- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04112602
Respiratory Cathepsins, Proteases Inhibitors and Glycosaminoglycans (GAG) in Mucopolysaccharidosis (RespiGAG)
Respiratory Impairment in Mucopolysaccharidosis Patients: Impact of Glycosaminoglycans (GAG) on the Proteases/Antiproteases Balance
Study Overview
Status
Conditions
Intervention / Treatment
Detailed 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:
- Better understanding of the respiratory pathophysiology in MPS patients: by understanding the molecular cathepsins/GAGs interactions.
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.
- 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 Type
Enrollment (Actual)
Contacts and Locations
Study Locations
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-
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Angers, France
- Metabolic Disease Competence Centre - Medical Genetics Department - University Hospital, Angers
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Bordeaux, France
- Metabolic Disease Reference Centre - Medical Genetics Department - University Hospital, Bordeaux
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Brest, France
- Metabolic Disease Competence Centre - Medical Genetics Department - University Hospital, Brest
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Rennes, France
- Metabolic Disease Competence Centre - Pediatrics Department - University Hospital, Rennes
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Toulouse, France
- Metabolic Disease Reference Centre - Pediatrics Department - University Hospital, Toulouse
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Tours, France
- Metabolic Disease Reference Centre - Pediatrics Department - University Hospital, Tours
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Tours, France
- Pediatric Resuscitation Unit - Universty Hospital, Tours
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
Patients with MPS:
In this cohort are included patients under 18 years old with MPS (all types). The objective is to be representative of the diversity of MPS, and of this evolution.
Non-MPS patients:
In this control group are included patients under 18 years old, with no respiratory problems, no MPS.
Description
Patients with MPS:
Inclusion Criteria:
- Patient with a confirmed diagnosis (enzymatic activity, and/or genotyping) of MPS, all types (I, II, III, IV, VI, VII, IX)
- Aged from 0 to 17 years old
Non inclusion Criteria:
- Chronic respiratory disease independent of MPS disease (potential interferences with our analyzes)
- Inability to obtain pulmonary samples
- Refusal of the patient, parent or legal representative to participate in this study
Exclusion Criteria:
- Impossibility to use pulmonary samples (insufficient volume, conservation problem, etc.)
Non-MPS patients:
Inclusion Criteria:
- Patient with no respiratory disease
- Aged from 0 to 17 years old
Non inclusion Criteria:
- Emergency medical situation
- Inability to obtain pulmonary expectoration
- Refusal of the patient, parent or legal representative to participate in this study
Exclusion Criteria:
- Impossibility to use pulmonary samples (insufficient volume, conservation problem, etc.)
Study Plan
How is the study designed?
Design Details
- Observational Models: Case-Control
- Time Perspectives: Prospective
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
---|---|
Patients with MPS
In this cohort are included patients under 18 years old with MPS (all types).
The objective is to be representative of the diversity of MPS, and of this evolution.
|
Sputum will be collected after a respiratory physiotherapy session, scheduled as part of routine care.
Tracheal aspirations will be collected in intubated patients (intubation for surgery under general anesthesia).
|
Non-MPS patients
In this control group are included patients under 18 years old, with no respiratory problems, no MPS.
|
Tracheal aspirations will be collected in intubated patients (intubation for surgery under general anesthesia).
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Evaluation of the expression of pulmonary cathepsins, proteases inhibitors and GAGs in MPS patients.
Time Frame: Day 1
|
Detection and identification by Western blot.
Results will be compared to non-MPS patients.
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Day 1
|
Quantification of pulmonary cathepsins, protease inhibitors and GAGs in MPS patients.
Time Frame: Day 1
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Quantification by kinetics and ELISA assays.
Results will be compared to non-MPS patients.
|
Day 1
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pulmonary cathepsins enzymatic activity measurement.
Time Frame: Day 1
|
Enzyme activity measurement by enzymatic kinetics techniques.
|
Day 1
|
Collaborators and Investigators
Sponsor
Investigators
- Study Director: François Labarthe, MD-PhD, University Hospital, Tours
Publications and helpful links
General Publications
- Khan SA, Peracha H, Ballhausen D, Wiesbauer A, Rohrbach M, Gautschi M, Mason RW, Giugliani R, Suzuki Y, Orii KE, Orii T, Tomatsu S. Epidemiology of mucopolysaccharidoses. Mol Genet Metab. 2017 Jul;121(3):227-240. doi: 10.1016/j.ymgme.2017.05.016. Epub 2017 May 26.
- Rapoport DM, Mitchell JJ. Pathophysiology, evaluation, and management of sleep disorders in the mucopolysaccharidoses. Mol Genet Metab. 2017 Dec;122S:49-54. doi: 10.1016/j.ymgme.2017.08.008. Epub 2017 Aug 25.
- Kobayashi H. Recent trends in mucopolysaccharidosis research. J Hum Genet. 2019 Feb;64(2):127-137. doi: 10.1038/s10038-018-0534-8. Epub 2018 Nov 19.
- Wilson S, Hashamiyan S, Clarke L, Saftig P, Mort J, Dejica VM, Bromme D. Glycosaminoglycan-mediated loss of cathepsin K collagenolytic activity in MPS I contributes to osteoclast and growth plate abnormalities. Am J Pathol. 2009 Nov;175(5):2053-62. doi: 10.2353/ajpath.2009.090211. Epub 2009 Oct 15.
- Lalmanach G, Saidi A, Marchand-Adam S, Lecaille F, Kasabova M. Cysteine cathepsins and cystatins: from ancillary tasks to prominent status in lung diseases. Biol Chem. 2015 Feb;396(2):111-30. doi: 10.1515/hsz-2014-0210.
- Bromme D, Lecaille F. Cathepsin K inhibitors for osteoporosis and potential off-target effects. Expert Opin Investig Drugs. 2009 May;18(5):585-600. doi: 10.1517/13543780902832661.
- Baldo G, Tavares AM, Gonzalez E, Poletto E, Mayer FQ, Matte UD, Giugliani R. Progressive heart disease in mucopolysaccharidosis type I mice may be mediated by increased cathepsin B activity. Cardiovasc Pathol. 2017 Mar-Apr;27:45-50. doi: 10.1016/j.carpath.2017.01.001. Epub 2017 Jan 6.
- Sage J, Mallevre F, Barbarin-Costes F, Samsonov SA, Gehrcke JP, Pisabarro MT, Perrier E, Schnebert S, Roget A, Livache T, Nizard C, Lalmanach G, Lecaille F. Binding of chondroitin 4-sulfate to cathepsin S regulates its enzymatic activity. Biochemistry. 2013 Sep 17;52(37):6487-98. doi: 10.1021/bi400925g. Epub 2013 Sep 4.
- Kubaski F, Tomatsu S, Patel P, Shimada T, Xie L, Yasuda E, Mason R, Mackenzie WG, Theroux M, Bober MB, Oldham HM, Orii T, Shaffer TH. Non-invasive pulmonary function test on Morquio patients. Mol Genet Metab. 2015 Aug;115(4):186-92. doi: 10.1016/j.ymgme.2015.06.007. Epub 2015 Jun 23.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- RIPH3-RNI19/RespiGAG
- 2019-A01361-56 (Other Identifier: IdRCB)
- 19.05.17.43323 RIPH 3 HPS (Other Identifier: CPP)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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