Ocular Gene Therapy

The identification of pro- (e.g. vascular endothelial growth factor [VEGF] tyrosine tRNA synthetase fragments) and anti-angiogenic factors (e.g. tryptophan tRNA synthetase fragments; soluble VEGF receptor, [sFlt-1]) has provided a better understanding of the role of angiogenesis in neovascular eye diseases and cancer. While several recent studies using adenovirus (Ad) to deliver anti-angiogenics to the eye have shown promise in terms of identifying anti-angiogenic targets for further investigation, the low level of Ad-mediated gene delivery to specific cell types in the eye other than retinal pigmented epithelial cells remains a significant problem. To address this limitation, our laboratory, in collaboration with that of Dr. Glen Nemerow, has tested modified Ad vectors that can deliver genes to different cell types in the eye. We demonstrated that intravitreal administration of an Ad3 fiber-pseudotyped Ad vector allowed enhanced gene delivery to the ciliarybody while vectors equipped with the Ad37 fiber efficiently transduced photoreceptors. Thus, significant advances have been made toward improving adenovirus-mediated gene delivery to specific ocular cell types. The ability to administer adenovirus locally as well as the relatively immunoprivileged status of the posterior segment of the eye makes adenovirus a particularly attractive vector for treating retinal and choroidal neovascular diseases.These studies demonstrate cell type-selective gene delivery in vivo with retargeted Ads, provide information about the cellular tropism of several Ad serotypes, and should lead to improved adenovirus-delivery based therapeutic strategies for preserving vision.

Relevant Publications:

Dorrell MI, Aguilar E, Jacobson R, Yanes O, Gariano R, Heckenlively J, Banin E, Ramirez GA, Gasmi M, Bird A, Siuzdak G, Friedlander M. (2009). Antioxidant or neurotrophic factor treatment preserves function in a mouse model of neovascularization-associated oxidative stress. J. Clin. Invest. 119(3): 611-623. PMCID: PMC2648679.

Von Seggern, D. J., Aguilar, E., Kinder, K., Fleck, S. K., Armas, J. C. G., Stevenson, S. C., Ghazal, P., Nemerow, G. R. and Friedlander, M. (2003). In vivo transduction of photoreceptors or ciliary body by intravitreal injection of pseudotyped adenoviral vectors. Molecular Therapy, 7, 27-34.