Identification of a novel genetic model for retinal neovascularization

Abstract

Purpose: Retinal vascular disease is a hallmark of many blinding disorders. This includes diseases such as diabetic retinopathy (DR) (that affects millions worldwide), age related macular degeneration (AMD) (that affects 1:3 over the age of 65) and childhood diseases such as retinopathy of prematurity. These diseases cause the formation of de novo extra blood vessels (referred as neovascularization) and lead to debilitating vision loss and eventually blindness. There are no long-term viable treatment options or cures for these disorders. Further, for DR and AMD the genetic causes are not known and no genetic model is available to date. Here we report the characterization of Nrv1 mouse, the only known genetic model that recapitulates the vascular disease observed in humans.

Methods: The Nrv1 mouse was generated by ENU-induced mutagenesis. For the clinical and phenotypic characterization of the mouse model we performed the following analyses: ophthalmoscopy, fluoroangiography, histology and immunohistochemistry on flat-mount retinas and retinal sections. A linkage analysis followed by next generation sequencing was performed to identify the causative gene.

Results: The Nrv1 mouse exhibits abnormal production of de novo blood vessels in the retina that innervate into the vitreous. The blood vessels in the retina are disorganized and clumped. A disorganized astrocytes network underlines the abnormal vascular topography. The abnormal blood vessels into the vitreous originate from retinal vasculature and are preceded by the uncommon presence of astrocytes into the vitreous. The overall data suggests misguidance defects due to the astrocytes. Linkage analyses mapped the vascular disorder to a 1Mb region on the chromosome 9. We are currently sequencing this region in order to identify the mutation and the causative gene.

Conclusions: The Nrv1 mouse model is the first genetic model for retinal neovascularization described thus far and recapitulates the vascular phenotype observed in patient with DR. Characterization of this mouse model and its genetic cause will have profound impact in understanding the molecular causes of human neovascular diseases and in the development of a viable treatment that can prevent, attenuate, or cure these diseases.

Keywords: 700 retinal neovascularization