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Improved precision of nucleic acid based therapy of cystic fibrosis

Objective

The epithelial sodium channel (ENaC) is assumed to play a major role in the pathogenesis of chronic lung disease incystic fibrosis patients. Its natural regulation by the cystic fibrosis transmembrane conductance regulator (CFTR)appears to be compromised based on the impaired function of CFTR. The missing downregulation of the channel results in increased absorption of sodium ions and fluid across airway epithelia leading to the depletion of the peculiarly liquid layer and to the depression of mucus clearance. Several observations suggest that a downregulation of Ancestors the perciliary liquid layer, thereby rehydrating the mucus and improving ciliary clearance in the lung. Therefore we propose to specifically downregulate ENaC expression by RNA interference. For this purpose we develop and apply new means of nucleic acid precision targeting both on the molecular and macroscopic level. The first level of precisionist introduced by the use of ENaC-specific siRNA, a technology known for its high downregulating specificity. The second level of precision is brought about by uPA-receptor binding and nuclear localization peptide modules of novel nonviral molecular constructs for nucleic acid delivery. Protein transduction domain peptides will be used for the delivery of synthetic siRNA. A level of loco-regional precision is contributed by the administration of such constructs via the airwaysupon aerosolization. Yet another and novel level of precision and targeting is introduced by the association of viral and nonviral constructs for siRNA delivery and/or expression with magnetic nanoparticles, such that lung-specific accumulation and retention can be mediated by external magnetic fields. For this purpose novel magnetic vector formulations as well as magnetic field generating equipment are developed. These novel constructs and technologies will be evaluated in fetal and postnatal animal models in order to demonstrate their efficacy.

Call for proposal

FP6-2003-LIFESCIHEALTH-I
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Funding Scheme

STREP - Specific Targeted Research Project

Coordinator

LUDWIG MAXIMILIANS UNIVERSITAET
Address
Geschwister Scholl Platz 1
Muenchen
Germany

Participants (10)

FONDAZIONE CENTRO SAN RAFFAELE DEL MONTE TABOR
Italy
Address
Via Olgettina 60
Milan
UNIVERSITY OF ROME LA SAPIENZA
Italy
Address
P.le Aldo Moro 5
Rome
OZ BIOSCIENCES
France
Address
Parc Scientifique Et Technologique De Luminy, Bat Ccimp - Case 922
Marseille
IMPERIAL COLLEGE OF SCIECE TECHNOLOGY AND MEDICINE
United Kingdom
Address
South Kensington Campus
London
ERASMUS UNIVERSITY MEDICAL CENTER ROTTERDAM
Netherlands
Address
Dr Molewater Pln 50
Rotterdam
MCS MICRO CARRIER SYSTEMS GMBH
Germany
Address
Stresemannallee 6
Neuss
ISTITUTO GIANNINA GASLINI
Italy
Address
L.go G. Gaslini, 5
Genoa
COMENIUS UNIVERSITY, FACULTY OF MATHEMATICS, PHYSICS AND INFORMATICS,
Slovakia
Address
Mlynska Dolina F2
Bratislava
FRAUNHOFER GESELLSCHAFT ZUR FOERDERUNG DER ANGEWANDTEN WISSENSCHAFT E.V.
Germany
Address
Hansastraße 27C
Munich
KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITÄT MÜNCHEN
Germany
Address
Ismaninger Str. 22
Munich