, Gavin Y. Oudit
More recently, the iminosugar 1-deoxygalactonojirimycin (migalastat hydrochloride) has been approved for treatment of FD. It functions as a pharmacological chaperone and potent inhibitor of α-Gal A that binds the active site of the enzyme and improves its folding, stability, and lysosomal trafficking, after which it dissociates to allow an α-Gal A to catalyze the degradation of Gb3.31–33 Migalastat has been shown to cause durable increase in α-Gal A activity and significant reduction in glycosphingolipid levels in lysates from the kidneys, heart, and liver.31,32 Migalastat presents several advantages over ERT: its ability to cross the blood-brain barrier, oral rather than intravenous route of administration, and higher volume of distribution, which may enhance α-Gal A levels in multiple organs.26,33 However, migalastat only improves the stability and activity of α-Gal A in patients with amenable missense mutations causing misfolding of α-Gal A, 78 of which have been identified to date.31,32 Therefore, many nonsense and missense mutations resulting in both classic and variant phenotypes are not amenable to this treatment.
Fabry disease
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Activation of mutant enzymes by compounds such as 1-deoxygalactonojirimycin are being explored in novel approaches to the treatment of glycosphingolipidoses [76, 77]. This compound is an inhibitor of lysosomal α-galactosidase but, in low doses, it serves as an activator increasing activity in mutant enzymes up to 14 times. These compounds have been referred to as chemical chaperones, because they accelerate transport and maturation of the enzyme molecule. Chaperone therapy with migalastat was found to confer results equal to enzyme replacement therapy [78, 79]. Renal, cardiac, or cerebrovascular events continued to occur in both groups but results were encouraging for mono therapy. A pharmacogenetic test in which mutations were expressed in HEK cells identified mutations amenable to treatment with migalastat [80].
Migalastat for the treatment of Fabry disease
Published in Expert Opinion on Orphan Drugs, 2018
Gere Sunder-Plassmann, Raphael Schiffmann, Kathleen Nicholls
Fabry disease is a rare X-linked disorder caused by lysosomal α-galactosidase A deficiency. Accumulation of α-galactosidase A substrates can cause progressive multiorgan damage. ERT is current standard therapy for Fabry disease, although many patients progress despite treatment. Migalastat is a small-molecule pharmacological chaperone that is currently approved for the treatment of Fabry disease in patients with amenable GLA mutations. Pivotal Phase-III studies indicated that migalastat effectively reduced disease substrate and demonstrated efficacy against both renal and cardiac manifestations. Direct comparison between migalastat and ERT indicated the former may be associated with better cardiac outcomes; however, the superiority of migalastat to ERT for renal outcomes and in a broader Fabry disease population has not been demonstrated. Migalastat was generally well tolerated in Phase-I, -II and -III trials; no observed cases of migalastat-related serious AEs were reported. Taken together, available clinical data to date indicate that migalastat is an effective treatment option for patients with Fabry disease and amenable GLA mutations.