3). In particular, EXTL2 and EXTL3 are key proteins involved in the HS chain elongation. Small interference RNAs (siRNAs), discovered in the late 1990s4, were shown to inhibit mammalian genes5, and may be applicable in substrate reduction therapy (SRT) for Sanfilippo C patients. For other types of MPS, two different approaches using siRNAs or shRNAs have been previously described which inhibit different genes in the HS synthetic pathway6, 7. Here, EXTL2 is linked to mucopolysaccharidosis type 3C.