SFEBES2009 Oral Communications Young Endocrinologists prize session (8 abstracts)
Men1 gene replacement therapy using a modified adenoviral vector demonstrates reduced proliferation rates in pituitary tumours from mice deleted for a multiple endocrine neoplasia type 1 allelle
Mahsa Javid 1 , Gerard Walls 1 , Manuel Lemos 1 , Jeshmi Jeyabalan 1 , Miriam Bazan-Peregrino 2 , Damian Tyler 3 , Daniel Stuckey 3 , Len Seymour 2 & Rajesh Thakker 1
1Academic Endocrine Unit, University of Oxford, Oxford, UK; 2Deparment of Clinical Pharmacology, University of Oxford, Oxford, UK; 3Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
Multiple endocrine neoplasia type 1 (MEN1) is characterised by the combined occurrence of pituitary, pancreatic and parathyroid tumours. The MEN1 gene encodes a 610-amino acid tumour suppressor, menin, and MEN1-associated tumours show loss of heterozygosity. This indicates that replacement of the wild-type MEN1 gene may inhibit tumourigenesis. We have previously demonstrated that a recombinant adenoviral vector could be safely injected directly into pituitary tumours of heterozygous (Men1+/−) mice via the transauricular route. We now report the results of a blinded randomised-controlled trial to assess the efficacy of gene replacement in Men1+/− mice.
Mice were kept in accordance with UK home office welfare guidelines and project license restrictions. Men1+/− female mice aged 18.5 months, with pituitary tumours identified by MRI, were allocated to four groups. Anaesthetised mice received a 20 μl transauricular intra-tumoral injection of vehicle, Ad-GFP or Ad-Men1 (5×1010 viral particles of recombinant adenoviral vectors delivering green fluorescent protein (GFP) or Men1 genes, respectively) or no injection. Mice received 1 mg/ml 5-bromo-2-deoxyuridine (BrdU) in drinking water for 4 weeks post-injection before a repeat MRI scan.
Of 91 Men1+/− mice that underwent MRI, 22 had pituitary tumours. Immunohistochemical assessment revealed GFP expression in only the Ad-GFP treated mice. The expression of the Men1 gene product, menin, was moderate to high in Ad-Men1 treated mice, but minimal in other groups. Daily proliferation rates, assessed by the proportion of nuclei with BrdU incorporation, in tumours injected with vehicle (1.23±0.10%) or Ad-GFP (1.39±0.13%) were similar but Ad-Men1 treatment caused a significant reduction in tumour proliferation (0.45±0.09%, P<0.0001). Apoptotic rates, assessed using a TUNEL assay, and change in tumour volumes, assessed by MRI, remained similar in the groups.
Thus, in vivo Men1 gene replacement therapy for pituitary tumours was effective, demonstrated stable menin expression at 4 weeks and induced reduction of tumour proliferation.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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