Intracerebroventricular dosing of N-sulfoglucosamine sulfohydrolase in mucopolysaccharidosis IIIA mice reduces markers of brain lysosomal dysfunction.

Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder caused by N-sulfoglucosamine sulfohydrolase (SGSH) deficiency. SGSH removes the sulfate from N-sulfoglucosamine residues on the nonreducing end of heparan sulfate (HS-NRE) within lysosomes. Enzyme deficiency results in accumulation of partially degraded HS within lysosomes throughout the body, leading to a progressive severe neurological disease.

Quantitative Assessment of Neuroinflammation, Myelinogenesis, Demyelination, and Nerve Fiber Regeneration in Immunostained Sciatic Nerves From Twitcher Mice With a Tissue Image Analysis Platform.

Scoring demyelination and regeneration in hematoxylin and eosin-stained nerves poses a challenge even for the trained pathologist. This article demonstrates how combinatorial multiplex immunohistochemistry (IHC) and quantitative digital pathology bring new insights into the peripheral neuropathogenesis of the Twitcher mouse, a model of Krabbe disease. The goal of this investigational study was to integrate modern pathology tools to traditional anatomic pathology microscopy workflows, in order to generate quantitative data in a large number of samples, and aid the understanding of complex disease pathomechanisms.

Intermittent enzyme replacement therapy with recombinant human β-galactosidase prevents neuraminidase 1 deficiency.

Mutations in the β () gene cause lysosomal β-galactosidase (β-Gal) deficiency and clinical onset of the neurodegenerative lysosomal storage disease, GM1 gangliosidosis. β-Gal and neuraminidase 1 (NEU1) form a multienzyme complex in lysosomes along with the molecular chaperone, protective protein cathepsin A (PPCA). NEU1 is deficient in the neurodegenerative lysosomal storage disease sialidosis, and its targeting to and stability in lysosomes strictly depend on PPCA.

Translational studies of intravenous and intracerebroventricular routes of administration for CNS cellular biodistribution for BMN 250, an enzyme replacement therapy for the treatment of Sanfilippo type B.

BMN 250 is being developed as enzyme replacement therapy for Sanfilippo type B, a primarily neurological rare disease, in which patients have deficient lysosomal alpha-N-acetylglucosaminidase (NAGLU) enzyme activity. BMN 250 is taken up in target cells by the cation-independent mannose 6-phosphate receptor (CI-MPR, insulin-like growth factor 2 receptor), which then facilitates transit to the lysosome. BMN 250 is dosed directly into the central nervous system via the intracerebroventricular (ICV) route, and the objective of this work was to compare systemic intravenous (IV) and ICV delivery of BMN 250 to confirm the value of ICV dosing.