Rapid Test Expected to Help in Developing Treatments for Sanfilippo

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A 30-minute, inexpensive, and easy-to-use test may help measure the activity of NDST1, one of the main enzymes involved in heparan sulfate, the sugar molecule that build ups and causes Sanfilippo syndrome, a new study shows.

Supported by funds from the Cure Sanfilippo Foundation and Sanfilippo Children’s Foundation, the new test may help assess the potential of new therapies targeting the NDST1 enzyme to treat the disease.

“Basic science research such as this creates the tools needed to develop treatments for the children. Cure Sanfilippo Foundation is honored to support this research and congratulates the team on their novel work” Cara O’Neill, chief science officer of Cure Sanfilippo Foundation, said in a press release.

The study, “Fluorometric coupled enzyme assay for N sulfotransferase activity of N-deacetylase/N-sulfotransferase (NDST),“ was published in Glycobiology.

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Sanfilippo syndrome, or mucopolysaccharidosis type III (MPS III), is a genetic disorder wherein toxic levels of heparan sulfate (HS), a complex sugar molecule, accumulate and cause damage, especially to the brain.

Therapies that target HS production and avoid its accumulation are likely to ease Sanfilippo symptoms.

N-deacetylase/N-sulfotransferases (NDSTs) are a group of four enzymes involved in generating heparan sulfate, with two of them — NDST1 and NDST2 — being the most relevant. Targeting NDST1 could prevent heparan sulfate from building up, slowing disease progression.

However, to find effective treatments researchers need tests that can reliably assess the effects of potential therapies in the activity of enzymes involved in heparan sulfate production.

Classical methods to access the activity of NDSTs activity involve radioactivity, which is costly and generates radioactive waste.

Researchers at the University of Toronto Scarborough, in Canada, and their colleagues have developed an easy and rapid method that measures NSDTs’ activity by combining enzymatic reaction with fluorescence.

The new test can assess the activity of mouse NDST1 (mNDST1) by measuring fluorescence levels at the end of the reaction. Moreover, it can be performed in a small volume and only takes 30 minutes.

The results showed that this method could accurately assess the activity of mNDST1 in breaking down a sugar molecule, called K5 capsular polysaccharide, which resembles the natural human precursor molecule of heparan sulfate.

“Our assay represents a cost-effective, low-volume, fast and sensitive solution for monitoring the activity of mNDST1,” the researchers wrote.

Since mNDST1 is similar to the human enzyme, the test can help assess the potential of therapeutics that target the activity of NSDT1.

It likely “can be applied for secondary screening of NDST1 inhibitors and to quickly establish their inhibitory characteristics to assess candidate drugs derived from high-throughput drug screening campaigns,” the researchers added.

Overall, “our data demonstrate the capability of the mNDST1-coupled enzyme assay to characterize and validate the inhibitory effects of candidate drugs,” they said.

“The test was created to help measure the use and effectiveness of new drugs for Sanfilippo that would block or inhibit the formation of heparan sulfate thus reducing build up and tissue damage,” they added.

It  might also be able to measure NSDT1 activity in Sanfilippo patients, but this needs to be validated.

“This method has just been developed and has not yet been used on patient samples,” the researchers concluded.