RhDNase and Biodistribution of PMN Serine Proteases in Cystic Fibrosis Sputum
Information source: University Hospital, Tours
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Cystic Fibrosis
Intervention: Pulmozyme (Drug)
Phase: Phase 4
Status: Not yet recruiting
Sponsored by: University Hospital, Tours Official(s) and/or principal investigator(s): Patrice DIOT, PHD, Principal Investigator, Affiliation: University Hospital, Tours
Overall contact: Patrice DIOT, PHD, Email: diot@med.univ-tours.fr
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.
Clinical Details
Official title: RhDNase Effect on Biodistribution of PMN Serine Proteases in Cystic Fibrosis Sputum
Study design: Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science
Primary outcome: The biodistribution of elastase, Protease 3 and cathepsine G in the expectorations will be measured by the management report of these proteases between the freezing fractionand the soluble fraction, before and after rhDNase administration.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- cystic fibrosis disease
- with rhDNase treatment
Exclusion Criteria:
- Acute push of the bronchopulmonary attack or hospitalization for treatment of the
disease during 2 weeks previous
- Exposure to a antibiotherapy or treatment by corticoids
Locations and Contacts
Patrice DIOT, PHD, Email: diot@med.univ-tours.fr
University Hospital - Tours, Tours, France; Not yet recruiting Patrice DIOT, PHD, Email: diot@med.univ-tours.fr Pascaline Rameau, Email: rameau@med.univ-tours.fr Patrice DIOT, PHD, Principal Investigator Francoise Varaigne, MD, Sub-Investigator
Additional Information
Last updated: February 12, 2009
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