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Novel Pharmacologial Chaperones for Improved Enzyme Replacement Therapy


Enzyme replacement therapy (ERT) is a very costly therapeutic treatment. The costs of ERT starting in the symptomatic stage are between € 9 - € 10 million (£ 7.9 - £ 8.8 million, $ 13.0 - $ 14.5 million) during a patient's lifetime. The combination of small pharmacological chaperones (PCs) with ERT has shown a synergic effect in improved enzyme activity and reduction of toxic metabolites. Therefore, it is expected that the co-treatment PC-ERT may reduce the amount of ERT necessary to achieve the desired pharmacological effect and therefore may lower lysosomal storage diseases (LSDs) treatment costs.

Technology Overview

Leiden University researchers have developed a new class of pharmacological chaperones (PCs) named cyclosulfamidates. α-galactose configured cyclosulfamidate reacts reversibly with α-gal A and stabilized the enzyme in vitro and in situ. They have shown that α-cyclosulfamidate is able to stabilize the recombinant human enzyme in vitro and in situ cell experiments and increased α-gal A activity is observed in the medium of the cells co-treated with PC and recombinant α-gal A. This increase is translated in a slightly higher activity in the cells treated with ERT and PC combination for 24 h and 4 days.

The researchers also quantified the amount of Gb3 and lysoGb3 in treated and untreated cultured fibroblast lysates and they interestingly observed that the combination of ERT and α-cyclosulfamidate has a similar effect that ERT effect when compared to ERT alone. In conclusion, herein they describe the potential of a new small molecule, α-cyclosulfamidate, as stabilizer of α-gal A and its potential as new treatment for Fabry patients in combination with ERT.

A structure activity relationship (SAR) on the galactose configured cyclosulfamidate is ongoing. In addition, glucose configured cyclosulfamidates as new potential pharmacological chaperones for Pomple and Gaucher Disease are comparatively studied.


This invention provides various combinations of enzyme replacement therapy or (multi) gene therapies with a pharmacological chaperone for the treatment of lysosomal storage diseases and glycosidase deficiency related diseases, particularly Fabry, Gaucher or Pompe disease. This combination optimizes the clinical benefit, ie, reduced enzyme treatment, while minimizing disadvantages associated with ERT.

Key benefits

  • The combination of PC and ERT may reduce the amount of ERT necessary to achieve the desired pharmacological effect and therefore may lower the LSDs treatment costs.
  • When administered in combination with enzyme to cells, the compound stabilizes the recombinant enzyme and prevents its degradation, which is translated in an increased of α-gal A activity (>x2) when compared to fibroblasts treated with ERT alone.


Patent application submitted

Further information

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