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Review
. 2024 Jan 17;25(2):1113.
doi: 10.3390/ijms25021113.

Molecular Mechanisms in Pathophysiology of Mucopolysaccharidosis and Prospects for Innovative Therapy

Yasuhiko Ago  1 , Estera Rintz  2 , Krishna Sai Musini  1   3 , Zhengyu Ma  1 , Shunji Tomatsu  1   3   4   5
Affiliations
Review

Molecular Mechanisms in Pathophysiology of Mucopolysaccharidosis and Prospects for Innovative Therapy

Yasuhiko Ago et al. Int J Mol Sci. .

Abstract

Mucopolysaccharidoses (MPSs) are a group of inborn errors of the metabolism caused by a deficiency in the lysosomal enzymes required to break down molecules called glycosaminoglycans (GAGs). These GAGs accumulate over time in various tissues and disrupt multiple biological systems, including catabolism of other substances, autophagy, and mitochondrial function. These pathological changes ultimately increase oxidative stress and activate innate immunity and inflammation. We have described the pathophysiology of MPS and activated inflammation in this paper, starting with accumulating the primary storage materials, GAGs. At the initial stage of GAG accumulation, affected tissues/cells are reversibly affected but progress irreversibly to: (1) disruption of substrate degradation with pathogenic changes in lysosomal function, (2) cellular dysfunction, secondary/tertiary accumulation (toxins such as GM2 or GM3 ganglioside, etc.), and inflammatory process, and (3) progressive tissue/organ damage and cell death (e.g., skeletal dysplasia, CNS impairment, etc.). For current and future treatment, several potential treatments for MPS that can penetrate the blood-brain barrier and bone have been proposed and/or are in clinical trials, including targeting peptides and molecular Trojan horses such as monoclonal antibodies attached to enzymes via receptor-mediated transport. Gene therapy trials with AAV, ex vivo LV, and Sleeping Beauty transposon system for MPS are proposed and/or underway as innovative therapeutic options. In addition, possible immunomodulatory reagents that can suppress MPS symptoms have been summarized in this review.

Keywords: enzyme replacement therapy; gene therapy; immunomodulatory drugs; innate immunity; mucopolysaccharidosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Representative inflammatory pathways and activated innate immunity in MPS [226,227]. Black arrows indicate activated pathways in MPS. Green arrows indicate pathways that are not considered to be activated. Red arrows indicate enhanced expression of each substance. Short, flat vertical lines at the tips of the dotted lines indicate inhibition by the reagent. Reagents that have been tested in MPS models are colored red. HS: heparan sulfate; TLR: Toll-like receptor; MyD88: myeloid differentiation primary response protein 88; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; ATP: adenosine triphosphate; ROS: reactive oxygen species; TXNIP: thioredoxin-interacting protein; TRX: thioredoxin; NLRP3: NOD-like receptor family pyrin domain-containing 3; IL: interleukin; TNF-α: tumor necrosis factor-alpha; GSDMD: gasdermin D; MMPs: matrix metalloproteinases. This figure was created with Biorender.com (accessed on 1 December 2023).
Figure 2
Figure 2
Receptor-mediated transcytosis across the blood–brain barrier. Receptor-mediated transcytosis (RMT) (molecular Trojan horse) mediates the transfer of enzymes tagged with monoclonal antibodies or ligands targeting specific receptors on the surface of the endothelial cells of the blood–brain barrier. The modality of monoclonal antibodies or ligands targeting transferrin receptors differs depending on the gene product. ArmaGen, Inc. (Calabasas, CA, USA) and JCR Pharmaceuticals Co., Ltd. (Ashiya, Japan)—bivalent (enzyme fused with the whole antibody). DENALI Therapeutics (South San Francisco, CA, USA)—monovalent (enzyme fused with the Fc region of IgG). This figure was created with Biorender.com (accessed on 1 December 2023).
Figure 3
Figure 3
Three-dimensional structural model representing the surface of GALNS (Protein Data Bank ID: 4FDJ), cross-eyed stereo view. The blue area is the surface of the active site consisting of Asp39, Asp40, Arg83, Tyr108, Lys140, His142, His236, Asp288, Asn289, Lys310, and dihydroxyalanine 79. The red area is the surface of Trp520. These two areas are in contact. This model does not determine the location of two amino acid residues, Ser 521 and His 522, at the C-terminus. The molecule depicted in the stick model is N-acetylgalactosamine. This figure was created with PyMOL Version 2.5.2.
Figure 4
Figure 4
Electrostatic potential of AAV capsid protein and its affinity to targets. (A) Heparan sulfate proteoglycan (HSPG) is negatively charged with disaccharide units of β-D-glucuronic acid (GlcA) and N-acetylglucosamine (GlcNAc). It has an affinity towards the positively charged HSPG-binding domain of AAV capsid, which consists of basic amino acids such as Arg and Lys. (B) Modification of VP1 and VP2 capsid proteins with negatively charged amino acid (Asp) on AAV increases the affinity of the modified vector for positively charged calcium hydroxyapatite in bone matrix. This figure was created with Biorender.com (accessed on 1 December 2023).
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