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Delivery of therapeutic protein for prevention of neurodegenerative changes: comparison of different CSF-delivery methods.

Abstract：

:Injection of lysosomal enzyme into cisternal or ventricular cerebrospinal fluid (CSF) has been carried out in 11 lysosomal storage disorder models, with each study demonstrating reductions in primary substrate and secondary neuropathological changes, and several reports of improved neurological function. Whilst acute studies in mucopolysaccharidosis (MPS) type II mice revealed that intrathecally-delivered enzyme (into thoraco-lumbar CSF) accesses the brain, the impact of longer-term treatment of affected subjects via this route is unknown. This approach is presently being utilized to treat children with MPS types I, II and III. Our aim was to determine the efficacy of repeated intrathecal injection of recombinant human sulfamidase (rhSGSH) on pathological changes in the MPS IIIA dog brain. The outcomes were compared with those in dogs treated via intra-cisternal or ventricular routes. Control dogs received buffer or no treatment. Significant reductions in primary/secondary substrate levels in brain were observed in dogs treated via all routes, although the extent of the reduction differed regionally. Treatment via all CSF access points resulted in large reductions in microgliosis in superficial cerebral cortex, but only ventricular injection enabled amelioration in deep cerebral cortex. Formation of glutamic acid decarboxylase-positive axonal spheroids in deep cerebellar nuclei was prevented by treatment delivered via any route. Anti-rhSGSH antibodies in the sera of some dogs did not reduce therapeutic efficacy. Our data indicates the capacity of intra-spinal CSF-injected rhSGSH to circulate within CSF-filled spaces, penetrate into brain and mediate a significant reduction in substrate accumulation and secondary pathology in the MPS IIIA dog brain.

journal_name

Exp Neurol

journal_title

Experimental neurology

authors

Marshall NR,Hassiotis S,King B,Rozaklis T,Trim PJ,Duplock SK,Winner LK,Beard H,Snel MF,Jolly RD,Hopwood JJ,Hemsley KM

doi

10.1016/j.expneurol.2014.09.008

subject

Has Abstract

pub_date

2015-01-01 00:00:00

pages

79-90

eissn

0014-4886

issn

1090-2430

pii

S0014-4886(14)00291-X

journal_volume

263

pub_type

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Delivery of therapeutic protein for prevention of neurodegenerative changes: comparison of different CSF-delivery methods.