INVITED REVIEW New perspectives for gene therapy in endocrinology Luisa Barzon, Roberta Bonaguro 1 , Giorgio Palu Á 1 and Marco Boscaro Department of Medical and Surgical Sciences and 1 Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, Padova, Italy (Correspondence should be addressed to M Boscaro, Department of Medical and Surgical Sciences, Universityof Padova, Via Ospedale, 105, 35128 Padova, Italy; Email: mboscaro@ux1.unipd.it, or to G Palu Á, Department of Histology, Microbiology and Medical Biotechnologies, Universityof Padova, Via A Gabelli, 63, 35121 Padova, Italy; Email: gpalu@ux1.unipd.it) Abstract Gene therapy for endocrine diseases represents an exciting new type of molecular intervention that may be a curative one. Endocrine disorders that might be treated by gene therapy include monogenic diseases, such as GH de®ciency and hypothalamic diabetes insipidus, and multifactorial diseases, such as diabetes mellitus, obesity and cancer. Premises seem promising for endocrine tumours, but many combined approaches of cell and gene therapy are foreseeable also for other endocrine disorders. This review outlines the principles of gene therapy, describes the endocrine disorders that might take advantage of gene transfer approaches, as well as the gene therapy interventions that have already been attempted, their major limitations and the problems that remain to be solved. European Journal of Endocrinology 143 447±466 Introduction In the last three decades scienti®c progress in biomedi- cal research has revealed the molecular mechanisms and genetic bases of many human diseases. The obser- vation that some pathologies are caused by the inheri- tance of a single, functionally defective gene (monogenic diseases) generated the concept of gene-based therapy consisting of the supplementation of the defective gene with a functional one to be transferred to the affected cells. Gene therapy, in its initial and broadest sense, can be de®ned as the transfer of a gene to a patient for therapeutic purposes. Initially developed as a strategy to treat inherited monogenic disorders by supplying the correct, wild-type copy of a mutated gene, gene therapy has gained importance as a tool to treat a growing number of human diseases. Indeed, the origi- nal concept of gene therapy as `gene supplementation' has rapidly switched to the more general one of any strategy that employs genetic material (DNA or RNA) to prevent or cure a variety of diseases, many of which do not involve germ-line mutations, including multi- factorial and somatic genetic diseases, such as diabetes mellitus, obesity, hypertension and cancer. The development of more sophisticated techniques of molecular biology has allowed us to go rapidly from theory to application, as demonstrated by the 396 gene therapy clinical trials, involving 3278 patients world- wide, which have been undertaken since the ®rst one in 1989 (data from Journal of Gene Medicine, www. wiley.co.uk/genmed, updated to 1 September 1999) (1). Even though the disorders targeted by gene therapy approaches span the entire spectrum of human diseases, as shown in Table 1 cancer has become a major interest, with 63.6% of the ongoing protocols involving cancer patients (1). Notwithstanding the disappointing preliminary clini- cal results, gene therapy has become an established concept in medicine. The future success of gene therapy relies on the progress of the basic science, in the dis- covery of new disease-related genes, and in the devel- opment of suitable animal models of human diseases. As for endocrine diseases, gene therapy is still at an experimental stage, since no clinical studies have been published so far. However, signi®cant advances have been made during the last few years, and in vitro and in vivo studies suggest that several endocrine diseases could bene®t from gene therapy. Perspectives for gene therapy in endocrinology Gene therapy strategies for endocrine diseases Endocrine diseases can be divided into six broad cate- gories, including subnormal hormone production, hormone overproduction, production of abnormal hor- mones, resistance to hormone action, abnormalities European Journal of Endocrinology (2000) 143 447±466 ISSN 0804-4643 q 2000 Society of the European Journal of Endocrinology Online version via http://www.eje.org