Temporospatial Development of Neuropathologic Findings in a Canine Model of Mucopolysaccharidosis IIIB

Abstract

Mucopolysaccharidosis (MPS) IIIB is a neuropathic lysosomal storage disease characterized by the deficient activity of a lysosomal enzyme obligate for the degradation of the glycosaminoglycan (GAG) heparan sulfate (HS). The pathogenesis of neurodegeneration in MPS IIIB is incompletely understood. Large animal models are attractive for pathogenesis and therapeutic studies due to their larger size, outbred genetics, longer lifespan, and naturally occurring MPS IIIB disease. However, the temporospatial development of neuropathologic changes has not been reported for canine MPS IIIB. Here we describe lesions in 8 brain regions, cervical spinal cord, and dorsal root ganglion (DRG) in a canine model of MPS IIIB that includes dogs aged from 2 to 26 months of age. Pathological changes in the brain included early microscopic vacuolation of glial cells initially observed at 2 months, and vacuolation of neurons initially observed at 10 months. Inclusions within affected cells variably stained positively with PAS and LFB stains. Quantitative immunohistochemistry demonstrated increased glial expression of GFAP and Iba1 in dogs with MPS IIIB compared to age-matched controls at all time points, suggesting neuroinflammation occurs early in disease. Loss of Purkinje cells was initially observed at 10 months and was pronounced in 18- and 26-month-old dogs with MPS IIIB. Our results support the dog as a replicative model of MPS IIIB neurologic lesions and detail the pathologic and neuroinflammatory changes in the spinal cord and DRG of MPS IIIB-affected dogs.

Effects of oral Ambroxol on neuropathological measures in the canine model of Sanfilippo Syndrome type B

“…Histopathological changes in the canine MPS IIIB model are similar to those observed in people [25,26]. Neurons in various parts of the brain, including the cerebrum, caudate nucleus, hippocampus, thalamus, and hypothalamus, as well as different brainstem nuclei and spinal cord display cytoplasmic vacuolation ranging from mild to severe.…”

“…The study found significant changes in the expression of several genes that are important for maintaining neuroplasticity in MPS IIIB mice [39]. In dogs affected by MPS IIIB, mild reactive astrogliosis, characterized by increased labeling of GFAP in astrocytic processes with limited intertwining of processes, was observed in 2-month-old and 4-month-old dogs [26]. Lysosome-associated membrane protein 1 (LAMP1) has been utilized as an indirect indicator of lysosomal storage load and has demonstrated the ability to reflect the size of the lysosomal compartment, although it is not a direct measurement.…”

“…These findings suggested a primary accumulation of GAGs and secondary accumulation of gangliosides in affected cells. These observations have given us a better insight into the pathological changes experienced by MPS IIIB animals and may facilitate development of more effective treatment options [25,26].…”

Discrepancy in the Usage of GFAP as a Marker of Satellite Glial Cell Reactivity

“…The vast majority of studies described here find little or no GFAP expression in rat or mouse SGCs under naïve conditions. The same appears to be the case for the guinea pig [43], whereas basal expression levels were detected in the dog and monkey [40,89,90]. The purpose of animal models is often to deduce mechanistic insight of relevance to human diseases, but due to the general unavailability of human DRGs we still know relatively little about this tissue [91].…”

Tralesinidase Alfa Enzyme Replacement Therapy Prevents Disease Manifestations in a Canine Model of Mucopolysaccharidosis Type IIIB

“…Larger animal model of the mucopolysaccharidoses have been critical to the advancement of therapies ( Haskins et al, 2002 ) and are well suited to preclinical confirmation of the safety, efficacy, and pharmacologic activity of potential therapeutics. The canine MPS IIIB model is well characterized at the clinical, genetic, biochemical, and neuropathologic level ( Ellinwood et al, 2003 ; Egeland et al, 2020 ; Raj et al, 2020 ; Harm et al, 2021 ) and has been used in preclinical therapeutic evaluations ( Ellinwood et al, 2011 ). MPS IIIB dogs are deficient in NAGLU activity and show accumulation of HS in the CSF, CNS tissue, peripheral tissue, urine, and plasma, detectable as early as 1 month of age ( Ellinwood et al, 2003 ; Egeland et al, 2020 ).…”