RhDNase and Biodistribution of PMN Serine Proteases in Cystic Fibrosis Sputum (BioDNase)

Regional University Hospital Center (CHRU)

Status and phase

Completed

Phase 4

Conditions

Cystic Fibrosis

Treatments

Drug: Pulmozyme

Study type

Interventional

Funder types

Other

Identifiers

NCT00843817

PHAO08-PD BioDNase

Details and patient eligibility

About

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.

Enrollment

15 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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