Impact of high-dose, chemically modified sulfamidase on pathology in a murine model of MPS IIIA.

Mucopolysaccharidosis type IIIA (MPS IIIA) is a neurodegenerative lysosomal storage disorder that results from a deficiency of sulfamidase (N-sulfoglucosamine sulfohydrolase), with consequential accumulation of its substrate, partially degraded heparan sulfate. Conventional doses (e.g. 1mg/kg) of intravenously delivered recombinant human sulfamidase (rhSGSH) do not improve neuropathology in MPS IIIA mice due to an inability to traverse the blood-brain barrier; however high-dose treatment or administration of enzyme that has been chemically modified to remove mannose-6-phosphate glycans has been shown to reduce neuropathology in related animal models. We have combined these approaches to evaluate the ability of 1, 5, 10 or 20mg/kg of similarly chemically modified or unmodified rhSGSH to reduce neuropathology following repeated intravenous delivery to adult MPS IIIA mice. rhSGSH was detected in brain homogenates from mice treated with all doses of modified rhSGSH and those receiving the two higher doses of unmodified rhSGSH, albeit at significantly lower levels. Immunohistochemically, rhSGSH visualized in the brain was localized to the endothelium, meninges and choroid plexus, with no convincing punctate intra-neuronal staining seen. This presumably underlies the failure of the treatment to reduce the relative level of a heparan sulfate-derived oligosaccharide (GlcNS-UA), or secondarily stored substrates that accumulate in MPS IIIA brain cells. However, modification of rhSGSH significantly increased its effectiveness in degrading GlcNS-UA in non-CNS tissues, potentially as a result of its reduced plasma clearance. If this observation is generally applicable, chemical modification may permit the use of significantly lower doses of lysosomal enzymes in patients currently receiving intravenous enzyme replacement therapy.

Preclinical dose ranging studies for enzyme replacement therapy with idursulfase in a knock-out mouse model of MPS II.

Mucopolysaccharidosis II (MPS II; Hunter syndrome) is an X-linked metabolic disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S), which catalyzes the catabolism of glycosaminoglycans (GAG) by cleaving the O-linked sulfate from dermatan sulfate and heparan sulfate. Recently, enzyme replacement therapy (ERT) with recombinant human I2S (Elaprase (idursulfase), Shire Human Genetic Therapies, Inc.), has been approved in the US and European Union for the treatment and management of MPS II. The purpose of the studies presented here was to describe some of the preclinical development of idursulfase using the I2S knock-out mouse model of MPS II designed to study the effect of dose and various dosing regimens of idursulfase on urine and tissue GAG levels. Urine and tissue samples were collected prior to idursulfase treatment and periodically throughout each study and analyzed for GAGs. The presence of anti-idursulfase antibodies in the mice serum after idursulfase use was also determined. Results showed that idursulfase, at several doses and at several dosing frequencies, caused a reduction in tissue and urine GAG levels in a dose-dependent manner. These studies also demonstrated that after IV administration, idursulfase is biologically active in the IdS-KO mouse model and is transported to key target tissues, reaching the lysosomes in an active form, and degrading the accumulated GAG. In conclusion, these results indicated that ERT with idursulfase produced in a human cell line could be useful in the treatment and management of MPS II, and were used in the design of clinical studies to evaluate the efficacy of idursulfase in MPS II patients.