Possible New Treatment for Fabry Disease

Author: University of Massachusetts at Amherst
Published: 2011/12/22 - Updated: 2021/11/12
Contents: Summary - Main - Related Publications

Synopsis: Promising new treatment for a rare childhood metabolic disorder known as Fabry disease. Fabry Disease, also known as Fabry's disease, Anderson-Fabry disease, angiokeratoma corporis diffusum and alpha-galactosidase A deficiency, is a rare X-linked recessive lysosomal storage disease, which can cause a wide range of systemic symptoms. The interactions we looked at are exactly the things occurring in the clinical trial right now, further, the same concept is now being applied to other protein-folding diseases such as Parkinson's and Alzheimer's disease.

Main Digest

A research team led by biochemist Scott Garman at the 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. The discovery will help understanding of other protein-folding disorders such as Alzheimer's, Parkinson's and Huntington's diseases, as well.

Fabry Disease, also known as Fabry's disease, Anderson-Fabry disease, angiokeratoma corporis diffusum and alpha-galactosidase A deficiency, is a rare X-linked recessive (inherited) lysosomal storage disease, which can cause a wide range of systemic symptoms. The disease is named after one of its discoverers, Johannes Fabry.

People born with Fabry disease have a faulty copy of a single gene that codes for the alpha-galactosidase enzyme, one of the cell's "recycling" machines. When it performs normally, it breaks down an oily lipid known as GB3 in the cell's recycling center, or lysosome. But when it under-performs 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 lead to heart disease, for example.

The faulty gene causes its damage by producing a mis-folded protein, yielding an unstable, poorly functioning enzyme. Like origami papers, these proteins are unfolded to start and only become active when folded into precise shapes. At present, enzyme replacement therapy (ERT) is the only FDA-approved treatment for such lysosomal storage disorders as Fabry, Pompe and Gaucher diseases, but ERT requires a complicated and expensive process to purify and replace the damaged enzyme, and it must be administered by a physician.

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, says Garman.

Now, he and colleagues report results of a thorough exploration at the atomic level of the biochemical and biophysical basis of two small molecules for potentially stabilizing the enzyme. He says their use in PC therapy could one day be far less expensive than the current standard, ERT, and can be taken orally.

This work, which improves knowledge of a whole class of molecular chaperones, represents the centerpiece of UMass Amherst student Abigail Guce's doctoral thesis and was supported by the National Institutes of Health. Other members of the team are graduate students Nat Clark and Jerome Rogich.

"The interactions we looked at are exactly the things occurring in the clinical trial right now," Garman says. Further, "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 mis-folding by using small chaperone molecules. Our studies have definitely advanced the understanding of how to do that."

In their current paper, Garman and colleagues compare the ability of two small chaperone molecules, galactose and 1-deoxygalactononjirimycin (DGJ) to stabilize the 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, yet they differ in only two atomic positions.

"Tight is better, because you can use less drug for treatment," Garman says. "We now can explain DGJ's high potency, its tight binding, down to individual atoms."

In earlier studies as in the current work, the UMass Amherst team used their special expertise in 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 I-GAL that had never been observed before.

Crystallography on the two chaperones bound to the I-GAL enzyme showed that a single interaction between the enzyme and DGJ was responsible for DGJ's high affinity for the enzyme. Other experiments also showed the ability of the 11- and 12-atom chaperones to protect the large, 6,600-atom I-GAL from unfolding and degradation.

For the first time, by making a single change in one amino acid in protein, they forced the DGJ to bind weakly, indicating that one atomic interaction is responsible for DGJ's high affinity.

"It was surprising to find these two small molecules that look very much the same have very different affinities for this enzyme," says Garman, "and we now understand why. The iminosugar DGJ has high potency due to a single ionic interaction with 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."

The UMass Amherst team plans to next use the principles, assays and experiments they developed here on enzymes defective in other human diseases to examine new therapies for them and related disorders.

Attribution/Source(s):

This quality-reviewed publication pertaining to our Medical Research News section was selected for circulation by the editors of Disabled World due to its likely interest to our disability community readers. Though the content may have been edited for style, clarity, or length, the article "Possible New Treatment for Fabry Disease" was originally written by University of Massachusetts at Amherst, and submitted for publishing on 2011/12/22 (Edit Update: 2021/11/12). Should you require further information or clarification, University of Massachusetts at Amherst can be contacted at the umass.edu website. Disabled World makes no warranties or representations in connection therewith.

📢 Discover Related Topics


👍 Share This Information To:
𝕏.com Facebook Reddit

Page Information, Citing and Disclaimer

Disabled World is an independent disability community founded in 2004 to provide disability news and information to people with disabilities, seniors, their family and/or carers. You can connect with us on social media such as X.com and our Facebook page.

Permalink: <a href="https://www.disabled-world.com/news/research/fabry-disease.php">Possible New Treatment for Fabry Disease</a>

Cite This Page (APA): University of Massachusetts at Amherst. (2011, December 22). Possible New Treatment for Fabry Disease. Disabled World. Retrieved March 29, 2024 from www.disabled-world.com/news/research/fabry-disease.php

Disabled World provides general information only. Materials presented are never meant to substitute for qualified professional medical care. Any 3rd party offering or advertising does not constitute an endorsement.