An adenoviral vector regulated by hypoxia for the treatment of ischaemic disease and cancer.
Recombinant adenoviral vectors have a number of advantages for gene therapy, including transduction of a range of dividing and non-dividing cell types. However, this broad range may be a disadvantage if non-target cells are transduced and are adversely affected by expression of the transferred gene. Here we describe a novel adenoviral vector in which transcription of the transgene is restricted to the patho-physiological condition of low oxygen tension (hypoxia). Hypoxia activates the expression of a number of genes, principally via the stabilisation of members of the bHLH/PAS family of transcription factors that bind to a con- sensus DNA sequence, the hypoxia response element (HRE). We have configured an optimised HRE expression cassette into an adenoviral vector, AdOBHRE. A range of cell types, including primary human skeletal muscle, when transduced with AdOBHRE display a low basal level of transgene expression that is highly induced in hypoxia to levels equivalent to that obtained from the CMV promoter. The AdOBHRE vector could be exploited for transcriptionally targeted gene therapy for the treatment of diseases such as cancer, peripheral arterial disease, arthritis and anaemia where tissue hypoxia is a cardinal feature.
Binley
K
K
Oxford BioMedica (UK) Ltd, Medawar Centre, Oxford Science Park, Oxford, UK.
Iqball
S
S
Kingsman
A
A
Kingsman
S
S
Naylor
S
S
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007511:Ischemia / Q000628:therapy*; D051379:Mice; D009369:Neoplasms / Q000628:therapy*; D014407:Tumor Cells, Cultured