Gapmer Antisense Oligonucleotides as a New Class of Genetic Substrate Reduction Agents in Mucopolysaccharidosis IIIC

Background: Lysosomal storage disorders (LSDs) include over 70 rare inherited metabolic diseases caused by defective lysosomal enzymes or associated proteins, leading to the accumulation of undegraded substrates and progressive cellular dysfunction. Among these, Mucopolysaccharidoses (MPS) are a group characterized by storage of undegraded glycosaminoglycans (GAGs), including heparan, dermatan, keratan, and chondroitin sulfates. MPS type III (as known as Sanfilippo syndrome) predominantly affects the central nervous system (CNS) and manifests as severe neurodegeneration, behavioral abnormalities and cognitive decline. The subtype IIIC results from deficient activity of acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT) enzyme. Currently, treatment options for MPS III are limited, increasing the need to find alternative therapies. RNA-based therapies have recently gained attention as powerful alternatives to traditional treatments, with several already approved for clinical use in other diseases. Among these, antisense oligonucleotides (ASOs) stand out as a highly promising class of molecules for personalized medicine. ASOs are short, chemically synthesized strands of nucleic acids designed to bind specifically to target RNA sequences, thereby influencing gene expression. In this work, we explored the application of gapmer ASOs as a genetic substrate reduction therapy (gSRT) for MPS IIIC, with the goal of decreasing the expression of a gene, XYLT1, involved in the synthesis of the accumulated substrate, heparan sulfate (HS).