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.
journal_name
Mol Genet Metabjournal_title
Molecular genetics and metabolismauthors
Roberts AL,Rees MH,Klebe S,Fletcher JM,Byers Sdoi
10.1016/j.ymgme.2007.06.016subject
Has Abstractpub_date
2007-09-01 00:00:00pages
115-21issue
1-2eissn
1096-7192issn
1096-7206pii
S1096-7192(07)00201-6journal_volume
92pub_type
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pub_type: 杂志文章
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pub_type: 杂志文章
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