Is pituitary gene therapy realistic?
Current therapies for pituitary tumours are moderately successful in many cases but still suffer from significant limitations, with relatively poor long-term rates of endocrine cure from surgery, and long-term hypopituitarism after radiotherapy. Even in the case of the most readily treatable tumours, prolactinomas, medical therapy with dopamine agonists is limited by lack of response or side-effects in up to 10% of patients. This has led to increasing interest in the application of our knowledge of pituitary cell and molecular biology to evaluate the potential of gene therapy. Various vectors are available to facilitate gene delivery, and recombinant adenoviruses have been studied in detail because of their ability to transduce the postmitotic, nondividing cells of the pituitary gland. Various studies with reporter genes such as beta-galactosidase have demonstrated high efficiency and long lasting expression of adenoviral transgenes in cultured pituitary cells in vitro. The feasibility of high level transgene expression has also been shown in vivo, but so far this requires stereotaxic intrapituitary injection to achieve adequate transduction. Ablation of pituitary cells has been demonstrated in cultured cell lines and in subcutaneous tumours in nude mice, though alternative animal models will be required to evaluate efficacy in more slowly proliferating tumours as found in man. Inflammatory responses have been documented in the pituitary gland as in other tissues, and this will require the evaluation of modified vectors to avoid significant adverse effects before human applications can be considered. In summary, gene therapy for pituitary disease is likely to be feasible in the future, but will require careful and extensive evaluation of efficacy and safety, using a variety of possible methods of gene delivery.
Davis
J R
JR
Endocrine Sciences Research Group, University of Manchester, Manchester, UK. julian.davis@man.ac.uk
McNeilly
A S
AS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D005544:Forecasting; D015316:Genetic Therapy / Q000379:methods* / Q000639:trends; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D015552:Injections, Intralesional; D023421:Models, Animal; D010902:Pituitary Gland / Q000276:immunology / Q000821:virology; D010911:Pituitary Neoplasms / Q000628:therapy*; D015175:Prolactinoma / Q000628:therapy*; D012756:Sheep; D014161:Transduction, Genetic