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

Kim M. Hemsley, Amanda J. Luck, Allison C. Crawley, Sofia Hassiotis, Helen Beard, Barbara King, Tomas Rozek, Tina Rozaklis, Maria Fuller, John J. Hopwood

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63 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1197-1214
Number of pages18
JournalEuropean Journal of Neuroscience
Issue number6
Publication statusPublished - Mar 2009
Externally publishedYes


  • Cerebrospinal fluid
  • Lysosomal storage disorder
  • Mouse
  • Neuropathology
  • Sanfilippo


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