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Griesenbach U.,Imperial College London | McLachlan G.,Roslin Institute | Owaki T.,DNAVEC Corporation | Somerton L.,Imperial College London | And 9 more authors.
Gene Therapy | Year: 2011

We have previously shown that recombinant Sendai virus (SeV) vector, derived from murine parainfluenza virus, is one of the most efficient vectors for airway gene transfer. We have also shown that SeV-mediated transfection on second administration, although reduced by 60% when compared with levels achieved after a single dose, is still high because of the efficient transfection achieved by SeV vector in murine airways. Here, we show that these levels further decrease on subsequent doses. In addition, we validated SeV vector repeat administration in a non-natural host model, the sheep. As part of these studies we first assessed viral stability in a Pari LC Plus nebuliser, a polyethylene catheter (PEC) and the Trudell AeroProbe. We also compared the distribution of gene expression after PEC and Trudell AeroProbe administration and quantified virus shedding after sheep transduction. In addition, we show that bronchial brushings and biopsies, collected in anaesthetized sheep, can be used to assess SeV-mediated gene expression over time. Similar to mice, gene expression in sheep was transient and had returned to baseline values by day 14. In conclusion, the SeV vector should be strongly considered for lung-related applications requiring a single administration of the vector even though it might not be suitable for diseases requiring repeat administration. © 2011 Macmillan Publishers Limited All rights reserved. Source


Alton E.W.F.W.,UK CF Gene Therapy Consortium | Alton E.W.F.W.,Imperial College London | Boyd A.C.,UK CF Gene Therapy Consortium | Boyd A.C.,University of Edinburgh | And 24 more authors.
Gene Therapy | Year: 2014

For gene therapy to improve lung function in cystic fibrosis (CF) subjects, repeated administration of the gene transfer agent over the lifetime of patients is likely to be necessary. This requirement limits the utility of adenoviral and adeno-associated viral vectors (both previously evaluated in CF gene therapy trials) because of induced adaptive immune responses that render repeated dosing ineffective. For CF gene therapy trials, non-viral vectors are currently the only viable option. We previously showed that the cationic lipid formulation GL67A is the most efficient of several non-viral vectors analysed for airway gene transfer. Here, we assessed the efficacy and safety of administering 12 inhaled doses of GL67A complexed with pGM169, a CpG-free plasmid encoding human CFTR complementary DNA, into mice. We show that repeated administration of pGM169/GL67A to murine lungs is feasible, safe and achieves reproducible, dose-related and persistent gene expression (>140 days after each dose) using an aerosol generated by a clinically relevant nebuliser. This study supports progression into the first non-viral multidose lung trial in CF patients. © 2014 Macmillan Publishers Limited. Source


Armstrong D.K.,UK CF Gene Therapy Consortium | Cunningham S.,UK CF Gene Therapy Consortium | Davies J.C.,UK CF Gene Therapy Consortium | Davies J.C.,Imperial College London | And 4 more authors.
Archives of Disease in Childhood | Year: 2014

The principal cause of morbidity and mortality in cystic fibrosis (CF) is pulmonary disease, so the focus of new treatments in this condition is primarily targeted at the lungs. Since the cloning of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene in 1989, there has been significant interest in the possibility of gene therapy as a treatment for CF. Early studies using viral vectors carrying a healthy CFTR plasmid highlighted the difficulties with overcoming the body's host defences. This article reviews the work on gene therapy in CF to date and describes the ongoing work of the UK CF Gene Therapy Consortium in investigating the potential of gene therapy as a treatment for patients with CF. Source


Alton E.W.F.W.,UK CF Gene Therapy Consortium | Alton E.W.F.W.,Imperial College London | Alton E.W.F.W.,Foundation Medicine | Boyd A.C.,UK CF Gene Therapy Consortium | And 19 more authors.
Thorax | Year: 2013

The UK Cystic Fibrosis Gene Therapy Consortium has been working towards clinical gene therapy for patients with cystic fibrosis for several years. We have recently embarked on a large, multi-dose clinical trial of a nonviral, liposome-based formulation powered for the first time to detect clinical benefit. The article describes the details of the protocol. Source

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