Adenovirus-mediated gene transfer in canine eyes: a preclinical study for gene therapy of human uveal melanoma

Background Melanomas of the uveal tract are the most common intraocular mal ignancies in adults, with an incidence of six cases per million adults per year. Enucleation, which may enhance the dissemination of tumour cells into the systemic circulation is still required for eyes with large tumours. Ge ne therapy is proposed as a new therapeutic approach for uveal melanoma man agement. Methods The potential of adenovirus-mediated gene transfer to normal eyes o f two laboratory Beagles and in an iris tumour of a Great Dome were evaluat ed. Replication-defective adenoviral vectors (Ad beta gal) were used to ass ess the feasibility, efficiency and safety of direct adenoviral delivery to the anterior chamber of normal eyes and to an iris tumour. The expression of angiostatin into the aqueous humour following an adenoviral-mediated del ivery of human angiostatin (AdK3) was also investigated. Results The ciliary body was the area preferentially transduced after adeno viral injection into the anterior chamber. It was also demonstrated that a direct intratumoral injection of a recombinant adenovirus efficiently trans duces a canine uveal melanoma. Western blot analysis performed on the aqueo us humour revealed that the expression of the angiostatin recombinant prote in in the aqueous humour correlated with the dose of AdK3 administered. Lym phocyte infiltrates at the site of AdK3 injection indicated induction of a strong cellular immune response, and humoral immune responses developed in all three dogs. Conclusions The present study involving adenovirus-mediated gene transfer t o dog eyes provides an essential basis for gene therapy treatment of uveal melanoma-bearing patients. Copyright (C) 2001 John Wiley & Sons, Ltd.