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

Jou-Ku Chung,Luying Pan,Kathleen Palmieri,Amir Youssef,Thomas Mccauley

doi:10.3390/ijms18122594

Jou-Ku Chung, Luying Pan + Show 3 more

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https://doi.org/10.3390/ijms18122594

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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.

Highlights

Sanfilippo syndrome type A, called mucopolysaccharidosis type IIIA (MPS IIIA), is an autosomal recessive lysosomal disorder that causes a deficiency in the enzyme heparan N-sulfatase (HNS) [1]
cerebral spinal fluid (CSF) and blood samples were collected at specific time points after IV and IT dosing of Recombinant human heparan N-sulfatase (rhHNS) in six animals per dose group for HNS quantification by enzyme linked immunosorbent assay (ELISA)
CSF concentrations for this dose were below the limit of quantification (BLQ) for three animals across all time points and BLQ or less than the lower limit of quantification (LLOQ = 10 ng/mL) for seven of 10 time points for the remaining animals

Summary

Introduction

Sanfilippo syndrome type A, called mucopolysaccharidosis type IIIA (MPS IIIA), is an autosomal recessive lysosomal disorder that causes a deficiency in the enzyme heparan N-sulfatase (HNS) [1]. Consequent buildup of glycosaminoglycan (GAG)/heparan sulfate (HS) causes progressive neurodegeneration in affected children, with symptoms presenting in the second year of life. The cognitive development of affected children is marked by delays, arrest, and regression [2]. Their cognitive decline is accompanied by increasing behavioral and sleep disturbances, motor impairment, and, in some cases, seizures. The lifespan of children with MPS IIIA typically does not extend beyond late teens to early twenties [2,3]

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