Characterization of ocular pathology in canine models of mucopolysaccharidosis types I and IIIB with an additional study evaluating anti-inflammatory therapy

Abstract

The mucopolysaccharidoses (MPSs) are a group of rare lysosomal storage diseases (LSDs) caused by a genetic mutation affecting various enzymes responsible for the degradation and catabolism of glycosaminoglycans (GAGs). Two of the most common types of MPS are Mucopolysaccharidosis type I (MPS I; Hurler, OMIM 607014; Scheie, 607016; and Hurler-Scheie, 607015 syndromes) caused by an α-L-iduronidase enzyme deficiency, and Mucopolysaccharidosis type IIIB (MPS IIIB; OMIM:252920, Sanfilippo B syndrome) caused by an α-N-acetylglucosaminidase enzyme deficiency. These enzyme deficiencies lead to the accumulation of the GAGs Heparan sulfate and Dermatan sulfate in MPS I and the accumulation of Heparan sulfate in MPS IIIB. Accumulation of these GAGs occurs in many different cell types and tissues, with varying degrees of CNS, ocular, and somatic disease. Despite the differing phenotypes seen, ocular manifestations in humans with MPS I and MPS IIIB are common with pathological changes ranging from corneal opacification to retinopathy and optic nerve swelling/atrophy. Available treatments for both MPS I and MPS IIIB are suboptimal and fail to address any/all aspects of ocular disease. The goal of this dissertation was to characterize the clinical and pathological features of ocular disease in canine models of MPS I and MPS IIIB. Additionally, a pilot study was performed evaluating the efficacy of an anti-inflammatory drug, pentosan polysulfate (PPS), in improving ocular disease in the canine model of MPS IIIB. A variety of techniques were implemented to evaluate the ocular manifestations of disease ranging from ophthalmic examination (slit lamp biomicroscopy, indirect ophthalmoscopy, rebound tonometry, and ultrasonic pachymetry) to electroretinography (ERG) and finally microscopic evaluation of whole fixed globes with the use of histochemical stains (luxol fast blue (LFB), alcian blue (AB), Periodic-Acid Schiff (PAS)) and immunohistochemical markers (lysosomal integral membrane protein 2 (LIMP2) and Vimentin). Thorough characterization of large animal models of MPS I and MPS IIIB are critical for understanding the pathogenesis of disease and can be used in the screening and development of new therapeutics. This dissertation provides further insight into the characterization of canine ocular pathology in MPS I and MPS IIIB and provides foundational data for future pathogenesis and therapeutic studies.