Mucopolysaccharidosis IVA: Current Disease Models and Drawbacks

Abstract

Mucopolysaccharidosis IVA (MPS IVA) is a rare disorder caused by mutations in the N-acetylgalactosamine-6-sulfate-sulfatase (GALNS) encoding gene. GALNS leads to the lysosomal degradation of the glycosaminoglyccreasans keratan sulfate and chondroitin 6-sulfate. Impaired GALNS enzymes result in skeletal and non-skeletal complications in patients. For years, the MPS IVA pathogenesis and the assessment of promising drugs have been evaluated using in vitro (primarily fibroblasts) and in vivo (mainly mouse) models. Even though value information has been raised from those studies, these models have several limitations. For instance, chondrocytes have been well recognized as primary cells affected in MPS IVA and responsible for displaying bone development impairment in MPS IVA patients; nonetheless, only a few investigations have used those cells to evaluate basic and applied concepts. Likewise, current animal models are extensively represented by mice lacking GALNS expression; however, it is well known that MPS IVA mice do not recapitulate the skeletal dysplasia observed in humans, making some comparisons difficult. This manuscript reviews the current in vitro and in vivo MPS IVA models and their drawbacks.

Keywords: chondrocytes; fibroblasts; mouse; mucopolysaccharidosis IVA; rat.

Figure 1

GALNS enzyme activity and the most common mutations on the GALNS gene. Upper. Global mutation distribution for the GALNS gene. Note that missenses are the most common mutations. The most common mutations are displayed along the GALNS gene. Open rectangles represent exons made at scale. Mutations were chosen according to Tomatsu et al., 2005 [15]; Morrone et al., 2014 [13,16]; Cozma et al., 2015 [9]; Tapiero-Rodriguez et al., 2018 [17]; and Pachajoa et al., 2021 [10]. Bottom. Schematic representation of the GALNS activity on C6S and KS. Note that the GALNS enzyme (PDB-4FDI) is represented as a homodimer (green and red) that removes sulfate groups (green arrows). Impaired GALNS activity results in the lysosomal accumulation of C6S and KS. Historically, N-N-acetylgalactosamine-6-sulfate sulfatase catalyzes C6S, and galactosamine-6 sulfatase catalyzes KS.

Figure 2

Therapeutical strategies tested in MPS IVA. Strategies can be classified as substrate-, enzyme-, or gene-based approaches. A. Enzyme replacement therapy (ERT) leads the uptake of recombinant enzymes via mannose-6 phosphate receptors (M6PR) to be sorted into lysosomes where accumulated substrates will be degraded. B. Substrate degradation enzyme therapy (SDET) was evaluated in MPS IVA chondrocytes through incubation with a thermostable keratanase isolated from Bacillus circulans KsT202 [29], which specifically degraded KS. C. Gene therapy (GT) involves the delivery of therapeutic genes inside the nucleus, which can be attempted by using viral or non-viral vectors as carriers. D. Pharmacological chaperones (PCs) contribute to the thermal stability of proteins containing missense mutations that affect their folding. Consequently, stable proteins are sorted to the lysosome (E), where they can exert their catalytic activity on accumulated substrates. F. Lysosomal enzymes can also be released to the extracellular space (G) and taken up by neighboring cells (cross-correction mechanism). This last mechanism is the rationale for HSCT, engineered or not, and GT-based approaches. This figure was created with BioRender.com (accessed on 12 October 2023).