Imperial College London
Alternate

ProfessorUtaGriesenbach

Faculty of Medicine, National Heart & Lung Institute

Professor of Molecular Medicine
 
 
 
//

Contact

 

+44 (0)20 7594 7927u.griesenbach

 
 
//

Assistant

 

Miss Samia Soussi +44 (0)20 7594 7980

 
//

Location

 

Emmanuel Kaye BuildingRoyal Brompton Campus

//

Summary

 

Publications

Citation

BibTex format

@inproceedings{Pytel:2015:10.1136/thoraxjnl-2015-207770.123,
author = {Pytel, KM and Paul-Smith, MC and McIntosh, J and Chan, M and Meng, C and Pringle, I and Davis, L and Inoue, M and Hasegawa, M and Hyde, SC and Gill, DR and Nathwani, AC and Alton, EWFW and Griesenbach, U},
doi = {10.1136/thoraxjnl-2015-207770.123},
pages = {A67--A67},
publisher = {BMJ Publishing Group},
title = {F/HN-mediated gene therapy enables lungs to produce therapeutically relevant levels of FVIII},
url = {http://dx.doi.org/10.1136/thoraxjnl-2015-207770.123},
year = {2015}
}
Download

RIS format (EndNote, RefMan)

TY  - CPAPER
AB  - We have previously shown that lung when treated with Sendai virus-mediated gene transfer can produce secreted proteins and release them into the circulation (Griesenbach et al., Mol Therapy 2002). Despite the high levels of transduction efficiency the gene expression is transient and repeated administration is not feasible due to induction of immune responses. To overcome these barriers we developed a lentiviral vector specifically pseudotyped with the Sendai virus envelope proteins F and HN (rSIV. F/HN) to allow efficient transduction of the airways. Stable expression for >20 months after a single dose and efficient transduction after repeated administration despite detection of anti-rSIV. F/HN neutralising antibodies make the vector an attractive candidate for a large range of disease indications. Here, we first transduced mouse lung with rSIV. F/HN carrying the secreted reporter gene Gaussia luciferase (GLux) or a control virus by nasal instillation (1e6 transduction units (TU)/mouse, n = 5 –6/group). Persistent levels of GLux expression were detectable in lung (3 logs above control) and broncho-alveolar lavage fluid (BALF, 4 logs above control) for at least 12 months. Importantly, even this modest dose of virus lead to significant (p < 0.01) levels of GLux in serum (274 ± 72 RLU/ul, control: 41 ± 6 RLU/ul) which persisted for at least 12 months further supporting the hypothesis that the lung is a suitable, non-invasive factory for production of secreted proteins. Gene therapy strategies for haemophilia have focussed on intravenous or intramuscular delivery of the gene transfer agent. Here, we treated the murine lung with rSIV. F/HN carrying the FVIII cDNA (1.6e8–3.4e8 TU/mouse,) or placebo and assessed whether therapeutically relevant levels of FVIII can be produced. Significant (p < 0.05) and dose-related levels of FVIII were detectable in lungs and BALF 10 and 28 days post-transduction. Dose-related levels of FVIII were also
AU  - Pytel,KM
AU  - Paul-Smith,MC
AU  - McIntosh,J
AU  - Chan,M
AU  - Meng,C
AU  - Pringle,I
AU  - Davis,L
AU  - Inoue,M
AU  - Hasegawa,M
AU  - Hyde,SC
AU  - Gill,DR
AU  - Nathwani,AC
AU  - Alton,EWFW
AU  - Griesenbach,U
DO  - 10.1136/thoraxjnl-2015-207770.123
EP  - 67
PB  - BMJ Publishing Group
PY  - 2015///
SN  - 0040-6376
SP  - 67
TI  - F/HN-mediated gene therapy enables lungs to produce therapeutically relevant levels of FVIII
UR  - http://dx.doi.org/10.1136/thoraxjnl-2015-207770.123
UR  - http://hdl.handle.net/10044/1/40344
ER  -
Download