Sanfilippo Syndrome involves the accumulation of heparan sulphate (HS) in the body, resulting in progressive mental and physical deterioration. One therapeutic approach involves substrate reduction therapy (SRT), which aims to reduce the initial production of HS. As a result, there is less build-up over time, helping to slow disease progression and reduce symptoms.

In 2016, Prof. Andreas Schulze was awarded a translational grant co-funded by the Sanfilippo Children’s Foundation and Cure Sanfilippo Foundation (USA). For that project, Prof. Schulze performed high-throughput screening to identify potential SRT drugs for Sanfilippo and other MPS disorders involving HS accumulation. By screening over 7,100,000 compounds using computer modelling and 4,302 compounds in cells, Prof. Schulze and his team found nine potential drug candidates to further characterise, which will be the subject of this new project. 

Their SRT approach involves inhibiting the enzyme NDST, which plays an important role in the production of HS. Five of the candidates that will be evaluated in this study can prevent the enzyme from being produced, and the other four stop the produced NDST enzyme from working correctly. By targeting NDST, it may be possible to reduce HS production and improve symptoms.

To build upon their previous work, the research team will continue to evaluate the SRT potential of the nine candidates, in order to select the top compounds for future preclinical animal studies. The five compounds that prevent NDST production will be tested in new cell lines, including Sanfilippo types A, B and C cells, and a neuronal-like cell model. For the four that target the NDST enzyme directly, their exact mechanism of action will be investigated. Finally, all nine compounds will be studied in Sanfilippo types A, B and C skin cells, to determine their effectiveness in reducing HS production.

“We are very grateful for the continued funding collaboration with Cure Sanfilippo Foundation for this project,” said Megan Donnell, Founder of the Sanfilippo Children’s Foundation. “As supporters of this project since its inception, we are excited by how far it has come and to be able to support this next phase of the research, bringing it another step closer to clinical application.”

Project Update 

Professor Andreas Schulze and his team have completed their Translational extension grant awarded in 2020 from the Sanfilippo Children’s Foundation and Cure Sanfilippo Foundation. In this project, the team evaluated substrate reduction drug candidates originally identified in their 2016 translational grant also co-funded by the Foundations.

The team used two approaches to target NDST1, one of the enzymes that helps to make heparan sulfate, the molecule that builds up to toxic levels in Sanfilippo syndrome. One approach uses drugs that work by blocking the activity of NDST1 (class II inhibitor). The other approach aims to reduce the production of the NDST1 enzyme in the first place (class I inhibitor).

The team used a combination of techniques to look at the activity of the NDST1 gene and protein in this project. This included developing a new test (assay) to assess how well class II candidates can inhibit the NDST1 enzyme. They have published the protocol for their new assay in the journal Glycobiology which will help other researchers working in the field.

Using this new assay and other experiments, they confirmed that one of the candidates can successfully inhibit NDST1 enzyme activity. Some further candidates will be tested alone and in combination to determine the best NDST1 inhibitors. 

Their initial tests on the class 1 drug candidates, unfortunately, suggested that they do not reduce heparan sulfate levels. Additional experiments will be performed to confirm the results.

Prof. Schulze and his team will complete further analysis on more of the drug candidates originally identified and some new candidates. Based on the final results, they will determine the top substrate reduction drug candidates and the next steps for translation towards the clinic. As the drugs help to reduce heparan sulfate production, they have potential application for Sanfilippo and other similar diseases, including Hunter and Hurler syndromes.

Professor Andreas Schulze is a biochemist and pediatrician with over 26 years of experience in the diagnosis and management of patients with inherited metabolic diseases. He is the head of Metabolic Genetics at The Hospital for Sick Children, and leads a laboratory at the hospital’s dedicated Research Institute.

Project Summary

• Project title: Identify a novel class of substrate reduction therapy drugs for the mucopolysaccharidoses that inhibit N-deacetylase/N-sulfo-transferase (NDST)

• Chief investigator: Prof. Andreas Schulze

• Amount: $62,581, with Cure Sanfilippo Foundation contributing a further $62,581

• Duration: 1 year 

• Location: The Hospital for Sick Children, Toronto

• Status: Complete

• Start date: December 2020

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