New perspectives for gene therapy in endocrinology

Barzon, Luisa; Bonaguro, Roberta; Palù, Giorgio; Boscaro, Marco

doi:10.1530/eje.0.1430447

Cited by 23 publications

(12 citation statements)

References 205 publications

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“…However, the delicate nature and lifesustaining role of these highly differentiated organs along with current biotechnology limitations render such approaches unappealing, especially with respect to non-life threatening hormone deficiencies. Various tissues such as muscle, liver or lung have thus far been primarily targeted to overcome this obstacle (Barzon et al 2000, Auricchio et al 2002, Goldspink 2003, Harding et al 2004.…”

Section: Introductionmentioning

confidence: 99%

Salivary glands as a potential gene transfer target for gene therapeutics of some monogenetic endocrine disorders

Voutetakis

Bossis²,

Kok³

et al. 2005

Journal of Endocrinology

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Salivary glands (SGs) exhibit several important features which are also common to endocrine glands: selfcontainment due to a surrounding capsule, highly efficient protein production and the ability to secrete proteins into the bloodstream. We have hypothesized that SGs are potentially useful as gene transfer targets for the correction of inherited monogenetic endocrine disorders. In the present communication, we extend our studies and attempt to test our hypothesis by comparing the efficacy of two commonly used viral vectors and the resulting serum and salivary distribution of transgene encoded hormones.

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Section: Introductionmentioning

confidence: 99%

Salivary glands as a potential gene transfer target for gene therapeutics of some monogenetic endocrine disorders

Voutetakis

Bossis²,

Kok³

et al. 2005

Journal of Endocrinology

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“…Recombinant adenoviral vectors (RAVs), genetically modified by deletions within the viral genome to allow insertion of foreign genes (transgenes), have been successfully used for gene transfer to different tissues (2). Their limited effectiveness has been proven in phase I clinical trials to treat cystic fibrosis (3,4), as well as in the treatment of several tumors (5,6), including endocrine neoplasias (7,8). Recently, however, there have also been reports of significant toxicity associated with administration of RAVs to primates (9,10) and humans (11).…”

mentioning

confidence: 99%

Adenoviral vectors can impair adrenocortical steroidogenesis: Clinical implications for natural infections and gene therapy

Alesci

Ramsey

Bornstein

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Recombinant adenoviral vectors are effective in transferring foreign genes to a variety of cells and tissue types, both in vitro and in vivo. However, during the gene transfer, they may alter the principal function and local environment of transfected cells. Increasing evidence exists for a selective adrenotropism of adenovirus during infections and gene transfer. Therefore, using bovine adrenocortical cells in primary culture, we analyzed the influence of different adenoviral deletion mutants on cell morphology and physiology. Transfection of cells with an E1͞E3-deleted adenoviral vector, engineered to express a modified form of the Aequorea victoria green fluorescent protein, was highly efficient, as documented by fluorescent microscopy. Ultrastructural analysis, however, demonstrated nuclear fragmentation and mitochondrial alterations in addition to intranuclear viral particles. Basal secretion of 17-OH-progesterone, 11-deoxycortisol, and cortisol was significantly increased by E1͞E3-deleted vectors; yet, the corticotropinstimulated release of these steroids was decreased. Interestingly, neither purified viral capsids nor E3͞E4-deleted adenoviral mutants altered basal and stimulated steroidogenesis of adrenocortical cells. An intact adrenal response is crucial for adaptation to stress and survival. Therefore, the implications of our findings need to be considered in patients with adenoviral infections and those undergoing clinical studies using adenoviral gene transfer. At the same time, the high level of transfection in adrenocortical cells might make appropriately modified adenoviral vectors suitable for gene therapy of adrenocortical carcinomas with poor prognosis.

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“…Thus, the development of innovative therapeutic approaches, such as gene therapy, is needed. In this regard, several strategies have been designed so far for the treatment of thyroid carcinomas, including tumor suppressor gene replacement, prodrug activation, immunotherapy and oncolysis, and these have been demonstrated to be feasible in in vitro and in vivo studies (1,2). However, experience from clinical trials of cancer gene therapy indicates that no single therapeutic strategy can effectively eradicate cancer, whereas combined poly-gene therapy represents a more reliable approach to combat cancer.…”

Section: Introductionmentioning

confidence: 99%

Gene therapy of thyroid cancer via retrovirally-driven combined expression of human interleukin-2 and herpes simplex virus thymidine kinase

Barzon

Bonaguro²,

Castagliuolo³

et al. 2003

European Journal of Endocrinology

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Objective and design: Based on our clinical experience with combined gene therapy of glioblastoma, we developed a retroviral vector expressing two therapeutic genes (i.e. thymidine kinase of herpes simplex virus, HSV-TK, and interleukin-2, IL-2 ) and evaluated its efficiency in vitro and in vivo. Methods: Expression of therapeutic genes in transduced thyroid carcinoma cells was analyzed by realtime RT-PCR. Ganciclovir sensitivity of infected cells was assessed in vitro in thyroid carcinoma cell lines and in vivo in nude mice bearing xenografted thyroid cancers. The combined effect of IL-2/ HSV-TK was compared with the effect of IL-2 alone. Results: Expression of therapeutic genes was higher in differentiated than in anaplastic thyroid carcinoma cells. Ganciclovir treatment led to dose-and time-dependent killing of transduced cells in vitro. A bystander effect was demonstrated by using mixtures of infected and non-infected cells. In vivo studies showed a significant reduction of growth and the presence of an inflammatory infiltrate in transduced thyroid tumors expressing IL-2 alone, as compared with non-infected tumors. By using the retroviral vector expressing IL-2/HSV-TK, treatment with ganciclovir led to complete eradication of anaplastic tumors and a . 80% reduction of the size of differentiated thyroid carcinomas. Histological analysis of tumor specimens showed extensive necrosis and inflammatory cell infiltrates. The combination of IL-2/HSV-TK plus ganciclovir was significantly more efficient than IL-2 alone in eradicating tumor masses. The bystander effect was also obtained in vivo.Conclusions: These findings demonstrate the feasibility and efficiency of a combined immunomodulating and suicide gene therapy approach for thyroid carcinomas.

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New perspectives for gene therapy in endocrinology

Cited by 23 publications

References 205 publications

Salivary glands as a potential gene transfer target for gene therapeutics of some monogenetic endocrine disorders

Salivary glands as a potential gene transfer target for gene therapeutics of some monogenetic endocrine disorders

Adenoviral vectors can impair adrenocortical steroidogenesis: Clinical implications for natural infections and gene therapy

Gene therapy of thyroid cancer via retrovirally-driven combined expression of human interleukin-2 and herpes simplex virus thymidine kinase

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