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.

Mucopolysaccharidosis (MPS IVA) is caused by pathogenic variations in the GALNS gene, leading to the accumulation of glycosaminoglycans in tissues and causing progressive skeletal lesions. While conventional lentiviral vectors (LVs) provide long-term stable expression, they do not deliver therapeutic levels to bone and cartilage. We hypothesized that engineering the LV envelope with a collagen type II-targeting peptide (WYRGRL) increases the binding affinity of the LVs for bone and cartilage. These modified vectors carrying the CBh and COL2A1 promoters delivered the GALNS gene to MPS IVA newborn mice via intravenous (IV) or intraarticular (IA) administration. The peptide-modified LVs exhibited markedly increased uptake in the liver when administered IV, but lower enzyme activity than that of the conventional vector. The modified WYRGRL-LV-COL2A1 vector elevated GALNS activity in other tissues, suggesting systemic benefits. When administered IA, the modified vectors showed potential for local treatment due to the WYRGRL peptide-mediated uptake. Additionally, there was a reduction in keratan sulfate glycosaminoglycan levels in plasma and tissues, indicating that this peptide can be a suitable candidate for disease modification. These findings pave the way for further preclinical and clinical studies, offering new possibilities for the development of targeted therapies for skeletal diseases.

Mucopolysaccharidosis IVA (MPS IVA) results from deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), leading to progressive keratan sulfate accumulation, and current treatments have limited efficacy. Although adeno-associated virus (AAV) gene therapy can restore systemic enzyme activity, immune responses to the transgene and viral capsid restrict durability and prevent vector re-administration. We evaluated a combined strategy of antigen-specific oral immune tolerance and sequential AAV serotype delivery. Neonatal MPS IVA mice received a mixture of three immunodominant GALNS-derived T- and B-cell epitopes on alternate days for 20 days, followed by AAV9 at 4 weeks and redosing with either AAV9 or AAV8 at 10 weeks. Peptide-treated tolerized MPS IVA mice showed a 2–3-fold increase in circulating GALNS activity after the first dose and a 7–8-fold increase after redosing, whereas non-tolerized MPS IVA mice developed anti-GALNS antibodies that reduced enzyme levels. No cross-reactive neutralizing antibodies were detected between AAV9 and AAV8. Peptide-treated mice showed normalization of plasma and hepatic keratan sulfate (KS) and significant improvements in skeletal and cardiac histopathology, with the greatest benefit in the peptide-treated AAV9→AAV8 group. These findings demonstrate that oral immune tolerance enables safe AAV re-administration, enhances systemic enzyme bioavailability, and improves tissue correction, supporting a clinically translatable approach for durable treatment of MPS IVA.