Effect of Ambroxol chaperone therapy on Glucosylsphingosine (Lyso-Gb1) levels in two Canadian patients with type 3 Gaucher disease

Charkhand, Behshad; Scantlebury, Morris H.; Narita, Aya; Zimran, Ari; Al-Hertani, Walla

doi:10.1016/j.ymgmr.2019.100476

Cited by 23 publications

(27 citation statements)

References 6 publications

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“…Recently, a study assessed the effect of oral ambroxol supplementation in combination with ERT and an improvement in glucosylsphingosine levels on dried blood spots samples from GD2 and GD3 patients was observed. However, a variable clinical response was observed in the ambroxol treated patients, suggesting a genotype-dependent chaperone effect of this PC [58]. Non-inhibitory chaperones (i.e., allosteric binding molecules) have also been described as potential PCs for GD, since they can increase GCase activity, reduce substrate accumulation, and restore chemotaxis [59].…”

Section: Use Of Pharmacological Chaperones In Lsdsmentioning

confidence: 96%

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Diaz

Castillo

Rodríguez-López

et al. 2019

IJMS

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The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein aggregation, and defective transport to the lysosomes. It this sense, it has been proposed that the use of small molecules, called pharmacological chaperones (PCs), can restore the folding, trafficking, and biological activity of mutated enzymes. PCs have the advantages of wide tissue distribution, potential oral administration, lower production cost, and fewer issues of immunogenicity than enzyme replacement therapy. In this paper, we will review the advances in the identification and characterization of PCs for the MPS. These molecules have been described for MPS II, IVA, and IVB, showing a mutation-dependent enhancement of the mutated enzymes. Although the results show the potential of this strategy, further studies should focus in the development of disease-specific cellular models that allow a proper screening and evaluation of PCs. In addition, in vivo evaluation, both pre-clinical and clinical, should be performed, before they can become a real therapeutic strategy for the treatment of MPS patients.

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Section: Use Of Pharmacological Chaperones In Lsdsmentioning

confidence: 96%

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Diaz

Castillo

Rodríguez-López

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

Section: Use Of Pharmacological Chaperones In Lsdsmentioning

confidence: 89%

Pharmacological Chaperones for the Mucopolysaccharidoses

Jc¹,

J²,

Rodríguez-López³

et al. 2019

Preprint

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The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein aggregation, and defective transport to the lysosomes. The use of small molecules, called pharmacological chaperones (PCs), that can restore the folding, trafficking and biological activity of mutated enzymes has been extensively explored in LSDs as a therapeutic alternative. PCs have the advantage of wide tissue distribution, potential oral administration, lower production cost, and fewer issues of immunogenicity. In this paper, we will review the advances in the identification and characterization of PCs for the MPS. These molecules, mainly based in molecules mimicking the enzyme substrates, have been described for MPS II, IVA, and IVB, showing a mutation-dependent enhancement of the mutated enzymes. Although the results show the potential of this strategy, further studies should focus in the development of disease-specific cellular models that allow a proper screening and evaluation of the identified PCs. In addition, in vivo evaluation, both pre-clinical and clinical, should be performed, before they can become a real therapeutic strategy for the treatment of MPS patients.

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“…One of these small molecules with the prediction of good BBB penetration, ambroxol, was identified as a pharmacological chaperone for GCase [48,49]. Ambroxol therapy also has an excellent safety record, even with high doses [50][51][52]. Ambroxol has unique chaperone characteristics: it works at neutral and acidic pH of the endoplasmic reticulum (ER) and lysosomes.…”

Section: Ambroxol Therapy For Gd Patients and Mitochondrial Functionmentioning

confidence: 99%

Altered Sphingolipids Metabolism Damaged Mitochondrial Functions: Lessons Learned From Gaucher and Fabry Diseases

Ivanova

2020

JCM

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Sphingolipids represent a class of bioactive lipids that modulate the biophysical properties of biological membranes and play a critical role in cell signal transduction. Multiple studies have demonstrated that sphingolipids control crucial cellular functions such as the cell cycle, senescence, autophagy, apoptosis, cell migration, and inflammation. Sphingolipid metabolism is highly compartmentalized within the subcellular locations. However, the majority of steps of sphingolipids metabolism occur in lysosomes. Altered sphingolipid metabolism with an accumulation of undigested substrates in lysosomes due to lysosomal enzyme deficiency is linked to lysosomal storage disorders (LSD). Trapping of sphingolipids and their metabolites in the lysosomes inhibits lipid recycling, which has a direct effect on the lipid composition of cellular membranes, including the inner mitochondrial membrane. Additionally, lysosomes are not only the house of digestive enzymes, but are also responsible for trafficking organelles, sensing nutrients, and repairing mitochondria. However, lysosomal abnormalities lead to alteration of autophagy and disturb the energy balance and mitochondrial function. In this review, an overview of mitochondrial function in cells with altered sphingolipid metabolism will be discussed focusing on the two most common sphingolipid disorders, Gaucher and Fabry diseases. The review highlights the status of mitochondrial energy metabolism and the regulation of mitochondria–autophagy–lysosome crosstalk.

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Effect of Ambroxol chaperone therapy on Glucosylsphingosine (Lyso-Gb1) levels in two Canadian patients with type 3 Gaucher disease

Cited by 23 publications

References 6 publications

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Pharmacological Chaperones for the Mucopolysaccharidoses

Altered Sphingolipids Metabolism Damaged Mitochondrial Functions: Lessons Learned From Gaucher and Fabry Diseases

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