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Type: Journal article
Title: Examination of intravenous and intra-CSF protein delivery for treatment of neurological disease
Author: Hemsley, K.
Luck, A.
Crawley, A.
Hassiotis, S.
Beard, H.
King, B.
Rozek, T.
Rozaklis, T.
Fuller, M.
Hopwood, J.
Citation: European Journal of Neuroscience, 2009; 29(6):1197-1214
Publisher: Blackwell Science Ltd
Issue Date: 2009
ISSN: 0953-816X
Statement of
Kim M. Hemsley, Amanda J. Luck, Allison C. Crawley, Sofia Hassiotis, Helen Beard, Barbara King, Tomas Rozek, Tina Rozaklis, Maria Fuller and John J. Hopwood
Abstract: Mucopolysaccharidosis type IIIA is a neurodegenerative lysosomal storage disorder characterized by progressive loss of learned skills, sleep disturbance and behavioural problems. Absent or greatly reduced activity of sulphamidase, a lysosomal protein, results in intracellular accumulation of heparan sulphate. Subsequent neuroinflammation and neurodegeneration typify this and many other lysosomal storage disorders. We propose that intra-cerebrospinal fluid protein delivery represents a potential therapeutic avenue for treatment of this and other neurodegenerative conditions; however, technical restraints restrict examination of its use prior to adulthood in mice. We have used a naturally-occurring Mucopolysaccharidosis type IIIA mouse model to determine the effectiveness of combining intravenous protein replacement (1 mg/kg) from birth to 6 weeks of age with intra-cerebrospinal fluid sulphamidase delivery (100 μg, fortnightly from 6 weeks) on behaviour, the level of heparan sulphate-oligosaccharide storage and other neuropathology. Mice receiving combination treatment exhibited similar clinical improvement and reduction in heparan sulphate storage to those only receiving intra-cerebrospinal fluid enzyme. Reductions in micro- and astrogliosis and delayed development of ubiquitin-positive lesions were seen in both groups. A third group of intravenous-only treated mice did not exhibit clinical or neuropathological improvements. Intra-cerebrospinal fluid injection of sulphamidase effectively, but dose-dependently, treats neurological pathology in Mucopolysaccharidosis type IIIA, even when treatment begins in mice with established disease.
Keywords: cerebrospinal fluid
lysosomal storage disorder
DOI: 10.1111/j.1460-9568.2009.06666.x
Appears in Collections:Aurora harvest 5
Paediatrics publications

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