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Improvement in behaviour after substrate deprivation therapy with rhodamine B in a mouse model of MPS IIIA
Ainslie L K Roberts1, Matthew H Rees, Sonja Klebe
1Department of Genetic Medicine, Children, Youth and Women's Health Service, North Adelaide, Australia.
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.
Insights
Substrate deprivation therapy (SDT) using rhodamine B improved cognitive function in mice with Mucopolysaccharidosis type IIIA (MPS IIIA), a rare genetic disorder. This novel approach targets glycosaminoglycan (GAG) synthesis, offering potential therapeutic benefits for affected children.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder caused by sulphamidase deficiency, leading to heparan sulphate glycosaminoglycan (GAG) accumulation.
- This accumulation results in severe central nervous system (CNS) degeneration and milder systemic pathology.
Purpose of the Study:
- To investigate the efficacy of substrate deprivation therapy (SDT) in improving CNS function in a mouse model of MPS IIIA.
- To evaluate the potential of inhibiting GAG biosynthesis as a therapeutic strategy for MPS disorders.
Main Methods:
- MPS IIIA mice were treated with rhodamine B, a GAG biosynthesis inhibitor, at 1mg/kg weekly via intravenous injection for six months.
- Cognitive function, specifically spatial learning and memory, was assessed using a 4-arm water cross maze.
Main Results:
- Untreated MPS IIIA mice exhibited impaired performance in the water maze, characterized by longer escape latencies and more errors.
- Rhodamine B treatment significantly improved the performance of MPS IIIA mice, reducing escape latency and incorrect entries while increasing correct entries, bringing them closer to normal levels.
Conclusions:
- This study demonstrates the first successful application of SDT to ameliorate CNS dysfunction in an MPS disorder model.
- Targeting GAG synthesis through SDT represents a promising therapeutic avenue for children diagnosed with MPS IIIA.
