Abstract | BACKGROUND: The hallmark of lysosomal storage disorders (LSDs) is microscopically demonstrable lysosomal distension. In mucopolysaccharidosis type IIIA ( MPS IIIA), this occurs as a result of an inherited deficiency of the lysosomal hydrolase sulphamidase. Consequently, heparan sulphate, a highly sulphated glycosaminoglycan, accumulates primarily within the cells of the reticulo-endothelial and monocyte-macrophage systems and, most importantly, neurones. Children affected by MPS IIIA experience a severe, progressive neuropathology that ultimately leads to death at around 15 years of age. METHODS: RESULTS: After intravenous gene delivery, liver sulphamidase was restored to approximately 30% of wild-type levels. The resultant widespread delivery of enzyme secreted from transduced cells to somatic tissues via the peripheral circulation corrected most somatic pathology. However, unlike an earlier study, central nervous system (CNS) pathology remained unchanged. Conversely, intraventricular gene delivery resulted in widespread sulphamidase gene delivery in (and reduced lysosomal storage throughout) the brain. Improvements in behaviour were observed in these mice, and interestingly, pathological urinary retention was prevented. CONCLUSIONS: The CNS remains the last major barrier to effective therapy for children affected by LSDs. The blood-brain barrier (BBB) limits the uptake of lysosomal enzymes from the peripheral circulation into the CNS, making direct gene delivery to the brain a reasonable, albeit more challenging, therapeutic option. Future work will further assess the relative advantages of directly targeting the brain with somatic gene delivery with sulphamidase modified to increase the efficiency of transport across the BBB.
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Authors | Chantelle McIntyre, Sharon Byers, Donald S Anson |
Journal | The journal of gene medicine
(J Gene Med)
Vol. 12
Issue 9
Pg. 717-28
(Sep 2010)
ISSN: 1521-2254 [Electronic] England |
PMID | 20683858
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Hydrolases
- N-sulfoglucosamine sulfohydrolase
- beta-N-Acetylhexosaminidases
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Topics |
- Animals
- Behavior, Animal
- Blood-Brain Barrier
- Brain
(metabolism, pathology)
- Disease Models, Animal
- Gene Transfer Techniques
- Genetic Therapy
- Genetic Vectors
- Hydrolases
(genetics, metabolism)
- Infusions, Intraventricular
- Injections, Intraventricular
- Lentivirus
(genetics)
- Liver
(enzymology)
- Lysosomes
- Mice
- Mice, Inbred C57BL
- Mucopolysaccharidosis III
(genetics, pathology, therapy)
- beta-N-Acetylhexosaminidases
(metabolism)
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