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

NCT04112602 | Completed

• 3 other identifiers: RIPH3-RNI19/RespiGAG2019-A01361-5619.05.17.43323 RIPH 3 HPS
• Study Type: observational
• Target: 27
• Locations: 1 country
• Sites: 7

Brief 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.

Conditions

Mucopolysaccharidoses

Keywords

mucopolysaccharidosis; lung cathepsins; proteases inhibitors; glycosaminoglycans

Outcome Measures

Primary Outcomes (2)

• Evaluation of the expression of pulmonary cathepsins, proteases inhibitors and GAGs in MPS patients.

  Detection and identification by Western blot. Results will be compared to non-MPS patients.

  Day 1

• Quantification of pulmonary cathepsins, protease inhibitors and GAGs in MPS patients.

  Quantification by kinetics and ELISA assays. Results will be compared to non-MPS patients.

  Day 1

Secondary Outcomes (1)

• Pulmonary cathepsins enzymatic activity measurement.

  Day 1

Study Arms (2)

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.

Other: Sputum; Other: Tracheal aspiration

Non-MPS patients

In this control group are included patients under 18 years old, with no respiratory problems, no MPS.

Other: Tracheal aspiration

Interventions

Sputum OTHER

Sputum will be collected after a respiratory physiotherapy session, scheduled as part of routine care.

Patients with MPS

Tracheal aspiration OTHER

Tracheal aspirations will be collected in intubated patients (intubation for surgery under general anesthesia).

Non-MPS patients; Patients with MPS

Eligibility Criteria

• Age: Up to 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

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.

You may qualify if:

• 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
• 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

You may not qualify if:

• Impossibility to use pulmonary samples (insufficient volume, conservation problem, etc.)
• Non-MPS patients:
• Patient with no respiratory disease
• Aged from 0 to 17 years old
• Emergency medical situation
• Inability to obtain pulmonary expectoration
• Refusal of the patient, parent or legal representative to participate in this study
• Impossibility to use pulmonary samples (insufficient volume, conservation problem, etc.)

Sponsors & Collaborators

• University Hospital, Tours: lead

Study Sites (7)

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

Angers, France

Location

Metabolic Disease Reference Centre - Medical Genetics Department - University Hospital, Bordeaux

Bordeaux, France

Location

Metabolic Disease Competence Centre - Medical Genetics Department - University Hospital, Brest

Brest, France

Location

Metabolic Disease Competence Centre - Pediatrics Department - University Hospital, Rennes

Rennes, France

Location

Metabolic Disease Reference Centre - Pediatrics Department - University Hospital, Toulouse

Toulouse, France

Location

Metabolic Disease Reference Centre - Pediatrics Department - University Hospital, Tours

Tours, France

Location

Pediatric Resuscitation Unit - Universty Hospital, Tours

Tours, France

Location

Related Publications (9)

• 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.

  PMID: 28595941 BACKGROUND

• 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.

  PMID: 28964643 BACKGROUND

• 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.

  PMID: 30451936 BACKGROUND

• 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.

  PMID: 19834056 BACKGROUND

• 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.

  PMID: 25178906 BACKGROUND

• 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.

  PMID: 19388876 BACKGROUND

• 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.

  PMID: 28104572 BACKGROUND

• 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.

  PMID: 23968158 BACKGROUND

• 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.

  PMID: 26116954 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Pulmonary samples (sputum / tracheal aspiration)

MeSH Terms

Conditions

Mucopolysaccharidoses

Condition Hierarchy (Ancestors)

Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• François Labarthe, MD-PhD

  University Hospital, Tours

  STUDY DIRECTOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 1, 2019
• First Posted: October 2, 2019
• Study Start: November 12, 2019
• Primary Completion: June 26, 2020
• Study Completion: June 26, 2020
• Last Updated: January 4, 2022

Record last verified: 2022-01

Locations

FR (7)