Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung (2011)

McLachlan, G., Davidson, H., Holder, E., Davies, L. A., Pringle, I. A., Sumner-Jones, S. G., Baker, A., Tennant, P., Gordon, C., Vrettou, C., Blundell, R., Hyndman, L., Stevenson, B., Wilson, A., Doherty, A., Shaw, D. J., Coles, R. L., Painter, H. A., Cheng, S. H., Scheule, R. K., Davies, J. C., Innes, J. A., Hyde, S. C., Griesenbach, U., Alton, E. W. F. W., Boyd, A. C., Porteous, D., Gill, D. R. & Collie, D. D. S.

Gene Therapy, Advanced online publication

Journal    Back

We employ both large and small animal models in our pre-clinical evaluation of gene transfer agents (GTAs) for cystic fibrosis gene therapy. Here we report the use of a large animal model to assess three non-viral GTAs: 25kDa-branched polyethyleneimine (PEI), the cationic liposome (GL67A) and compacted DNA nanoparticle (NP) formulated with polyethylene glycol (PEG)-substituted lysine 30-mer. GTAs complexed with plasmids expressing human CFTR cDNA were administered to the sheep lung (n=8/group) by aerosol. All GTAs gave evidence of gene transfer and expression one day after treatment. Vector-derived mRNA was expressed in lung tissues, including epithelial cell-enriched bronchial brushing samples, with median group values reaching 1-10% of endogenous CFTR mRNA levels. GL67A gave the highest levels of expression. Human CFTR protein was detected in small airway epithelial cells in some animals treated with GL67A (2 out of 8) and PEI (1 out of 8). Bronchoalveolar lavage neutrophilia, lung histology and elevated serum haptoglobin levels indicated that gene delivery was associated with mild local and systemic inflammation. Our conclusion, that GL67A was the best non-viral GTA currently available for aerosol delivery to the sheep lung, led to the selection of GL67A as our lead GTA for clinical trials in CF patients.

Home
News
Introductory Videos
Medical Futures Innovation Award 2011
Twitter Feed
About Us
Contact Us
Careers
Resources
Lab Events
Environemental Policy
About this Site

Google Site Search

Site Feedback Form

All Site Images

 

UK CFGTC

How the Consortium works/FAQs

Consortium Website

Centre for Molecular Medicine, Edinburgh
The Roslin Institute
Dep of Gene Therapy, Imperial

Milestones

GL67A/pGM169

The Run-in Study

Single Dose Clinical Trial

Multi Dose Clinical Trial

 

Our Research

Non-viral Vector Development

Aerosol Mediated Gene Delivery

Viral Vector Development

Taqman Core Facility

Cystic Fibrosis

History of CF

Discovery of the CFTR Gene

CFTR Protein Structure

CFTR Function

CF Links

 

Gene Therapy

Introduction to Gene Therapy

Other CF Gene Therapy Groups

Why use Gene Therapy for CF

Target Cells for CF Gene Therapy

Barriers for CF Gene Therapy

Clinical Trials

Gene Therapy Successes

Gene Therapy Links

 

 

Publications

Papers in Journals

Conference Posters & Presentations

Book Chapters

D.Phil Theses

Lectures

 

Gene Therapy Seminars

Schedule

Directions & Venue