Pharmacological chaperones: A promising new treatment for genetic diseases

Potential applications for Gaucher disease and Tay-Sachs disease

By Alexandria Daum


Every protein in a cell is sorted in the endoplasmic reticulum before it moves to other parts of the cell – think of it as a mailroom for proteins. If a piece of mail is missing an address, it’s thrown in the garbage. The same thing happens to defective proteins in a cell.

One way proteins can be defective is that they don’t fold into the right shape. But in many genetic diseases, including Gaucher disease and Tay-Sachs disease, a mutation prevents proteins from folding properly, but the proteins actually still work. If only they weren’t thrown in the garbage, they would be able to perform their proper function. That’s where a pharmacological chaperone, a small molecule that helps proteins fold, can assist.

“One of the most exciting aspects of this project is that we’re really at the cutting edge of the development of a novel group of therapeutic drugs,” says Dr. Lorne Clarke, a professor at the University of British Columbia and lead investigator on the GlycoNet project developing this therapy.

pharma-article2“If you isolate the protein and protect it from being degraded, it actually is active,” says Clarke. “For proteins taking too long to fold, chaperones encourage the proteins to fold and allow them to be escorted to where they should be – the lysosome.”

Clarke and co-investigator Dr. Stephen Withers are testing pharmacological chaperones in humanized mice models as potential treatments for Gaucher disease and Tay-Sachs disease, and so far they’ve had promising results. Their preliminary data for Gaucher disease indicated that their compounds resulted in a two-fold increase in the amount of proteins active in their mice. The next step will be tweaking their compounds.

“The molecules we have now are designed to be inhibitors. The inhibitor will hold the protein in the folded state in order for it to be targeted properly in the cell,” says Clarke. “But the inhibitors that we made are so good that they continue to inhibit the enzyme once it leaves the endoplasmic reticulum. The next step is making the inhibitor good in the endoplasmic reticulum, but poor in the lysosome where we want the enzyme to function properly.”

The hope is that by preserving the protein and preventing it from being degraded, it will ultimately work as intended, decreasing symptoms in patients.

“We specifically chose these disorders because we know the proteins still work in isolation,” adds Clarke. “Another exciting thing is the link between mutations in Gaucher disease and Parkinson’s disease. So chemical chaperones may be applicable for Parkinson’s.”

The genetic mutation that indicates a risk for Parkinson’s disease is the same mutation present in Gaucher disease, and so a link seems likely.

Gaucher disease is a genetic lipid storage disease that affects 1 in 50,000 people, resulting in liver malfunction, neurological complications, skeletal complications and more. While some treatments are already available for Gaucher disease, they are not effective for all patients. Tay-Sachs disease causes the deterioration of nerve cells in the brain and spinal cord and there is no known treatment. The most common form of Tay- Sachs disease occurs in infants who usually do not survive past early childhood.

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