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Diseases 2017, 5(1), 5; doi:10.3390/diseases5010005

Substrate Deprivation Therapy to Reduce Glycosaminoglycan Synthesis Improves Aspects of Neurological and Skeletal Pathology in MPS I Mice

1
Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia
2
Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA 5005, Australia
3
School of Molecular & Biomedical Science, The University of Adelaide, Adelaide, SA 5005, Australia
*
Author to whom correspondence should be addressed.
Academic Editor: Luis M. Jiménez Jiménez
Received: 29 December 2016 / Revised: 14 February 2017 / Accepted: 21 February 2017 / Published: 23 February 2017
(This article belongs to the Collection Lysosomal Storage Diseases)
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Abstract

Mucopolysaccharidosis type I (MPS I) is the most common form of the MPS group of genetic diseases. MPS I results from a deficiency in the lysosomal enzyme α-l-iduronidase, leading to accumulation of undegraded heparan and dermatan sulphate glycosaminoglycan (GAG) chains in patient cells. MPS children suffer from multiple organ failure and die in their teens to early twenties. In particular, MPS I children also suffer from profound mental retardation and skeletal disease that restricts growth and movement. Neither brain nor skeletal disease is adequately treated by current therapy approaches. To overcome these barriers to effective therapy we have developed and tested a treatment called substrate deprivation therapy (SDT). MPS I knockout mice were treated with weekly intravenous injections of 1 mg/kg rhodamine B for six months to assess the efficacy of SDT. Mice were assessed using biochemistry, micro-CT and a battery of behaviour tests to determine the outcome of treatment. A reduction in female bodyweight gain was observed with the treatment as well as a decrease in lung GAG. Behavioural studies showed slight improvements in inverted grid and significant improvements in learning ability for female MPS I mice treated with rhodamine B. Skeletal disease also improved with a reduction in bone mineral volume observed. Overall, rhodamine B is safe to administer to MPS I knockout mice where it had an effect on improving aspects of neurological and skeletal disease symptoms and may therefore provide a potential therapy or adjunct therapy for MPS I patients. View Full-Text
Keywords: mucopolysaccharidosis type I; substrate deprivation; rhodamine B; lysosomal storage disorder; glycosaminoglycans mucopolysaccharidosis type I; substrate deprivation; rhodamine B; lysosomal storage disorder; glycosaminoglycans
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MDPI and ACS Style

Derrick-Roberts, A.L.K.; Jackson, M.R.; Pyragius, C.E.; Byers, S. Substrate Deprivation Therapy to Reduce Glycosaminoglycan Synthesis Improves Aspects of Neurological and Skeletal Pathology in MPS I Mice. Diseases 2017, 5, 5.

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