Short-interfering RNA to reduce heparan sulfate in Sanfilippo B syndrome

Awardee: Patricia Dickson

Institution: Washington University in St. Louis

Grant Amount: $60,000

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

This is a proposal to use ribonucleic acid (RNA) interference to reduce the production of heparan sulfate in the brain for Sanfilippo syndrome. Substrate reduction therapy aims to reduce the amount of substrate, or material, that cannot be broken down by the body. In Sanfilippo, the substrate is heparan sulfate. Heparan sulfate is made by dedicated proteins that help assemble the molecule (biosynthesis). We aim to inhibit three genes that are involved in heparan sulfate production (Exostosin1 (EXT 1), Exostosin 2 (EXT2), and N-Deacetylase And N-Sulfotransferase 2 (NDST2)). Our initial tests show that we can turn down the production of these genes and that doing so reduces the amount of heparan sulfate in the brain. Here, we propose to determine the most effective combination of RNA to reduce heparan sulfate in the brains of mice with Sanfilippo B syndrome. We then plan to study the effects of substrate reduction therapy using this RNA approach on behavior, pathology, and heparan sulfate levels long term. If successful, this approach could be applied to all Sanfilippo types and to other mucopolysaccharidoses (MPS) in which heparan sulfate accumulates in excess.