A CBB staining of cocoon-derived IDUA, Endo-D-treated GlcNAc-IDUA, and Endo-M N175Q-treated M6P-IDUAB M6PR-Dom9 lectin blotting for cocoon-derived IDUA, Endo-D-treated GlcNAc-IDUA, and Endo-M N175Q-treated C A Japanese macaque animal with MPS1-like phenotypesD Established fibroblasts derived from a Japanese macaque animalE Restoration of IDUA activity by M6P-dependent IDUA replacement and competitive inhibition in the presence of administration of cocoon-derived recombinant human IDUA for the Japanese macaque monkey. However, as expected, we observed slight effectiveness on bone deformity, joint contracture and valvular heart dysfunction.Compared to those therapeutic effects of cocoon-derived IDUA, the dosing of M6P-IDUA (0.58 mg protein/kg body weight, biweekly, six times) caused a significant decrease in urinal excretion of HS as probably resulting from the incorporation of M6P-IDUA into renal cells, including tubular and endothelial cells, via cell surface M6P receptors. Other improvements by previous iv administration of cocoon-derived IDUA were maintained during the M6P-IDUA administration. Unfortunately, we could not observe the efficacy of bone deformity, increase in joint motion range, and valvular heart dysfunction of the MPS1 monkey.Figure 3. NeoglycoIDUA replacement effects on MPS1 Japanese macaque fibroblasts via cell surface M6P receptorWe further performed iv ERT for an MPS1 Japanese macaque animal (4y11m-old female) using cocoon-derived IDUA in the 1st cool and then neoglycoIDUA (M6P-IDUA) in the 2nd cool after two months interval. The IDUA dose (0.58 mg protein/kg body weight) per iv injection was according to the clinical dose of laronidase for MPS1 patients. The iv administration under anesthesia interval was two weeks different from one week for MPS1 patients, considering the monkey’s tolerance for anesthesia. After six times iv administrations of cocoon-derived IDUA, the MPS1 monkey showed remarkable improvement in daily behavioral activity, more than expected, from slow movement to playing on the swing and quality of life (QOL). The efficacies of cocoon-derived IDUA, including regression of hyperplastic gingiva and restoration of thickened skin flexibility, were observed. In addition, there were no adverse effects for about three months. We could confirm the safety of plural iv M6P-IDUAM6P89
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