Project Summary: The fetal, or hyaloid, vasculature nourishes the lens and retina during ocular development, subsequently regressing after the formation of retinal vessels. The failure of the fetal vasculature to regress leads to serious problems with vision, a condition known as persistent fetal vasculature (PFV) disease. The exact prevalence of PFV is unknown; however, a study on childhood blindness and visual loss in the United States showed that PFV accounts for 5% of all childhood cases of blindness. A major finding from our previous studies on PFV is that astrocytes abnormally migrate into the vitreous and ensheath the hyaloid artery, suggesting a direct cause and effect relationship between astrocyte association and vascular retention. Astrocytes are not known to be involved in either the formation or regression of the hyaloid artery. Our data suggested that the defective lysosomal function in astrocytes is linked to increased astrocyte migration and ensheathment of the hyaloid artery. Several mouse models of PFV, in addition to those we have studied, appear to have astrocytes associated with the persistent hyaloid artery. Importantly, we have also shown that astrocytes abnormally ensheath the hyaloid artery in clinical specimens from PFV patients. PFV involves persistence of components of the normally transient fetal intraocular vasculature and can vary widely in terms of completeness and severity. While increased vascular endothelial growth factor (VEGF) in the vitreous is certainly an important factor in the etiology of severe PFV, it is likely not the case in mild or moderate PFV. Our focus in this proposal is to develop a therapy for mild/moderate disease. PFV is a complex and heterogeneous disease and no single therapy is likely to be effective for all patients. Appropriate treatment may well depend upon disease severity. With severe disease with a fibrotic stalk, the drug(s) that we develop here may be efficacious if given prior to vitrectomy, analogous to anti-VEGFA injections being given prior to vitrectomy for diabetic traction detachment to make the surgery technically simpler with reduced intraoperative and postoperative hemorrhaging. Here we will test the hypothesis that “restoring normal astrocyte function is an effective therapeutic strategy for PFV disease”. This objective will be accomplished by pursuing the following Specific Aims: Specific Aim 1: To demonstrate if A1-crystallin overexpression can rejuvenate astrocyte function and thereby rescue the PFV-like phenotype; Specific Aim 2: To test if inhibiting gefitinib and activating autophagic lysosomal reformation triggers normal regression of the hyaloid vasculature and Specific Aim 3: To identify factors released by A1 KD astrocytes that could inhibit normal developmental remodeling (regression) of the fetal vasculature. The proposed study is significant because we now have the appropriate animal models to test novel therapeutic approaches to treat PFV based on our stu...