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

Cure Sanfilippo Foundation is joining Sanfilippo Children’s Foundation (Australia) to co-fund a two-year project by Andreas Schulze, MD, PhD, at The Hospital for Sick Children, Clinical and Medical Genetics to identify a novel class of substrate reduction therapy drug for the mucopolysaccharidoses that inhibits N-deacetylase/N-sulfo-transferase (NDST).

Dr. Schulze has identified NDST1 as druggable target for the treatment of Sanfilippo Syndrome (MPS III). The belief is that by decreasing NDST activity, the overall amount of heparan sulfate (HS) being synthesized could be decreased or the percentage of indigestible S-domains in the newly-synthesized HS could be lowered.

This project sets out identifying two classes of drugs that attenuate the activity of NDST1, either by decreasing the transcription from the NDST1 gene (Class I SRT) or by directly inhibiting the activity of the enzyme (Class II SRT).

The project will use in vitro assays, structure guided hit-to-lead optimization, phenotypic screening, and mouse models to develop lead candidates for the treatment of patients with Sanfilippo Syndrome. Specifically, it seeks to address the following aims.

1. Characterization of inhibitory potential of Class I/II SRT candidates
2. Structure-Based Guided Hit-To-Lead Optimization of Class II SRT candidates
3. Phenotypic screening of Class I and II SRT candidates in Drosophila MPS IIIA model

This work seeks to address the major challenge of the lack of an imminent treatment for Sanfilippo Syndrome by identifying a novel class of substrate reduction therapy drug for the mucopolysaccharidoses that inhibits N-deacetylase/N-sulfo-transferase (NDST).

Learn more about research funded by the Foundation.