SFEBES2008 Poster Presentations Endocrine tumours and neoplasia (31 abstracts)
In vivo delivery of an adenoviral gene therapy vector to pituitary tumours in Men1 deficient mice
Manuel Lemos 1 , Brian Harding 1 , Anita Reed 1 , Gerard Walls 1 , Damian Tyler 2 , Miriam Bazan-Peregrino 3 , Olaf Ansorge 4 , Kieran Clarke 2 , Len Seymour 3 & Rajesh Thakker 1
1Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Departments of 2Physiology, Anatomy and Genetics, 3Clinical Pharmacology and 4Clinical Neurology, University of Oxford, Oxford, UK.
The mouse knockout model for multiple endocrine neoplasia type 1 (MEN1) closely resembles the phenotype of the human disorder, with frequent development of tumours of the parathyroids, pancreas and pituitary. These tumours have loss of heterozygosity (LOH) of the Men1 locus and lack expression of the encoded protein (menin).
The aim of this study was to investigate the feasibility of detecting pituitary tumours in heterozygous (Men1+/−) knockout mice, by magnetic resonance imaging (MRI), and of delivering an adenoviral gene therapy vector to these tumours.
Mice were kept in accordance with UK Home Office welfare guidelines and project license restrictions. A total of 62 Men1+/− C57BL/6 female mice, aged 19.5±0.9 months, underwent cranial MRI. Pituitary tumours were identified in 36 mice (58%). MRI screening of pituitary tumours had a sensitivity of 86% and a specificity of 100%. Anaesthetised mice with pituitary tumours were randomized to receive a 20 μl transauricular, intra-tumoural, injection of a menin-expressing adenovirus (5×107 viral particles), a Green Fluorescence Protein (GFP)-expressing adenovirus (5×107 viral particles), a menin-expressing plasmid (20 μg), a control saline solution, or no injection. Accurate targeting of tumours was confirmed by MRI immediately after the injection. The immediate procedure-related mortality was 13% and this was similar in all groups. Mortality during a 4-week post-treatment period was also similar, ranging from 14 to 33%, in all experimental groups and in a control group of tumour-free Men1+/− mice, indicating that the adenoviral gene therapy is not associated with a higher mortality.
Thus, this pilot study demonstrates that cranial MRI is efficient for the in vivo identification of pituitary tumours in Men1+/− mice. In addition, our results show that direct intra-tumoural injection of a recombinant adenoviral gene therapy vector can be administered effectively and safely. These results open the way for future gene therapy pre-clinical trials.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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