Examination of intravenous and intra-CSF protein delivery for treatment of neurological disease.

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 microg, 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.

• Authors: Kim M Hemsley, Amanda J Luck, Allison C Crawley, Sofia Hassiotis, Helen Beard, Barbara King, Tomas Rozek, Tina Rozaklis, Maria Fuller, John J Hopwood
• Journal: The European journal of neuroscience (Eur J Neurosci) Vol. 29 Issue 6 Pg. 1197-214 (Mar 2009) ISSN: 1460-9568 [Electronic] France
• PMID: 19302155 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Proteins
• lysosomal proteins
• Heparitin Sulfate
• Hydrolases
• N-sulfoglucosamine sulfohydrolase

Topics

• Analysis of Variance
• Animals
• Antibodies (administration & dosage)
• Body Weight (drug effects, genetics)
• Brain (enzymology)
• Chromatography, High Pressure Liquid (methods)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Administration Routes
• Exploratory Behavior (drug effects, physiology)
• Heparitin Sulfate (administration & dosage)
• Hydrolases (administration & dosage, immunology)
• Lysosomal Storage Diseases (drug therapy, genetics, physiopathology)
• Male
• Maze Learning (drug effects, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mucopolysaccharidosis III (genetics, metabolism)
• Necrosis (drug therapy, etiology)
• Proteins (administration & dosage, immunology)
• Tandem Mass Spectrometry (methods)
• Time Factors