Intracerebroventricular enzyme infusion corrects central nervous system pathology and dysfunction in a mouse model of metachromatic leukodystrophy.

Abstract

Arylsulfatase A (ASA) catalyzes the desulfation of sulfatide, a major lipid component of myelin. Inherited functional deficiencies of ASA cause the lysosomal storage disease (LSD) metachromatic leukodystrophy (MLD), which is characterized by intralysosomal accumulation of sulfatide, progressive neurological symptoms and early death. Enzyme replacement therapy (ERT) using intravenous injection of active enzyme is a treatment option for many LSDs as exogenous lysosomal enzymes are delivered to lysosomes of patient's cells via receptor-mediated endocytosis. Efficient treatment of MLD and other LSDs with central nervous system (CNS) involvement is, however, hampered by the blood-brain barrier (BBB), which limits transfer of therapeutic enzymes from the circulation to the brain parenchyma. To bypass the BBB, we infused recombinant human ASA (rhASA) by implanted miniature pumps into the cerebrospinal fluid (CSF) of a conventional and a novel, genetically aggravated ASA knockout mouse model of MLD. rhASA continuously delivered to the lateral ventricle for 4 weeks penetrated the brain parenchyma and was targeted to the lysosomes of brain cells. Histological analysis revealed complete reversal of lysosomal storage in the infused hemisphere. rhASA concentrations and sulfatide clearance declined with increasing distance from the infusion site. Correction of the ataxic gait indicated reversal of central nervous system dysfunctions. The profound histopathological and functional improvements, the requirement of low enzyme doses and the absence of immunological side effects suggest intracerebroventricular ERT to be a promising treatment option for MLD and other LSDs with prevailing CNS disease.

• Authors: Stijn Stroobants, Debora Gerlach, Frank Matthes, Dieter Hartmann, Jens Fogh, Volkmar Gieselmann, Rudi D'Hooge, Ulrich Matzner
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 20 Issue 14 Pg. 2760-9 (Jul 15 2011) ISSN: 1460-2083 [Electronic] England
• PMID: 21515587 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Recombinant Proteins
• Cerebroside-Sulfatase

Topics

• Animals
• Cerebroside-Sulfatase (therapeutic use)
• Disease Models, Animal
• Enzyme Replacement Therapy (methods)
• Humans
• Infusions, Intraventricular
• Leukodystrophy, Metachromatic (drug therapy, enzymology, genetics, pathology)
• Mice
• Mice, Knockout
• Recombinant Proteins (therapeutic use)
• Recovery of Function (drug effects)
• Time Factors