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

• Published in: The European journal of neuroscience Vol. 29; no. 6; pp. 1197 - 1214
• Main Authors: Hemsley, Kim M., Luck, Amanda J., Crawley, Allison C., Hassiotis, Sofia, Beard, Helen, King, Barbara, Rozek, Tomas, Rozaklis, Tina, Fuller, Maria, Hopwood, John J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.03.2009
• Subjects: Analysis of Variance; Animals; Antibodies - administration & dosage; Body Weight - drug effects; Body Weight - genetics; Brain - enzymology; cerebrospinal fluid; Chromatography, High Pressure Liquid - methods; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Exploratory Behavior - drug effects; Exploratory Behavior - physiology; Heparitin Sulfate - administration & dosage; Hydrolases - administration & dosage; Hydrolases - immunology; Lysosomal Storage Diseases - drug therapy; Lysosomal Storage Diseases - genetics; Lysosomal Storage Diseases - physiopathology; lysosomal storage disorder; Male; Maze Learning - drug effects; Maze Learning - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; mouse; Mucopolysaccharidosis III - genetics; Mucopolysaccharidosis III - metabolism; Necrosis - drug therapy; Necrosis - etiology; neuropathology; Proteins - administration & dosage; Proteins - immunology; Sanfilippo; Tandem Mass Spectrometry - methods; Time Factors
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2009.06666.x

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.