Blood-brain barrier impairment in MPS III patients

Abstract

BackgroundMucopolysaccharidosis type III (MPS III) is an autosomal recessive disorder caused by deficiency of a specific enzyme leading to heparan sulfate (HS) accumulation within cells and to eventual progressive cerebral and systemic organ abnormalities. Different enzyme deficiencies comprise the MPS III subcategories (A, B, C, D). Since neuropathological manifestations are common to all MPS III types, determining blood-brain barrier (BBB) condition may be critical to understand potential additional disease mechanisms.MethodsWe investigated BBB integrity in various brain structures of post-mortem tissues from an eleven year old Caucasian female with MPS III A and from a twenty four year old Caucasian female with MPS III D. Control tissues were obtained post-mortem from three Caucasians without neurological deficits: a twelve year old male, a twenty four year old female, and a twenty seven year old female. BBB capillary ultrastructure (electron microscopy) and capillary functional integrity (IgG leakage, tight junction proteins, and lysosomal accumulation within endothelium) were examined.ResultsCompromised BBB integrity was found in both MPS III cases. Major study findings were: (1) capillary endothelial and pericyte cell damage; (2) mucopolysaccharide bodies in a majority of endothelial cells and pericytes rupturing cell membranes; (3) severe extracellular edema; (4) IgG microvascular leakage and reductions of occludin and claudin-5 with variations between MPS III types; (5) extensive lysosomal accumulation in capillary endothelium.ConclusionsThese new findings of BBB structural and functional impairment, although from only two cases, MPS III A and III D, may have implications for disease pathogenesis and should be considered in treatment development for MPS III.

Pentosan Polysulfate Treatment of Mucopolysaccharidosis Type IIIA Mice

“…Importantly, subQ PPS administration also had an impact on the brains of the MPS IIIA mice, suggesting that the administered PPS may cross the BBB. It is important to note that impairment of the BBB has been previously described in this mouse model (Garbuzova-Davis et al 2011), as well as in patients with MPS IIIA and IIID (Garbuzova-Davis et al 2013). We have also previously detected reduction in CSF cytokine levels in MPS I…”

Targeted Polymeric Nanoparticles for Brain Delivery of High Molecular Weight Molecules in Lysosomal Storage Disorders

“…In particular, evaluations performed in the animal models of Gaucher disease and GM1 gangliosidosis showed important BBB alterations, while analysis of the barrier in the mouse model of the late onset Tay-Sachs disease did not reveal any abnormalities [ 41 , 42 ]. In addition, in the MPS III condition, endothelial cell damage with possible compromise of the BBB was described, indicated, among others, by Evans Blue and albumin microvascular leakage, in various brain structures [ 38 , 39 , 43 ]. On the opposite, a similar analysis conducted in this work for both wt and Idua-ko mice, by using Evans Blue ( S1 Text ) and FITC-albumin, revealed no altered permeability, thus possibly suggesting modified pathways of uptake.…”

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

“…The development of rhHNS administered into the CSF via a surgically implanted IDDD for patients with MPS IIIA attempts to overcome the inability of this ERT to cross the BBB via IV administration. As the disease progresses, structural and functional damage to the highly integrated microvascular CNS barrier can cause impairment to both influx and efflux systems, thus adding further uncertainty to IV dosing strategies [ 23 ]. One advantage of delivering the ERT directly to the CSF space was described by Calias et al in a review on protein therapeutics in the CSF [ 24 ].…”