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Pharmacological chaperone therapy by active-site-specific chaperones in Fabry disease: in vitro and preclinical

D P Germain1, J-Q Fan

  • 1Laboratoire de Génétique et Biologie Cellulaire, Université de Versailles-St Quentin en Yvelines, Versailles, France. dominique.germain@rpc.aphp.fr

International Journal of Clinical Pharmacology and Therapeutics
|December 31, 2009
PubMed

Insights

Competitive inhibitors can act as chaperones to improve protein folding in genetic disorders. This approach enhances enzyme activity and reduces degradation, offering a potential therapeutic strategy for conditions like Fabry disease.

Area of Science:

  • Biochemistry
  • Genetics
  • Pharmacology

Background:

  • Genetic disorders often stem from protein misfolding and premature degradation in the endoplasmic reticulum (ER).
  • ER-associated degradation (ERAD) can lead to loss of function even when protein functionality is not directly impaired by mutation.
  • Active-site-specific chaperones, particularly competitive inhibitors at sub-inhibitory concentrations, can assist in proper protein folding.

Purpose of the Study:

  • To investigate the potential of competitive inhibitors as active-site-specific chaperones for misfolded proteins.
  • To evaluate the efficacy of 1-deoxygalactonojirimycin in enhancing residual enzyme activity in Fabry disease models.
  • To assess the therapeutic potential of oral 1-deoxygalactonojirimycin in vivo.

Main Methods:

  • Utilized sub-inhibitory concentrations of competitive inhibitors as active-site-specific chaperones.
  • Assessed the enhancement of mutant lysosomal enzyme folding and escape from ERAD.
  • Measured residual enzyme activity in cultured cells and in transgenic mouse models of Fabry disease.

Main Results:

  • 1-deoxygalactonojirimycin effectively enhanced residual alpha-galactosidase A (alpha-gal A) activity in patient-derived cell lines.
  • Oral administration of 1-deoxygalactonojirimycin increased alpha-gal A activity in major tissues of R301Q mutant human alpha-gal A transgenic mice.
  • The compound promoted escape from ER-associated degradation, improving enzyme trafficking and activity.

Conclusions:

  • Competitive inhibitors can serve as effective active-site-specific chaperones to counteract protein misfolding defects.
  • 1-deoxygalactonojirimycin shows promise as a therapeutic agent for Fabry disease by enhancing mutant alpha-gal A activity.
  • This strategy offers a viable approach to increase functional enzyme levels in genetic disorders caused by protein misfolding and ERAD.

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