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 malignancies 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. Gene therapy is proposed as a new therapeutic approach for uveal melanoma management.


METHODS
The potential of adenovirus-mediated gene transfer to normal eyes of two laboratory Beagles and in an iris tumour of a Great Dane were evaluated. Replication-defective adenoviral vectors (Adbetagal) were used to assess 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 delivery of human angiostatin (AdK3) was also investigated.


RESULTS
The ciliary body was the area preferentially transduced after adenoviral injection into the anterior chamber. It was also demonstrated that a direct intratumoral injection of a recombinant adenovirus efficiently transduces a canine uveal melanoma. Western blot analysis performed on the aqueous humour revealed that the expression of the angiostatin recombinant protein in the aqueous humour correlated with the dose of AdK3 administered. Lymphocyte 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 to dog eyes provides an essential basis for gene therapy treatment of uveal melanoma-bearing patients.
Andrawiss
M
M
UMR 1582 CNRS-IGR-Aventis Gencell, Villejuif, France. m.andrawiss@ucl.ac.uk
Maron
A
A
Beltran
W
W
Opolon
P
P
Connault
E
E
Griscelli
F
F
Yeh
P
P
Perricaudet
M
M
Devauchelle
P
P
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D043168:Angiostatins; D000818:Animals; D000867:Anterior Chamber / Q000821:virology; D000917:Antibody Formation; D001082:Aqueous Humor / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005240:Feasibility Studies; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods* / Q000639:trends; D005822:Genetic Vectors / Q000235:genetics* / Q000276:immunology; D006801:Humans; D010446:Peptide Fragments / Q000235:genetics; D010958:Plasminogen / Q000235:genetics; D014604:Uveal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*
D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen