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Int. J. Mol. Sci. 2017, 18(12), 2594; https://doi.org/10.3390/ijms18122594

Whole Body and CNS Biodistribution of rhHNS in Cynomolgus Monkeys after Intrathecal Lumbar Administration: Treatment Implications for Patients with MPS IIIA

1
Nonclinical Development, Research and Discovery, Shire, 300 Shire Way, Lexington, MA 02421, USA
2
KinderPharm/PKPD Bioscience Inc., 100 Arrandale Blvd #101, Exton, PA 19341, USA
Jou-Ku Chung and Thomas G. McCauley were employees of Shire at the time of these studies.
*
Author to whom correspondence should be addressed.
Received: 5 October 2017 / Revised: 13 November 2017 / Accepted: 18 November 2017 / Published: 1 December 2017
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Abstract

Mucopolysaccharidosis III type A (MPS IIIA; Sanfilippo syndrome), a genetic lysosomal disorder causing a deficiency of heparan N-sulfatase (HNS), leads to progressive cognitive decline from an early age. An effective enzyme replacement therapy (ERT) for MPS IIIA requires central nervous system (CNS) biodistribution. Recombinant human heparan N-sulfatase (rhHNS), an investigatory ERT for MPS IIIA, has been formulated for intrathecal (IT) administration since intravenous (IV) administration cannot cross the blood brain barrier (BBB) in sufficient amounts to have a therapeutic effect. In this study, systemic and CNS distribution of rhHNS in cynomolgus monkeys following IV and IT administration was evaluated by quantitation of rhHNS in serum, cerebral spinal fluid (CSF) and various tissues, and positron emission tomography (PET) imaging of live animals. Following IV administration, rhHNS levels were low to non-detectable in the CSF, and systemic clearance was rapid (≤2 h). With IT administration, rhHNS was observable in CNS tissues in ≤1 h, with varying Tmax (1–24 h). Appreciable systemic distribution was observed up to 7 days. This provides evidence that in this animal model, intrathecal administration of rhHNS delivers the replacement enzyme to therapeutically relevant tissues for the treatment of Sanfilippo Syndrome type A. Penetration into grey matter and cortex was 3–4 times greater than concentrations in white matter and deeper parenchymal regions, suggesting some limitations of this ERT strategy. View Full-Text
Keywords: enzyme replacement therapy; recombinant human heparan N-sulfatase; mucopolysaccharidosis III type A; Sanfilippo syndrome; lysosomal disorder; intrathecal administration; positron emission tomography; pharmacokinetics; cerebral spinal fluid enzyme replacement therapy; recombinant human heparan N-sulfatase; mucopolysaccharidosis III type A; Sanfilippo syndrome; lysosomal disorder; intrathecal administration; positron emission tomography; pharmacokinetics; cerebral spinal fluid
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Chung, J.-K.; Pan, L.; Palmieri, K.; Youssef, A.S.; McCauley, T.G. Whole Body and CNS Biodistribution of rhHNS in Cynomolgus Monkeys after Intrathecal Lumbar Administration: Treatment Implications for Patients with MPS IIIA. Int. J. Mol. Sci. 2017, 18, 2594.

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