RhDNase and Biodistribution of PMN Serine Proteases in Cystic Fibrosis Sputum
Summary
Serine proteases belonging to the elastase family are mainly responsible for lung tissue destruction as observed during cystic fibrosis. But anti-inflammatory therapies based on systemic or aerosolized protease-inhibitors administration, have not given the expected results until now. One reason would be the impaired access of therapeutic inhibitors to their molecular targets. It was recently shown that neutrophils actively secrete neutrophil extracellular traps (NETs) made of DNA that binds cationic proteases among other molecules. NETs together with DNA passively released from dead neutrophils contribute to the viscosity of CF expectorations which explains that rhDNase treatment fluidifies expectorations and improves the patient status. Preliminary experiments in our laboratory have shown that DNA degradation was associated with a significant increase of proteolytic activity in the sputum soluble fraction. However the efficacy of exogenous inhibitors is also improved in these conditions. Using the specific substrates and methodologies that we developed previously to measure cell-surface associated proteolytic activities, we will study the effects of DNase on the activity of individual proteases, their biodistribution in sputum and their regulation by potential therapeutic inhibitors. Enzymatic, immunochemical and microscopic (confocal and scanning) techniques will first be used for ex vivo studies on sputa freshly collected at the adult and paediatric CRCM in Tours, then on sputa from patients before and after administration of aerosolized rhDNase. We hypothesize that a better understanding of the biodistribution of neutrophil serine proteases and especially their binding to DNA will help designing new therapeutic strategies that facilitate inhibitor access to their protease targets.
Study Design
Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science
Conditions
Cystic Fibrosis
Intervention
Pulmozyme
Location
University Hospital - Tours
Tours
France
Status
Not yet recruiting
Source
University Hospital, Tours
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT00843817
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Cystic Fibrosis
An autosomal recessive genetic disease of the EXOCRINE GLANDS. It is caused by mutations in the gene encoding the CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR expressed in several organs including the LUNG, the PANCREAS, the BILIARY SYSTEM, and the SWEAT GLANDS. Cystic fibrosis is characterized by epithelial secretory dysfunction associated with ductal obstruction resulting in AIRWAY OBSTRUCTION; chronic RESPIRATORY INFECTIONS; PANCREATIC INSUFFICIENCY; maldigestion; salt depletion; and HEAT PROSTRATION.
Cystic Fibrosis Transmembrane Conductance Regulator
A chloride channel that regulates secretion in many exocrine tissues. Abnormalities in the CFTR gene have been shown to cause cystic fibrosis. (Hum Genet 1994;93(4):364-8)
Mice, Inbred Cftr
A strain of mice widely studied as a model for cystic fibrosis. These mice are generated from embryonic stem cells in which the CFTR (cystic fibrosis transmembrane conductance regulator) gene is inactivated by gene targeting. As a result, all mice have one copy of this altered gene in all their tissues. Mice homozygous for the disrupted gene exhibit many features common to young cystic fibrosis patients, including failure to thrive, meconium ileus, and alteration of mucous and serous glands.
Stenotrophomonas Maltophilia
A species of STENOTROPHOMONAS, formerly called Xanthomonas maltophilia, which reduces nitrate. It is a cause of hospital-acquired ocular and lung infections, especially in those patients with cystic fibrosis and those who are immunosuppressed.
Drainage, Postural
A rehabilitation therapy for removal of copious mucus secretion from the lung of patients with diseases such as CHRONIC BRONCHITIS; BRONCHIECTASIS; PULMONARY ABSCESS; or CYSTIC FIBROSIS. The patient's head is placed in a downward incline (so the TRACHEA is inferior to the affected area) for 15- to 20-minute sessions.
Clinical Trials
Pulmozyme in Cystic Fibrosis With Sinusitis
The hypothesis is that the intranasal use of Pulmozyme will decrease the severity of sinusitis in Cystic Fibrosis and lead to an improved quality of life.
Rhinosinusitis disorders are often associated with Cystic Fibrosis. They can restrict quality of life enormously and give cause to repeated ENT surgery. The basic defect in CF is a dysfunc...
Comparison of Inhaled Mannitol and rhDNase in Children With Cystic Fibrosis
The purpose of this study is to determine the medium term efficacy and safety profile of inhaled mannitol, on its own and also as an additional therapy to rhDNase (pulmozyme). In particula...
A Study of Pulmozyme® (Dornase Alpha) in 3- to 5-Year-Old Patients With Cystic Fibrosis
This is a Phase IV, multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate the effect of Pulmozyme on pulmonary function, HRQOL, and respiratory symptoms in 3...
Miglustat / OGT 918 in the Treatment of Cystic Fibrosis
Cystic fibrosis is a genetic disease caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR). The purpose of the study is to investigate the effects of miglust...
PubMed Articles
New therapies in cystic fibrosis.
Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that lead to abnormalities in transepithelial ion transport in the airways of affected pat...
A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.
Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis.
Treatment of cystic fibrosis associated cutaneous vasculitis with chloroquine.
Vasculitis is a well recognised complication of Cystic Fibrosis. Corticosteroids are the mainstay of treatment but some cases can be resistant and may require additional disease modifying agents. We d...
Adherence to dornase alfa treatment among commercially insured patients with cystic fibrosis.
Abstract Objective: To investigate adherence to dornase alfa therapy among commercially-insured patients with cystic fibrosis (CF) and to examine the impact of adherence on health and economic outcome...
