Treatment of Experimental Choroidal Neovascularization via RUNX1 Inhibition.
Lucia Gonzalez-Buendia, Santiago Delgado-Tirado, Miranda An, Michael O'Hare, Dhanesh Amarnani, Hannah A B Whitmore, Guannan Zhao, Jose M Ruiz-Moreno, Joseph F Arboleda-Velasquez, Leo A Kim
Author Information
Lucia Gonzalez-Buendia: Schepens Eye Research Institute of Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
Santiago Delgado-Tirado: Schepens Eye Research Institute of Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
Miranda An: Schepens Eye Research Institute of Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
Michael O'Hare: Schepens Eye Research Institute of Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
Dhanesh Amarnani: Schepens Eye Research Institute of Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
Hannah A B Whitmore: Schepens Eye Research Institute of Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
Guannan Zhao: Schepens Eye Research Institute of Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.
Jose M Ruiz-Moreno: Department of Ophthalmology, Castilla la Mancha University, Puerta de Hierro-Majadahonda University Hospital, Madrid, Spain; Vissum Corporation, Alicante, Spain.
Joseph F Arboleda-Velasquez: Schepens Eye Research Institute of Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts. Electronic address: joseph_arboleda@meei.harvard.edu.
Leo A Kim: Schepens Eye Research Institute of Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts. Electronic address: leo_kim@meei.harvard.edu.
Choroidal Neovascularization (CNV) is a prevalent cause of vision loss in patients with age-related macular degeneration. Runt-related transcription factor 1 (RUNX1) has been identified as an important mediator of aberrant retinal angiogenesis in proliferative diabetic retinopathy and its modulation has proven to be effective in curbing pathologic angiogenesis in experimental oxygen-induced retinopathy. However, its role in CNV remains to be elucidated. This study demonstrates RUNX1 expression in critical cell types involved in a laser-induced model of CNV in mice. Furthermore, the preclinical efficacy of Ro5-3335, a small molecule inhibitor of RUNX1, in experimental CNV is reported. RUNX1 inhibitor Ro5-3335, aflibercept-an FDA-approved vascular endothelial growth factor (VEGF) inhibitor, or a combination of both, were administered by intravitreal injection immediately after laser injury. The CNV area of choroidal flatmounts was evaluated by immunostaining with isolectin B4, and vascular permeability was analyzed by fluorescein angiography. A single intravitreal injection of Ro5-3335 significantly decreased the CNV area 7 days after laser injury, and when combined with aflibercept, reduced vascular leakage more effectively than aflibercept alone. These data suggest that RUNX1 inhibition alone or in combination with anti-VEGF drugs may be a new therapy upon further clinical validation for patients with neovascular age-related macular degeneration.
