Glycosaminoglycan storage in neuroanatomical regions of mucopolysaccharidosis I dogs following intrathecal recombinant human iduronidase

Abstract

Intrathecal (IT) recombinant human α-l-iduronidase (rhIDU) has been shown to reduce mean brain glycosaminoglycans (GAGs) to normal levels in mucopolysaccharidosis I (MPS I) dogs. In this study, we examined storage in neuroanatomical regions of the MPS I dog brain, including frontal lobe, cerebellum, basal ganglia, thalamus, hippocampal formation, and brainstem, to determine the response of these functional regions to treatment with IT rhIDU. GAG storage in untreated MPS I dogs was significantly different from normal dogs in all examined sections. GAG levels in normal dogs varied by region: frontal lobe (mean: 2.36 ± 0.54 μg/mg protein), cerebellum (2.67 ± 0.33), basal ganglia and thalamus (3.51 ± 0.60), hippocampus (3.30 ± 0.40), and brainstem (3.73 ± 1.10). Following IT treatment, there was a reduction in GAG storage in each region in all treatment groups, except for the brainstem. Percent reduction in GAG levels from untreated to treated MPS I dogs in the deeper regions of the brain was 30% for basal ganglia and thalamus and 30% for hippocampus, and storage reduction was greater in superficial regions, with 61% reduction in the frontal lobe and 54% in the cerebellum compared with untreated MPS I dogs. Secondary lipid storage in neurons was also reduced in frontal lobe, but not in the other brain regions examined. Response to therapy appeared to be greater in more superficial regions of the brain, particularly in the frontal lobe cortex.

Fig. 1

Mean GAG levels in different neuroanatomical regions. Error bars reflect standard deviations. FL = frontal lobe, CB = cerebellum, BGT = Basal ganglia and thalamus, HF = hippocampal formation, BS = brainstem.

Fig. 2

Lysosomal storage in untreated and IT-treated MPS I dogs. Cortical neuron in the frontal lobe of an untreated MPS I dog (a) and an IT-treated MPS I dog (b) 6500x. Purkinje cells of cerebellum from an untreated (c) and treated (d) MPS I dog, 4000x. Neurons in the hippocampus in untreated (e) and treated (f) MPS I dog, 6500x. Neuronal storage (arrows) had the morphological characteristics of complex lipid storage (inset, a). Perivascular storage (arrowhead) had the characteristics of GAG storage. N: neuron, PV: perivascular cell, uranyl acetate-lead citrate.

Fig. 3

Perivascular cells in the cerebellum of an untreated (a) and treated (b) MPS I dog. Perivascular storage (arrowhead) had the characteristics of GAG storage, 6500x, uranyl acetate-lead citrate.