Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice

Mika Aoyagi-Scharber,Gouri Yogalingam,Bridget Yates,Catherine Vitelli,Evan G Adintori,Sara Rigney,Stuart Bunting,Heather Prill,Jonathan H Lebowitz,Sherry Bullens,Roger Lawrence,Brett E Crawford,Jon Vincelette,Jeremy L Van Vleet,Pascale M.N Tiger,Amanda Lee,John Holtzinger,Danielle Crippen-Harmon,Melanie J Lo,Bryan K Yip,Olivia Gorostiza,Brian Baridon,Terri Christianson ,Paul Fitzpatrick ,Wesley Minto

doi:10.1016/j.omtm.2017.05.009

Mika Aoyagi-Scharber, Gouri Yogalingam + Show 23 more

Open Access

https://doi.org/10.1016/j.omtm.2017.05.009

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Abstract

Sanfilippo syndrome type B (mucopolysaccharidosis IIIB), caused by inherited deficiency of α-N-acetylglucosaminidase (NAGLU), required for lysosomal degradation of heparan sulfate (HS), is a pediatric neurodegenerative disorder with no approved treatment. Intracerebroventricular (ICV) delivery of a modified recombinant NAGLU, consisting of human NAGLU fused with insulin-like growth factor 2 (IGF2) for enhanced lysosomal targeting, was previously shown to result in marked enzyme uptake and clearance of HS storage in the Naglu−/− mouse brain. To further evaluate regional, cell type-specific, and dose-dependent biodistribution of NAGLU-IGF2 (BMN 250) and its effects on biochemical and histological pathology, Naglu−/− mice were treated with 1–100 μg ICV doses (four times over 2 weeks). 1 day after the last dose, BMN 250 (100 μg doses) resulted in above-normal NAGLU activity levels, broad biodistribution, and uptake in all cell types, with NAGLU predominantly localized to neurons in the Naglu−/− mouse brain. This led to complete clearance of disease-specific HS and reduction of secondary lysosomal defects and neuropathology across various brain regions lasting for at least 28 days after the last dose. The substantial brain uptake of NAGLU attainable by this highest ICV dosage was required for nearly complete attenuation of disease-driven storage accumulations and neuropathology throughout the Naglu−/− mouse brain.

Highlights

Sanfilippo syndrome type B (Sanfilippo type B, mucopolysaccharidosis IIIB, or MPS IIIB) is a rare inherited lysosomal storage disorder caused by mutations in the gene encoding a-N-acetylglucosaminidase (NAGLU, EC 3.2.1.50), an enzyme required for the degradation of the glycosaminoglycan heparan sulfate (HS).[1]
BMN 250 treatments led to a notable reduction of b-hexosaminidase activity, which is typically increased in NagluÀ/À mouse tissues.[25] b-Hexosaminidase enzyme activity, elevated at least 2-fold above normal in NagluÀ/À mouse brains, significantly decreased over time for 28 days after the treatments to levels closer to (1.4- to 1.6-fold) those in Naglu+/À and Naglu+/+ control mouse brains (Figure 3B)
We further evaluated regional, cell type-specific, and dose-dependent distribution of ICV-delivered recombinant human NAGLU-insulin-like growth factor 2 (IGF2) fusion protein and its effectiveness in normalizing primary lysosomal storage and secondary brain pathology

Summary

Introduction

Sanfilippo syndrome type B (Sanfilippo type B, mucopolysaccharidosis IIIB, or MPS IIIB) is a rare inherited lysosomal storage disorder caused by mutations in the gene encoding a-N-acetylglucosaminidase (NAGLU, EC 3.2.1.50), an enzyme required for the degradation of the glycosaminoglycan heparan sulfate (HS).[1] NAGLU deficiency leads to lysosomal accumulation of partially degraded HS, primarily in cells of the CNS.[2] Clinically, the disease is predominantly characterized by progressive, severe cognitive and neurological deterioration with relatively less profound somatic manifestations compared with other types of MPS disease. Several investigational therapies are currently being developed that aim to clear the pathological accumulation of HS, thereby slowing or preventing the subsequent progression of clinical symptoms.[5,6,7]

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