Biodistribution of Idursulfase Formulated for Intrathecal Use (Idursulfase-IT) in Cynomolgus Monkeys after Intrathecal Lumbar Administration

Jou-Ku Chung,Bob Crooker,Eilish Brown,Thomas G Mccauley,Kathleen J Palmieri,Mária A Deli

doi:10.1371/journal.pone.0164765

Abstract

Enzyme replacement therapy with intravenous idursulfase (recombinant iduronate-2-sulfatase) is approved for the treatment of Hunter syndrome. Intravenous administration does not, however, treat the neurological manifestations, due to its low central nervous system bioavailability. Using intrathecal-lumbar administration, iduronate-2-sulfatase is delivered directly to the central nervous system. This study investigates the central nervous system biodistribution of intrathecal-lumbar administered iduronate-2-sulfatase in cynomolgus monkeys. Twelve monkeys were administered iduronate-2-sulfatase in one 30 mg intrathecal-lumbar injection. Brain, spinal cord, liver, and kidneys were collected for iduronate-2-sulfatase concentration (measured by an enzyme linked immunosorbent assay) and enzyme activity measurement (via a method utilizing 4-methylumbelliferyl-α-iduronate-2-sulfate) at 1, 2, 5, 12, 24, and 48 hours following administration. The tissue enzyme linked immunosorbent assay confirmed iduronate-2-sulfatase uptake to the brain, spinal cord, kidneys, and liver in a time-dependent manner. In spinal cord and brain, iduronate-2-sulfatase appeared as early as 1 hour following administration, and peak concentrations were observed at ~2 and ~5 hours. Iduronate-2-sulfatase appeared in liver and kidneys 1 hour post intrathecal-lumbar dose with peak concentrations between 5 and 24 hours. Liver iduronate-2-sulfatase concentration was approximately 10-fold higher than kidney. The iduronate-2-sulfatase localization and enzyme activity in the central nervous system, following intrathecal administration, demonstrates that intrathecal-lumbar treatment with iduronate-2-sulfatase may be considered for further investigation as a treatment for Hunter syndrome patients with neurocognitive impairment.

Highlights

Hunter syndrome is an X-linked disease caused by a deficiency or absence of the enzyme iduronate-2-sulfatase (I2S), a lysosomal storage enzyme required for the degradation of glycosaminoglycans [1]
In order to determine the background, endogenous levels of I2S in these animals, cerebrospinal fluid (CSF) and serum samples were collected prior to idursulfase-IT dosing in all animals
The validated 4-MUF assay cannot differentiate between endogenous and exogenous I2S, and substantial levels of endogenous I2S activity were detected in the serum (847 nU/mL) and CSF (85.4 nU/mL) prior to idursulfase-IT administration

Summary

Introduction

Hunter syndrome is an X-linked disease caused by a deficiency or absence of the enzyme iduronate-2-sulfatase (I2S), a lysosomal storage enzyme required for the degradation of glycosaminoglycans [1]. It has an incidence of about 1 in 170,000 male births [2]. There is currently no cure for this disease, intravenous enzyme replacement therapy with recombinant human I2S (idursulfase, Elaprase Shire, Lexington, MA) is an approved treatment in over 50 countries for Hunter syndrome. It is important to find an effective method of drug delivery for therapy to the brain

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