Abstract
An intrathecal (IT) formulation of recombinant human heparan N-sulfatase (HNS) is under development for the treatment of the neurological symptoms of mucopolysaccharidosis IIIA (MPS IIIA; Sanfilippo A disease), the defining clinical feature of this disorder. Since the average age of MPS IIIA patients is 4.5 years, the pivotal toxicology studies for HNS were conducted in juvenile cynomolgus monkeys to evaluate the effects on the developing brain. Monkeys were implanted with an IT-lumbar drug delivery device and dosed every other week by slow bolus administration (1.5, 4.5, or 8.3 mg/dose HNS for 6 months; 12 doses), with device and vehicle controls receiving phosphate-buffered saline or vehicle, respectively. Eight animals per group (four/sex) were necropsied at 3 and 6 months (device control group necropsied at 3 months), and eight animals from the vehicle group and the three HNS-dosed groups were necropsied 1 month after the final IT dose. No HNS-related clinical signs or gross central nervous system lesions were observed. Compared with controls, there were cellular infiltrates of slight-to-minimal mean severity in the meninges/perineurium surrounding the brain/spinal cord correlating with transient increases in cerebrospinal ...Continue Reading
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