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New Perspectives for Gene Therapy in Endocrinology European Journal of Endocrinology (2000) 143 447±466 ISSN 0804-4643 INVITED REVIEW New perspectives for gene therapy in endocrinology Luisa Barzon, Roberta Bonaguro1, Giorgio PaluÁ 1 and Marco Boscaro Department of Medical and Surgical Sciences and 1Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, Padova, Italy (Correspondence should be addressed to M Boscaro, Department of Medical and Surgical Sciences, University of Padova, Via Ospedale, 105, 35128 Padova, Italy; Email: [email protected], or to G PaluÁ, Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, Via A Gabelli, 63, 35121 Padova, Italy; Email: [email protected]) 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 1989 (data from Journal of Gene Medicine, www. wiley.co.uk/genmed, updated to 1 September 1999) (1). In the last three decades scienti®c progress in biomedi- Even though the disorders targeted by gene therapy cal research has revealed the molecular mechanisms approaches span the entire spectrum of human and genetic bases of many human diseases. The obser- diseases, as shown in Table 1 cancer has become a vation that some pathologies are caused by the inheri- major interest, with 63.6% of the ongoing protocols tance of a single, functionally defective gene (monogenic involving cancer patients (1). diseases) generated the concept of gene-based therapy Notwithstanding the disappointing preliminary clini- consisting of the supplementation of the defective gene cal results, gene therapy has become an established with a functional one to be transferred to the affected concept in medicine. The future success of gene therapy cells. relies on the progress of the basic science, in the dis- Gene therapy, in its initial and broadest sense, can covery of new disease-related genes, and in the devel- be de®ned as the transfer of a gene to a patient for opment of suitable animal models of human diseases. therapeutic purposes. Initially developed as a strategy As for endocrine diseases, gene therapy is still at an to treat inherited monogenic disorders by supplying experimental stage, since no clinical studies have been the correct, wild-type copy of a mutated gene, gene published so far. However, signi®cant advances have therapy has gained importance as a tool to treat a been made during the last few years, and in vitro and growing number of human diseases. Indeed, the origi- in vivo studies suggest that several endocrine diseases nal concept of gene therapy as `gene supplementation' could bene®t from gene therapy. 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 Perspectives for gene therapy do not involve germ-line mutations, including multi- factorial and somatic genetic diseases, such as diabetes in endocrinology mellitus, obesity, hypertension and cancer. Gene therapy strategies for endocrine diseases The development of more sophisticated techniques of molecular biology has allowed us to go rapidly from Endocrine diseases can be divided into six broad cate- theory to application, as demonstrated by the 396 gene gories, including subnormal hormone production, therapy clinical trials, involving 3278 patients world- hormone overproduction, production of abnormal hor- wide, which have been undertaken since the ®rst one mones, resistance to hormone action, abnormalities q 2000 Society of the European Journal of Endocrinology Online version via http://www.eje.org Downloaded from Bioscientifica.com at 09/27/2021 10:22:59AM via free access 448 L Barzon and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2000) 143 Table 1 Update of gene therapy clinical trials. effects, such as tyrosine hydroxylase in prolactinomas (3), or the inhibition of genes associated with hormone Protocols Patients hypersecretion, by the use of antisense oligonucleotides Number % Number % or ribozymes. Endocrine hypofunction may require the delivery of the wild-type gene coding for the lacking Cancer 252 63.6 2269 69.2 hormone, such as the growth hormone (GH) gene in GH Monogenic diseases 53 13.4 298 9.1 de®ciency. Immunomodulating gene therapy could be Gene marking 41 10.4 227 6.9 Infectious diseases 33 8.3 412 12.6 useful in the treatment of autoimmune diseases that Healthy volunteers 2 0.5 6 0.2 result in either endocrine hyperfunction or hypofunc- Other 15 3.8 66 2 tion. Benign and malignant endocrine tumours would Total 396 100 3278 100 take advantage of tumour suppressor gene delivery, oncogene inhibition, anti-angiogenic approaches or suicide and immunomodulating gene therapy. of hormone transport or metabolism, and multiple Methods of gene transfer hormone abnormalities, including endocrine tumours (2). These disorders can result in either endocrine Gene therapy requires ef®cient delivery of nucleic acid hyperfunction or hypofunction. Research progress in sequences to target cells, adequate and prolonged endocrinology has allowed the identi®cation of inheri- expression of the introduced gene, without any toxic ted and acquired genetic disorders, as well as the side-effects for the target tissue and for the individual molecular bases of many endocrine diseases, opening as a whole. Ex vivo and in vivo approaches have been the possibility of correcting the underlying defect. used. Ex vivo strategies require the removal of cells Indeed, conventional treatments of most human dis- from the body, their transduction by viral or non-viral orders are often focused at improving symptoms, rather vectors carrying the therapeutic gene, and their reinfu- than at correcting the causative defects. Notwith- sion into the patient. The ex vivo approach has the standing the success of current conventional therapy, advantage that safety of modi®ed cells can be evaluated the question arises as to whether there is a true need before their administration to the patient. However, for gene therapy of endocrine diseases. A ®rst answer isolation of a suf®cient number of cells and their could be that, in many cases, current therapeutic appropriate manipulation in culture without causing approaches cannot truly cure the patient, and that hor- undesirable changes in their biological properties are mone replacement cannot always reproduce physio- required. In the in vivo approach the vector carrying logical hormone levels. Moreover, gene therapy may the therapeutic gene is directly administered to the provide useful tools for the treatment of endocrine patient. tumours and of immune-based endocrine disorders Given the identi®cation and availability of a large which do not respond to conventional treatments. number of therapeutic sequences, the limiting step for Different approaches of genetic intervention are fore- a successful gene therapy is the development of an seeable for endocrine diseases, as summarised in Fig. 1. ef®cient gene transfer system to reach the target cells. Strategies for gene therapy of endocrine hyperfunction With few exceptions, such as the skeletal muscle require either the transfer of a gene with ameliorating and the skin, naked DNA is not ef®ciently taken up Figure 1 Gene therapy approaches for endocrine diseases. www.eje.org Downloaded from Bioscientifica.com at 09/27/2021 10:22:59AM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2000) 143 Gene therapy in endocrinology 449 Table 2 Main features of the most commonly used vector systems. Retrovirus Adenovirus HSV AAV Liposomes Naked DNA Insert size 8 kb 35 kb >20 kb <4kb >20 kb >20 kb Functional titre (cfu/ml) 107 1011 1010 109 Not de®ned Not de®ned Integration Yes No No Unsure No No Sustained expression Variable Transient Transient Variable Transient Transient In vivo delivery Poor High High High Variable Muscular tissue Quiescent cells Only lentivirus Yes Yes Yes Yes Yes and expressed by mammalian cells. For this reason it the disease that has to be treated. An ideal vector is necessary to design suitable vectors for gene transfer containing all the possible components to overcome and gene expression. Most vectors presently in use are the barriers to gene delivery is depicted in Fig. 2. based upon viruses, such as retroviruses, adenoviruses, adeno-associated viruses (AAVs) and herpes viruses. The wild-type virus is genetically modi®ed to be Targeted gene therapy in endocrinology unable to replicate and to be non-pathogenic, while An important issue in the development of gene therapy retaining infectivity. Each viral vector presents advan- protocols is the need to target therapeutic gene delivery. tages and disadvantages; as a group, viral vectors still Indeed, safety is a primary concern of gene therapy, cause much concern about safety. Non-viral vectors, and targeted vectors are required both to minimise the such as liposomes and molecular conjugates, partially risk of germ-line cell transduction and to prevent side- overcome this last issue, but remain much less ef®cient effects to the surrounding healthy tissues. Moreover, than viral vectors (Table 2). targeting can reduce vector wastage, and the amount The choice of a vector is dependent upon the target of vector stocks that need to be produced and adminis- cell. In gene therapy approaches for rapidly proliferat- tered in vivo in order to achieve therapeutic levels of ing cells, such as cancer cells, retroviral vectors are transduction.
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