Researchers develop molecule that binds to GAA enzymes key to progress of Pompe disease

Researchers at Leiden University have made a breakthrough in the study of the hereditary Pompe disease. Together with colleagues in York, they have developed a molecule that binds to the enzyme that is key to the progress of the disease. The findings have been published in ACS Central Science.

Pioneering technique

The enzyme in question is lysosomal alpha glucosidase, the so-called GAA enzyme. Leiden researchers Hermen Overkleeft and Hans Aerts and their teams have developed a pioneering technique whereby synthetically developed molecules (also known as activity-based probes) bind exclusively and irreversibly to the GAA enzymes, thus making them visible. This makes it possible to chart the number of enzymes and how they function. The evidence that the molecule does actually bind to the GAA enzymes and in the way the researchers want was provided by Liang Wu and Gideon Davies at the University of York.

Potental applications

This revolutionary method has particular significance for diagnostics: it is now possible to determine whether the enzyme is present or not. But Overkleeft, Leiden Professor of Bio-Organic Synthesis, sees other potential applications: 'Once you have identified whether the enzyme is active in a patient, you can in principle then determine how effective it is by administering a recombinant enzyme, a process known as enzyme replacement therapy, or by raising the level of activity of the body's own enzyme - pharmacological chaperone therapy.' Overkleeft stresses firmly that a cure for Pompe disease is nowhere in sight yet, but this discovery may speed up the development of an effective medicine.

Pompe disease

Pompe disease is a so-called lysosomal storage disorder. It is a rare, hereditary disease that can be passed from parents to children and can affect anyone at any age. Pompe is a neuromuscular disease, the most common characteristics being muscle weakness and respiratory problems. The condition was brought into the public eye in 2010 as a result of the film Extraordinary Measures in which Harrison Ford plays the main character.

Broader palette

The researchers want to broaden their palette of molecules for enzymes whose malfunctioning causes other lymosomal storage diseases. Again, the aim will be to assist with diagnostics, but in future they may also look at methods of helping to speed up drug development. The diseases in question are Schindler, Gaucher and Fabry.


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