Slow, continuous enzyme replacement via spinal CSF in dogs with the paediatric-onset neurodegenerative disease, MPS IIIA.
Intra-cerebrospinal fluid (CSF) injection of recombinant human lysosomal enzyme is a potential treatment strategy for several neurodegenerative lysosomal storage disorders including Sanfilippo syndrome (Mucopolysaccharidosis type IIIA; MPS IIIA). Here we have utilised the MPS IIIA Huntaway dog model to compare the effectiveness of the repeated intermittent bolus injection strategy being used in the trials with an alternate approach; slow, continual infusion of replacement enzyme (recombinant human sulphamidase; rhSGSH) into the spinal CSF using a SynchroMed II® pump attached to a spinal infusion cannula. The ability of each enzyme delivery strategy to ameliorate lesions in MPS IIIA brain was determined in animals treated from ∼three- to six-months of age. Controls received buffer or no treatment. Significant reductions in heparan sulphate (primary substrate) were observed in brain samples from dogs treated via either cisternal or lumbar spinal CSF bolus injection methods and also in slow intra-spinal CSF infusion-treated dogs. The extent of the reduction differed regionally. Pump-delivered rhSGSH was less effective in reducing secondary substrate (GM3ganglioside) in deeper aspects of cerebral cortex, and although near-amelioration of microglial activation was seen in superficial (but not deep) layers of cerebral cortex in both bolus enzyme-treated groups, pump-infusion of rhSGSH had little impact on microgliosis. While continual low-dose infusion of rhSGSH into MPS IIIA dog CSF reduces disease-based lesions in brain, it was not as efficacious as repeated cisternal or spinal CSF bolus infusion of rhSGSH over the time-frame of these experiments.
Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia.
Barbara
B
King
Institute of Veterinary, Animal and Biomedical Science, Massey University, Palmerston North, New Zealand.
Neil R
NR
Marshall
Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia.
Sofia
S
Hassiotis
Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia.
Paul J
PJ
Trim
Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia.
Justin
J
Tucker
Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia.
Kathryn
K
Hattersley
Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia.
Marten F
MF
Snel
Institute of Veterinary, Animal and Biomedical Science, Massey University, Palmerston North, New Zealand.
Robert D
RD
Jolly
Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia.
John J
JJ
Hopwood
Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia. Kim.Hemsley@sahmri.com.
Kim M
KM
Hemsley
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects*; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D056947:Enzyme Replacement Therapy / Q000379:methods; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000008:administration & dosage*; D008159:Lumbar Vertebrae / Q000378:metabolism*; D009084:Mucopolysaccharidosis III / Q000188:drug therapy* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage*
D006497:Heparan Sulfate; D006867:Hydrolases; D011994:Recombinant Proteins; C022708:N-sulfoglucosamine sulfohydrolase