Investigating NDST1 inhibitors as target for substrate reduction therapy for Sanfilippo

December 30, 2020

Identifying a novel class of substrate reduction therapy drugs for the mucopolysaccharidoses that inhibit N-deacetylase/N-sulfo-transferase (NDST)

Cure Sanfilippo Foundation has co-funded a one-year research project with Sanfilippo Children’s Foundation (Australia) to Professor Andreas Schulze at The Hospital for Sick Children in Toronto. Prof. Schulze will to continue his work on the development of substrate reduction therapy drugs for Sanfilippo and other similar conditions.

Sanfilippo syndrome involves the accumulation of heparan sulfate 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 Cure Sanfilippo Foundation and Sanfilippo Children’s Foundation. 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 characterize, 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. All nine compounds will be studied in Sanfilippo types A, B, and C skin cells to determine their effectiveness in reducing HS production.

Start Date: December 2020

This page’s content has been medically reviewed by Dr. Cara O’Neill, FAAP.

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