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Enzyme replacement therapy in alpha-mannosidosis guinea-pigs
Allison C Crawley1, Barbara King, Thomas Berg
1Lysosomal Diseases Research Unit, Department of Genetic Medicine, Children, Youth and Women's Health Service, 72 King William Rd., North Adelaide, South Australia 5006, Australia. allison.crawley@adelaide.edu.au <allison.crawley@adelaide.edu.au>
Molecular Genetics and Metabolism
|June 30, 2006
Summary
Enzyme replacement therapy using recombinant human alpha-mannosidase showed promise in reducing oligosaccharide buildup in alpha-mannosidosis guinea pigs. However, immune responses and lack of brain histological improvement limit long-term treatment efficacy.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Alpha-mannosidosis is a rare lysosomal storage disorder caused by alpha-mannosidase deficiency, leading to oligosaccharide accumulation and severe clinical manifestations.
- The disease presents with neurological, skeletal, and immune system defects, significantly impacting patient quality of life.
- Alpha-mannosidosis guinea pig models accurately replicate human disease pathology, making them suitable for therapeutic investigations.
Purpose of the Study:
- To evaluate the efficacy of enzyme replacement therapy (ERT) using recombinant human alpha-mannosidase in a preclinical model of alpha-mannosidosis.
- To assess the biodistribution, pharmacokinetics, and substrate reduction capabilities of the enzyme in affected tissues, including the brain.
- To investigate the impact of ERT on histological changes and potential immune responses in the guinea pig model.
Main Methods:
- Intravenous administration of recombinant human alpha-mannosidase at doses of 1mg/kg and 10mg/kg to alpha-mannosidosis guinea pigs.
- Monitoring of enzyme activity, substrate levels (using tandem mass spectrometry), and tissue distribution post-injection.
- Histopathological examination of various organs, including the brain, liver, kidney, and spleen, to assess treatment effects.
- Evaluation of humoral immune response following multiple enzyme administrations.
Main Results:
- Recombinant human alpha-mannosidase exhibited a half-life of 53 hours and achieved therapeutic enzyme levels in circulation and tissues, including the brain.
- ERT effectively reduced stored oligosaccharide substrates in peripheral tissues and the brain (up to 39% at 10mg/kg dose).
- Significant reductions in lysosomal vacuolation were observed in multiple organs, and a decrease in trigeminal ganglion neuron pathology was noted, though no brain histological improvements occurred.
Conclusions:
- Enzyme replacement therapy demonstrates therapeutic potential for alpha-mannosidosis by reducing substrate accumulation in peripheral organs and the brain.
- While ERT shows biochemical benefits, the lack of brain histological improvement and the rapid induction of humoral immune responses pose challenges for long-term therapeutic application.
- Further research is needed to optimize delivery strategies and mitigate immune responses for effective alpha-mannosidosis treatment.