Treatment of canine fucosidosis by intracisternal enzyme infusion

The blood brain barrier is the major obstacle to treating lysosomal storage disorders of the central nervous system such as canine fucosidosis. This barrier was overcome by three, monthly injections of recombinant canine α- l-fucosidase enzyme were given intracisternally. In dogs treated from 8 week...

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Bibliographic Details
Published in:Experimental neurology 2011-08, Vol.230 (2), p.218-226
Main Authors: Kondagari, Gauthami S., King, Barbara M., Thomson, Peter C., Williamson, Peter, Clements, Peter R., Fuller, Maria, Hemsley, Kim M., Hopwood, John J., Taylor, Rosanne M.
Format: Article
Language:English
Subjects:
alpha-L-Fucosidase - administration & dosage
alpha-L-Fucosidase - therapeutic use
Animals
Biological and medical sciences
Blood-Brain Barrier - enzymology
Brain - enzymology
Canine fucosidosis
Central nervous system
Cerebrospinal fluid
Disease Models, Animal
Dog Diseases - therapy
Dogs
Fucosidosis - therapy
Fucosidosis - veterinary
Immunomodulators
Infusions, Intraventricular
Intracisternal enzyme replacement therapy
Lysosomal storage disease
Mass Spectrometry
Medical sciences
Neurology
Pharmacology. Drug treatments
Spinal Cord - enzymology
Tandem mass spectrometry
Treatment Outcome
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Summary:The blood brain barrier is the major obstacle to treating lysosomal storage disorders of the central nervous system such as canine fucosidosis. This barrier was overcome by three, monthly injections of recombinant canine α- l-fucosidase enzyme were given intracisternally. In dogs treated from 8 weeks of age enzyme reached all areas of central nervous system as well as the cervical lymph node, bone marrow and liver. Brainstem and spinal cord samples from regions adjacent to the injection site had highest enzyme levels (39–73% of normal). Substantial enzyme activity (8.5–20% of normal controls) was found in the superficial brain compared to deeper regions (2.6–5.5% of normal). Treatment significantly reduced the fucosyl-linked oligosaccharide accumulation in most areas of CNS, liver and lymph node. In the surface and deep areas of lumbar spinal cord, oligosaccharide accumulation was corrected (79–80% reduction) to near normal levels ( p < 0.05). In the spinal meninges (thoracic and lumbar) enzyme activity (35–39% of normal control) and substrate reduction (58–63% affected vehicle treated samples) reached levels similar to those seen in phenotypically normal carriers ( p < 0.05).The procedure was safe and well-tolerated, treated (average 16%) dogs gained more weight ( p < 0.05) and there was no antibody formation or inflammatory reaction in plasma and CSF following treatments. The capacity of early ERT to modify progression of biochemical storage in fucosidosis is promising as this disease is currently only amenable to treatment by bone marrow transplantation which entails unacceptably high risks for many patients. ► The repeated intracisternal injection recombinant canine α-L-fucosidase in developing brain of fucosidosis dogs was safe. ► Three monthly enzyme infusions has led to higher enzyme activity and substrate reduction in spinal cord and brain stem ► However, treatments had led to significant enzyme activity and substrate reduction in CSF samples collected at the third infusion and at post-mortem.
ISSN:0014-4886
1090-2430
DOI:10.1016/j.expneurol.2011.04.019