Topics

Respiratory Cathepsins, Proteases Inhibitors and Glycosaminoglycans (GAG) in Mucopolysaccharidosis

2019-10-08 08:47:36 | BioPortfolio

Summary

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, with respiratory impairment. The cellular and molecular mechanisms responsible for the pulmonary impairment remain largely unknown. Specific GAGs, such as those accumulating in MPS, may act as potent inhibitors of some respiratory enzymes, like lysosomal cathepsins, depending on the nature of GAGs and their concentration. It is well established that deregulation of cathepsins levels plays a major role in the pathophysiology of some chronic respiratory diseases, such as cystic fibrosis. The role of cathepsins and their inhibitors in respiratory samples of MPS patients has never been studied. This study will focus on the status/activity of these proteases and their endogenous inhibitors in the sputum or tracheal aspiration of patients with MPS. Our main hypothesis is that high levels of GAGs in MPS patients impair the physiological activity of cathepsins and their inhibitors.

Description

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.

Patients with MPS will be recruited in some Reference and Competence Centers for Metabolic Diseases in France (Angers, Bordeaux, Brest, Rennes, Toulouse, Tours). The non-MPS patients will be recruited at the Tours University Hospital (Pediatric Resuscitation).

Some medical data of patients with MPS will be collected retrospectively from the medical record. These data will be age, sex, type of MPS, respiratory assessment.

The data collected for the non-MPS patients will be age and sex.

The expected benefits are:

1. Better understanding of the respiratory pathophysiology in MPS patients: by understanding the molecular cathepsins/GAGs interactions.

2. Development of new therapeutic approaches for respiratory disease in patients with MPS:

If we can prove that there is a dysregulation of pulmonary cathepsin activity in patients with MPS, a treatment that will restore this activity would be of great interest. This type of treatment is already studied in bone diseases such as osteoporosis. This treatment would be complementary to current conventional therapies, like stem cell transplant or enzyme replacement therapy.

3. New therapeutic approaches potentially effective for other problems in patients with MPS:

The mechanism of cathepsin activity inhibition by GAGs is probably not lung-specific. GAGs accumulation and cathepsin expression are ubiquitous in humans. The role of cathepsins dysregulation by GAGs has already been described to explain some bone or cardiac involvements. These new therapeutic approaches could therefore also have a beneficial effect on other organs involvement in patients with MPS.

Study Design

Conditions

Mucopolysaccharidoses

Intervention

Sputum, Tracheal aspiration

Location

Metabolic Disease Competence Centre - Medical Genetics Department - University Hospital, Angers
Angers
France

Status

Not yet recruiting

Source

University Hospital, Tours

Results (where available)

View Results

Links

Published on BioPortfolio: 2019-10-08T08:47:36-0400

Clinical Trials [567 Associated Clinical Trials listed on BioPortfolio]

Evaluation of the Effects os Losartan in Cardiovascular Disease Patient With Mucopolysaccharidoses IVA and VI

Mucopolysaccharidoses (MPS) are multisystemic diseases with significant clinical overlap between their types, with cardiac problems being among the most commonly observed manifestations an...

Effects of Tracheal Tube Size on Pulmonary Aspiration

Fluid leak around the cuff is minimized when the endotracheal tube size is small relative to the size of the trachea. In the current study, the investigators assess the influence of differ...

Minimal Occlusive Pressure With Cuffed ETTs: A Comparison of Two Different Techniques to Ensure a Tracheal Seal

In the past 5 years cuffed endotracheal tubes (ETT) have become the standard of care in pediatrics. However, hyperinflation of the cuff can compromise the tracheal mucosal perfusion while ...

Antigenic and Antibody Detection of Candida

In this study, a multicenter, prospective, synchronous blind, and controlled study was adopted to set the cut-off values of candida specific IgG, IgM, and Mn with the blood culture results...

Meconium Aspiration and Tracheal Suctioning—Feasibility Study

Feasibility study to randomize non-vigorous newborn infants born through meconium-stained amniotic fluid to endotracheal suctioning or immediate resuscitation.

PubMed Articles [618 Associated PubMed Articles listed on BioPortfolio]

Tracheal bridge for reconstruction of the upper airway in double tracheal stenosis.

Tracheal reconstruction is a complex surgical procedure which requires a well-trained, multidisciplinary team in order to achieve optimal results. No reviews or case reports involving the use of a hea...

Complete Tracheal Ring Deformity: A Translational Genomics Approach to Pathogenesis.

Complete tracheal ring deformity (CTRD) is a rare congenital abnormality of unknown etiology characterized by circumferentially continuous or nearly-continuous cartilaginous tracheal rings, variable d...

Exploring polycaprolactone in tracheal surgery: A scoping review of in-vivo studies.

Tracheal pathology can be life-threatening if not managed appropriately. There are still some surgical limitations today for certain pathologies, such as in severe tracheomalacia, or when long segment...

A case of tracheal obstruction caused by reflux and aspiration of semi-solid nutrients via the nasogastric tube.

Semi-solid nutrients have several advantages, including reduced cases of diarrhea and aspiration pneumonia, and are usually administered via percutaneous endoscopic gastrostomy owing to its high visco...

Segmental tracheal resection (nine rings) and reconstruction for carcinoma showing thymus-like differentiation (CASTLE) of the thyroid.

Tumors invading the trachea are rare, and although literature often suggests five tracheal rings as the maximum limit of tracheal resection with primary closure, longer tracheal resections and primary...

Medical and Biotech [MESH] Definitions

A type of lung inflammation resulting from the aspiration of food, liquid, or gastric contents into the upper RESPIRATORY TRACT.

Breathing in liquid or solids, such as stomach contents, into the RESPIRATORY TRACT. When this causes severe lung damage, it is called ASPIRATION PNEUMONIA.

A set of BACTERIAL ADHESINS and TOXINS, BIOLOGICAL produced by BORDETELLA organisms that determine the pathogenesis of BORDETELLA INFECTIONS, such as WHOOPING COUGH. They include filamentous hemagglutinin; FIMBRIAE PROTEINS; pertactin; PERTUSSIS TOXIN; ADENYLATE CYCLASE TOXIN; dermonecrotic toxin; tracheal cytotoxin; Bordetella LIPOPOLYSACCHARIDES; and tracheal colonization factor.

A condition caused by inhalation of MECONIUM into the LUNG of FETUS or NEWBORN, usually due to vigorous respiratory movements during difficult PARTURITION or respiratory system abnormalities. Meconium aspirate may block small airways leading to difficulties in PULMONARY GAS EXCHANGE and ASPIRATION PNEUMONIA.

Group of lysosomal storage diseases each caused by an inherited deficiency of an enzyme involved in the degradation of glycosaminoglycans (mucopolysaccharides). The diseases are progressive and often display a wide spectrum of clinical severity within one enzyme deficiency.

More From BioPortfolio on "Respiratory Cathepsins, Proteases Inhibitors and Glycosaminoglycans (GAG) in Mucopolysaccharidosis"

Quick Search

Relevant Topics

Respiratory
Asthma COPD Cystic Fibrosis Pneumonia Pulmonary Medicine Respiratory Respiratory tract infections (RTIs) are any infection of the sinuses, throat, airways or lungs.  They're usually caused by viruses, but they can also ...

Pulmonary
Pulmonary relating to or associated with the lungs eg Asthma, chronic bronchitis, emphysema, COPD, Cystic Fibrosis, Influenza,  Lung Cancer, Pneumonia, Pulmonary Arterial Hypertension, Sleep Disorders etc Follow and track Lung Cancer News ...

Cystic Fibrosis
Affecting over 8,500 people in the UK, Cystic Fibrosis (CF) is one of the UK's most common life-threatening inherited diseases. Around half of the CF population can expect to live over 38 years, although improvements in treatments mean a baby born ...


Searches Linking to this Trial