Mucopolysaccharidosis VII (MPS VII) is a rare
lysosomal storage disease characterized by a deficiency in the
enzyme β-
glucuronidase that has previously been successfully treated in a mouse model with
enzyme replacement therapy. Here, we present the generation of a novel, highly sialylated version of recombinant human β-
glucuronidase (rhGUS),
vestronidase alfa, that has high uptake, resulting in an improved
enzyme replacement therapy for the treatment of patients with MPS VII. In vitro,
vestronidase alfa has 10-fold more
sialic acid per mole of rhGUS monomer than a prior rhGUS version (referred to as GUS 43/44) and demonstrated very high affinity at ~1 nM half maximal uptake in human MPS VII fibroblasts.
Vestronidase alfa has a longer enzymatic half-life after uptake into fibroblasts compared with other
enzymes used as replacement
therapy for MPS (40 days vs 3 to 4 days, respectively). In pharmacokinetic and tissue distribution experiments in Sprague-Dawley rats,
intravenous administration of
vestronidase alfa resulted in higher serum rhGUS levels and enhanced β-
glucuronidase activity distributed to target tissues. Weekly
intravenous injections of
vestronidase alfa (0.1 mg/kg to 20 mg/kg) in a murine model of MPS VII demonstrated efficient
enzyme delivery to all tissues, including bone and brain, as well as reduced lysosomal storage of
glycosaminoglycans (GAGs) in a dose-dependent manner, resulting in increased survival after 8 weeks of treatment.
Vestronidase alfa was well-tolerated and demonstrated no toxicity at concentrations that reached 5-times the proposed clinical dose. In a first-in-human phase 1/2 clinical trial, a dose-dependent reduction in urine GAG levels was sustained over 38 weeks of treatment with
vestronidase alfa. Together, these results support the therapeutic potential of
vestronidase alfa as an
enzyme replacement therapy for patients with MPS VII.