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(American Journal of Pathology. 2001;159:313-320.)
© 2001 American Society for Investigative Pathology

Regular Articles

Inhibition of Choroidal Neovascularization by Intravenous Injection of Adenoviral Vectors Expressing Secretable Endostatin

Keisuke Mori*, Akira Ando*, Peter Gehlbach*, David Nesbitt*, Kyoichi Takahashi*, Donna Goldsteen{dagger}, Michael Penn{dagger}, Cheauyan T. Chen{dagger}, Keiko Mori*, Michele Melia*, Sandrina Phipps{dagger}, Diana Moffat{dagger}, Kim Brazzell{dagger}, Gene Liau{dagger}, Katharine H. Dixon{dagger} and Peter A. Campochiaro*

From the Departments of Ophthalmology and Neuroscience,*
The Johns Hopkins University School of Medicine, Baltimore; and Genetic Therapy,{dagger}
A Novartis Company, Gaithersburg, Maryland

Endostatin is a cleavage product of collagen XVIII that inhibits tumor angiogenesis and growth. Interferon {alpha}2a blocks tumor angiogenesis and causes regression of hemangiomas, but has no effect on choroidal neovascularization (CNV). Therefore, inhibitors of tumor angiogenesis do not necessarily inhibit ocular neovascularization. In this study, we used an intravenous injection of adenoviral vectors containing a sig-mEndo transgene consisting of murine immunoglobulin {kappa}-chain leader sequence coupled to sequence coding for murine endostatin to investigate the effect of high serum levels of endostatin on CNV in mice. Mice injected with a construct in which sig-mEndo expression was driven by the Rous sarcoma virus promoter had moderately high serum levels of endostatin and significantly smaller CNV lesions at sites of laser-induced rupture of Bruch’s membrane than mice injected with null vector. Mice injected with a construct in which sig-mEndo was driven by the simian cytomegalovirus promoter had ~10-fold higher endostatin serum levels and had nearly complete prevention of CNV. There was a strong inverse correlation between endostatin serum level and area of CNV. This study provides proof of principle that gene therapy to increase levels of endostatin can prevent the development of CNV and may provide a new treatment for the leading cause of severe loss of vision in patients with age-related macular degeneration.




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