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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
Substrate reduction therapy, specifically eliglustat tartrate (Genz-112638), is an emerging treatment for FD, and represents an alternative approach to reducing glycosphingolipid levels that has proven effective in treating Gaucher disease, another glycosphingolipidosis.34 Through inhibition of the glucosylceramide synthase enzyme that catalyzes the first step of glycosphingolipid synthesis, substrate reduction therapy reduces upstream production of glycosphingolipids.23 In FD mouse models, substrate reduction therapy has been shown to reduce Gb3 and lyso-Gb3 levels in the kidneys, heart, and liver, with maximal effect when used in conjunction with ERT.23,27 However, eliglustat was ineffective at lowering glycosphingolipid levels in the brain due to its poor ability to cross the blood-brain barrier.35 A novel oral glucosylceramide synthase inhibitor, ibiglustat (Genz-682452), was designed to cross the blood brain barrier and has shown efficacy in lowering Gb3 and lyso-Gb3 levels in the brain, especially in conjunction with ERT.34
Tay-Sachs disease/hexosaminidase A deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Pyrimethamine has been found to increase hexosaminidase activity, slowing the progression of late onset Tay-Sachs disease [67]. Substrate reduction therapy has been used in mice with N-butyldeoxynojirimycin [68]. Sialidase has been used in vivo to deplete cultured Tay-Sachs cells of GM2 ganglioside [69]. Miglustat, an inhibitor of glucosylceramide synthase, which catalyzes the first step in the syntheses of GM2 ganglioside, is also under investigation [70]. Creation of a novel variant of HexA incorporating β subunit sequences and an adenovirus vector has been shown to degrade GM2 storage in mice. Manipulation of cellular folding in certain variant HexA cells was found to alter mutant degradation [71].
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
Enzyme replacement therapy (usually fortnightly intravenous infusion) is the treatment of choice in type 1 and 3 disease and primarily improves the visceral and marrow symptoms. BMT has been partially effective but carries significant morbidity. Substrate reduction therapy has shown benefits and theoretically may offer better tissue penetration. Bone disease may be helped by the use of bisphosphonates. Unfortunately supportive therapy is all that is available for the acute neuronopathic form of the disease.
The budget impact of enzyme replacement therapy in type 1 Gaucher disease in the United States
Published in Journal of Medical Economics, 2022
Sepehr Farahbakhshian, Timothy J. Inocencio, Gregory Poorman, Ekaterina Wright, Ravi Ramesh Pathak, Michael Bullano
Patients with GD have a lysosomal enzyme deficiency resulting in a buildup of glucocerebroside1. For patients with symptomatic disease, long-term treatment with either ERT or substrate reduction therapy is needed8. ERT provides the enzymes needed to break down glucocerebrosides whereas substrate reduction therapy blocks the production of glucocerebrosides. Currently, several formulations of ERT are administered intravenously, usually once every 2 weeks. The three commercially available formulations of ERTs are not biosimilar; similarities and dissimilarities between imiglucerase, velaglucerase alfa, and taliglucerase alfa have been presented earlier22. Of the available ERTs, only velaglucerase alfa is produced by gene activation via a human cell line22. The resulting protein produced is identical in amino acid sequence to the naturally occurring enzyme. Differences in glycosylation patterns and manufacturing process from a human cell line may explain the lower immunogenicity of velaglucerase alfa, contributing to its improved efficacy22. More recently, studies have shown a steeper and faster decrease of lyso-Gb1 levels, a key GD-specific biomarker in velaglucerase alfa as compared to other ERTs6.
Glucocerebrosidase as a therapeutic target for Parkinson’s disease
Published in Expert Opinion on Therapeutic Targets, 2020
Yu Chen, Richard Sam, Pankaj Sharma, Lu Chen, Jenny Do, Ellen Sidransky
After several decades of preclinical work, the first effective therapy for Gaucher disease, enzyme replacement therapy (ERT) became available in 1991 [15]. While initially a placental derived product, a recombinant form of the enzyme, imiglucerase was soon developed, and currently there are several approved forms of the recombinant enzyme. Each successfully reverses the anemia, thrombocytopenia and hepatosplenomegaly associated with Gaucher disease, remarkably improving the current clinical course for patients with Gaucher disease. However, ERT is a treatment, but not a cure, and it requires regular intravenous infusions of the costly enzyme. Furthermore, it does not cross the blood-brain -barrier (BBB), and thus is not effective in treating manifestations specifically encountered in patients with neuronopathic forms of the disease. A second therapeutic approach is substrate reduction therapy (SRT) targeting glucosylceramide synthesis, which also effectively reduces non-neurologic manifestations of Gaucher disease. However, since both ERT and SRT are extremely expensive and do not reverse neuronopathic Gaucher disease, there remains a strong rationale for developing new therapeutic strategies for patients with Gaucher disease.
Cyclodextrin encapsulation of daidzein and genistein by grinding: implication on the glycosaminoglycan accumulation in mucopolysaccharidosis type II and III fibroblasts
Published in Journal of Microencapsulation, 2018
Barbara Fumić, Jasna Jablan, Dominik Cinčić, Marijana Zovko Končić, Mario Jug
Substrate reduction therapy (SRT) was proposed as a possible treatment that could be effective in the management of CNS-related symptoms of MPS. Genistein (GEN), an isoflavone, inhibits GAG synthesis in fibroblasts of patients with MPS I, II and III by inhibiting the tyrosine-specific protein kinase activity of epidermal growth factor (EGF) receptor that is required for full expression of genes coding for enzymes involved in GAG production (Delgadillo et al., 2011; Moskot et al., 2015). GEN can cross the blood–brain barrier (De Ruijter et al., 2012), thus it was proposed as a potential therapy in the reduction of substrates in patients with MPS. Recent studies showed that other flavonoids, such as daidzein (DAD) and kaempferol (KAM) also inhibit GAG synthesis significantly, reducing GAG storage in MPS III fibroblasts (Kloska et al., 2011). Furthermore, some experiments clearly suggested that such specific kind of SRT based on GEN could be used together with ERT for MPS treatment (Gabig-Cimińska et al., 2015).