Respiratory Impairment in Mucopolysaccharidosis Patients: Impact of Glycosaminoglycans (GAG) on the Proteases/Antiproteases Balance

Mucopolysaccharidosis (MPS) are a group of inherited, metabolic diseases caused by a deficiency of lysosomal enzymes that degrade glycosaminoglycans (GAGs). Loss of their activity results in cellular accumulation of GAGs fragments leading to progressive multi-system manifestations (central nervous system involvement, dysmorphism, skeletal abnormalities, cardiomyopathy, ear/nose/throat and respiratory problems). Impairment of pulmonary function is an important health problem for patients with MPS.

Various therapeutic approaches have been developed to restore deficient enzymatic activity (stem cell transplantation, enzyme replacement therapy, gene therapy), but new therapeutic approaches may be required, in addition to these current conventional treatments. In particular, respiratory failure is not fully restored. The cellular and molecular mechanisms responsible for lung dysfunction remain today largely unknown and require additional investigations. It is well established that GAGs, upon specific conditions either stimulate or inhibit the activity of specific enzymes named cathepsins.

Cysteine cathepsins are lysosomal proteases that can be secreted extracellularly by macrophages, epithelial cells and fibroblasts. Imbalance between cathepsins and their inhibitors in favor to proteolysis has been demonstrated in patients with chronic pulmonary diseases (silicosis, cystic fibrosis). By contrast, high levels of their endogenous inhibitors are found in idiopathic fibrosis. Interestingly, previous studies reported that accumulation of sulphated GAGs (chondroitin sulfate, heparan sulfate, dermatan sulfate) impaired the collagenolytic activity of cathepsin K in a MPS I mouse model, supporting that cathepsin K participates to the pathophysiology of the bone involvement in patients with MPS. Moreover, other related cathepsins are regulated in vitro by GAGs.

Thus, inhibition of cathepsins may contribute to the respiratory impairment in MPS patients. However, their expression and their role in the airway of MPS patients are still unknown. Moreover, little is known on GAG levels in MPS lungs. The main hypothesis of the proposed research is to evaluate the levels of sulfated GAGs (heparan sulfate, chondroitin sulfate, dermatan sulfate) in respiratory samples of MPS patients and the ability of theses GAGs to modulate the proteolytic activities of lysosomal cathepsins. This would lead to an abnormal remodeling of the extracellular matrix architecture, contributing to the respiratory disorders of patients with MPS. To validate this hypothesis, a correlational study will be performed to find a relationship between cathepsins expression/activity, GAGs concentrations and respiratory function.

This is a multicentre, prospective, non-interventional and case-control study (patients with MPS vs non-MPS patients). Pulmonary samples (biological waste) will be collected in patients after either a respiratory physiotherapy session (scheduled for routine care) or by tracheal aspiration when patients are intubated (intubation for imaging or surgery under general anesthesia). Collected samples will be used to assess the level of expression and activity of cathepsins and their inhibitors and the amount of sulfated GAGs.