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Novel Therapies

Andreotti G, Citro V, Correra A et al.

Università Federico II, Naples, Italy.

 Biochim Biophys Acta 2014;1840:1214–24.

Editor’s note: Fabry disease (FD) is caused by mutations that result in deficiency or instability of the enzyme α-galactosidase A (α-gal A). In certain cases, pharmacological chaperones can be used to stabilize the α-gal A and treat the disease. Such agents are typically identified through their stabilizing activity on wild-type α-gal A, but will not be effective in all mutant forms of the enzyme. This makes the evaluation of different chaperones difficult, as >400 FD mutations have been described, many occurring only in single individuals. The standard thermodynamic assays that are useful in evaluating potential chaperones for the wild-type enzyme are unlikely to be helpful for these rare mutant forms, as they require large quantities of the enzyme.

The current authors aimed to overcome this problem by determining the concentration of urea required to induce half-maximal folding of α-gal A and using this as a proxy of protein stability. This technique allowed the testing of protein stability in cell extracts containing only small amounts of the enzyme, in the presence or absence of different chaperones. This technique may prove to be useful in the development of individualized therapies for patients with FD, and indeed other lysosomal storage diseases.

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