ABSTRACT
Mucopolysaccharidosis type IIIA (MPS IIIA) is a specific lysosomal storage disorder caused by an enzyme deficiency in sulphamidase, which is required for the degradation of heparan sulphate glycosaminoglycan (gag). This deficiency results in widespread gag storage and leads to severe CNS degeneration and mild somatic pathology. We have developed substrate deprivation as a therapy (SDT) for MPS disorders to reduce the initial production of gag substrate for the deficient enzyme, using the compound rhodamine B as an inhibitor of gag biosynthesis. This should restore the balance between gag level and residual enzyme activity towards normal and improve patient outcome. To determine if SDT improved CNS function, MPS IIIA mice were treated for 6months with weekly, intravenous 1mg/kg rhodamine B and then tested in a 4-arm water cross maze, which measures spatial learning and memory. MPS IIIA untreated mice were unable to perform to the same level as normal littermates, having increased escape latency, increased incorrect entries and decreased correct entries. Rhodamine B treatment improved MPS IIIA performance towards normal with treated mice having decreased escape latency, decreased incorrect entries and increased correct entries when compared to MPS IIIA untreated littermates. This provides the first report of SDT resulting in a beneficial effect on CNS function in an MPS disorder and SDT targeting gag synthesis may be a viable treatment option for children with MPS.
