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

Ainslie Derrick-Roberts,Matilda Jackson,Carmen Pyragius,Sharon Byers

doi:10.3390/diseases5010005

Ainslie Derrick-Roberts, Matilda Jackson + Show 2 more

Open Access

https://doi.org/10.3390/diseases5010005

Copy DOI

Journal: Diseases	Publication Date: Feb 23, 2017
Citations: 18	License type: CC BY 4.0

Affiliation: University of Adelaide, South Australia Pathology

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.

Highlights

The mucopolysaccharidosis (MPS) disorders are a group of inherited metabolic diseases resulting from abnormalities in enzymes required for the turnover of intracellular glycosaminoglycan (GAG)chains
Because of the range of organs affected by Mucopolysaccharidosis type I (MPS I) and the progressive nature of pathology, finding an effective multi-tissue treatment for MPS I has been difficult, as it has been for all MPS types
All MPS I untreated mice gained weight more rapidly than normal control mice, with MPS I untreated females and males being significantly different from 3 months of age (Figure 1A and B respectively, females and males being significantly different from 3 months of age (Figure 1A and B respectively, p < 0.001)

Summary

Introduction

The mucopolysaccharidosis (MPS) disorders are a group of inherited metabolic diseases resulting from abnormalities in enzymes required for the turnover of intracellular glycosaminoglycan (GAG)chains. The mucopolysaccharidosis (MPS) disorders are a group of inherited metabolic diseases resulting from abnormalities in enzymes required for the turnover of intracellular glycosaminoglycan (GAG). MPS I is considered the classic MPS type and is the most common MPS occurring in approximately 1 in 100,000 newborns worldwide; incidence and prevalence of phenotypic groups vary from region to region [1,2]. It is caused by a reduction in, or a deficiency of, the lysosomal enzyme α-L-iduronidase (IDUA, E.C. 3.2.1.76), which is required for the intracellular degradation of heparan sulphate (HS) and dermatan sulphate (DS) GAG chains. Death most commonly arises from cardiac or respiratory failure in early adolescence

Objectives

Methods

Results

Discussion

Conclusion