Abstract
Mucopolysaccharidosis type IIIC is a neurodegenerative lysosomal storage disorder (LSD) characterized by the accumulation of undegraded heparan sulfate (HS) due to the lack of an enzyme responsible for its degradation: acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT). Classical treatments are ineffective. Here, we attempt a new approach in genetic medicine, genetic substrate reduction therapy (gSRT), to counteract this neurological disorder. Briefly, we used synthetic oligonucleotides, particularly gapmer antisense oligonucleotides (ASOs), to target the synthesis of the accumulated compounds at the molecular level, downregulating a specific gene involved in the first step of HS biosynthesis, XYLT1. Our goal was to reduce HS production and, consequently, its accumulation. Initially, five gapmer ASOs were designed and their potential to decrease XYLT1 mRNA levels were tested in patient-derived fibroblasts. Subsequent analyses focused on the two best performing molecules alone. The results showed a high inhibition of the XYLT1 gene mRNA (around 90%), a decrease in xylosyltransferase I (XT-I) protein levels and a reduction in HS storage 6 and 10 days after transfection (up to 21% and 32%, respectively). Overall, our results are highly promising and may represent the initial step towards the development of a potential therapeutic option not only for MPS IIIC, but virtually for every other MPS III form. Ultimately, the same principle may also apply to other neuropathic MPS.