Intra-amniotic Delivery of CFTR-expressing Adenovirus Does Not Reverse Cystic Fibrosis Phenotype in Inbred CFTR-knockout Mice

doi:doi:10.1038/mt.2008.26

Subject Category: Monogenic Disease

Molecular Therapy (2008); 16 5 819–824 doi:10.1038/mt.2008.26

Intra-amniotic Delivery of CFTR-expressing Adenovirus Does Not Reverse Cystic Fibrosis Phenotype in Inbred CFTR-knockout Mice

Suzanne MK Buckley¹, SN Waddington¹, S Jezzard², A Bergau², M Themis³, LJ MacVinish⁴, AW Cuthbert⁴, WH Colledge⁵ and C Coutelle²

¹Department of Haematology, Haemophilia Centre and Thrombosis Unit, Royal Free & University College Medical School, London, UK
²Gene Therapy Research Group, Department of Molecular Medicine, Imperial College, London, UK
³Genotoxicity Group, Division of Biosciences, Brunel University, Uxbridge, UK
⁴Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
⁵Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

Correspondence: Dr. Suzanne Buckley, Department of Haematology, Haemophilia Centre and Thrombosis Unit, Royal Free & University College Medical School, Rowland Hill Street, London, UK. E-mail: s.buckley@medsch.ucl.ac.uk

Received 18 December 2007; Accepted 29 January 2008; Published online 25 March 2008.

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Abstract

Due to its early onset and severe prognosis, cystic fibrosis (CF) has been suggested as a candidate disease for in utero gene therapy. In 1997, a study was published claiming that to how transient prenatal expression of CF transmembrane conductance regulator (CFTR) from an in utero –injected adenovirus vector could achieve permanent reversal of the CF intestinal pathology in adult CF knockout mice, despite the loss of CFTR transgene expression by birth. This would imply that the underlying cause of CF is a prenatal defect for which lifelong cure can be achieved by transient prenatal expression of CFTR. Despite criticism at the time of publication, no independent verification of this contentious finding has been published so far. This is vital for the development of future therapeutic strategies as it may determine whether CF gene therapy should be performed prenatally or postnatally. We therefore reinvestigated this finding with an identical adenoviral vector and a knockout CF mouse line (Cftr^tmlCam) with a completely inbred genetic background to eliminate any effects due to genetic variation. After delivery of the CFTR-expressing adenovirus to the fetal mouse, both vector DNA and transgenic CFTR expression were detected in treated animals postpartum but statistically no significant difference in survival was observed between the Cftr^–/– mice treated with the CFTR-adenovirus and those treated with the control vector.