New treatment Fabry disease

New treatment for Fabry disease

2:38 AM, 2nd January 2012
New treatment for Fabry disease
New treatment for Fabry disease

MASSACHUSETTS, US:  A research team led by Scott Garman, Biochemist, University of Massachusetts Amherst has discovered a key interaction at the heart of a promising new treatment for a rare childhood metabolic disorder known as Fabry disease. People born with Fabry disease have a faulty copy of a single gene that codes for the alpha-galactosidase (α-GAL) enzyme; one of the cell’s ‘recycling’ machines. When it performs normally, α-GAL breaks down an oily lipid known as GB3 in the cell’s recycling center, or lysosome. But when it underperforms or fails, Fabry symptoms result. Patients may survive to adulthood, but the disorder leads to toxic lipid build-up in blood vessels and organs that compromise kidney function or may lead to heart disease.

At present, enzyme replacement therapy is the only FDA-approved treatment for such lysosomal storage disorders as Fabry, Pompe and Gaucher diseases, but enzyme replacement therapy requires a complicated and expensive process to purify and replace the damaged α-GAL enzyme. “Instead of replacing the damaged enzyme, an alternative route called pharmacological chaperone (PC) therapy is currently in Phase III clinical trials for Fabry disease. It relies on using smaller, ‘chaperone’ molecules to keep proteins on the right track toward proper folding, but their biochemical mechanism is not well understood,” said Garman. Use in PC therapy could one day be far less expensive than enzyme replacement therapy and can be taken orally.

“The interactions we looked at are exactly the things occurring in the clinical trial right now. The same concept is now being applied to other protein-folding diseases such as Parkinson’s and Alzheimer’s disease. Many medical researchers are trying to keep proteins from misfolding by using small chaperone molecules. Our studies have definitely advanced the understanding of how to do that,” Garman added.

Garman and colleagues compared the ability of two small chaperone molecules, galactose and 1-deoxygalactononjirimycin (DGJ) to stabilize the α-GAL protein, to help it resist unfolding in different conditions such as high temperature and different pH levels. They found that each chaperone has very different affinities. DGJ binds tightly and galactose binds loosely to the α-GAL, yet they differ in only two atomic positions. Tight is better, because use of less drug for treatment.

UMass Amherst team used X-ray crystallography to create three-dimensional images of all atoms in the protein to understand how it carries out its metabolic mission. They also found a new binding site for small molecules on human α-GAL that had never been observed before. Crystallography on the two chaperones bound to the α-GAL enzyme showed that a single interaction between the enzyme and DGJ was responsible for DGJ’s high affinity for the enzyme, indicating that one atomic interaction is responsible for DGJ’s high affinity.

“The iminosugar DGJ has high potency due to a single ionic interaction with α-GAL. Overall, our studies show that this small molecule keeps the enzyme from unfolding, or when it unfolds, the process happens more slowly, all of which you need in treating disease,” said Garman.

© University of Massachusetts Amherst News

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