Diabetic retinopathy (DR) remains one of the leading causes of blindness in the United States. Among African Americans, the prevalence of diabetes is high and the incidence is increasing. The goal of this study is to further ascertain the relationship of risk factors to the incidence and progression of DR. A unique cohort of patients, enrolled in a previous clinical study, are being reexamined to determine

• the 6-year incidence and progression of DR, as graded from standard fundus photographs, and associated incidence of visual impairment; and
• risk factors for incidence and progression of DR, including systemic (glycemic control, blood pressure, renal disease, age, duration of diabetes, and gender); behavioral (smoking, alcohol consumption, and illicit drug use); treatment and socioeconomic (ophthalmic care, health insurance coverage, education level, income, and occupation) factors.

No population-based data exist for African American patients with type 1 diabetes, particularly data addressing the natural history and progression of the disease. Results so far indicate that of the 725 patients recruited into the study, 463 (64%) had any disease, 137 (19%) had proliferative diabetic retinopathy, 89 (12.3%) had macular edema, and 149 (20.6%) had retinal hard exudates. Dr. Roy has established that longer duration of diabetes, poor glycemic control, renal disease, and, to a lesser extent, systemic hypertension are risk factors for any disease and proliferative retinopathies. She has found that macular edema and hard exudates are associated significantly with longer duration of diabetes and severity of diabetic retinopathy. Proteinuria, skipping even one insulin injection per week, and longer duration of diabetes are factors that are both significantly and independently associated with severity of retinal hard exudates.

Currently, no proved treatment options exist for patients with geographic atrophy, an advanced form of age-related macular degeneration (AMD). For selected patients with extensive drusen or geographic atrophy threatening the fovea, cell transplants might prevent central vision loss through replacement of dysfunctional or dead retinal pigment epithelium (RPE) cells. Anti-vascular endothelial growth factor therapy is currently the best treatment available for AMD-associated CNVs, but randomized studies indicate that only 25%-40% of treated patients experience at least moderate visual improvement. Thus, even today, a significant number of patients become blind despite the availability of pathway-based therapy for AMD-associated CNVs. If cell transplants could prevent CNV development or rescue photoreceptors following CNV excision, then these transplants also might have an impact on CNV-related blindness.

A major obstacle to the success of RPE transplants in AMD patients is the failure of transplanted RPE cells to survive and become functional in the diseased AMD eye. RPE transplantation in patients with AMD (atrophic and neovascular) typically has produced limited visual recovery regardless of the type of cell transplanted (eg, autologous or allogeneic, adult or fetal RPE) or whether the cells are transplanted with or without choroid. In contrast, RPE transplantation in animal models of retinal degeneration has been proved to rescue photoreceptors and preserve visual acuity. Although animal studies validate cell transplantation as a means of achieving photoreceptor rescue, an important distinction between humans with AMD and laboratory animals in which RPE transplantation has been successful is the age- and AMD-related modifications of the surface on which human RPE reside in situ (ie, Bruch’s membrane), which may have a significant effect on RPE graft survival. Evidence from human donor eye organ culture experiments indicates that healthy RPE cannot survive for an extended period of time on aged submacular Bruch’s membrane, and the poorest survival is observed on AMD Bruch’s membrane. These in vitro studies were performed on human submacular Bruch’s membrane with no treatment to improve cell survival. Previous studies to improve cell survival on aged Bruch’s membrane included adding extracellular matrix (ECM) ligands singly or in combination to “coat” Bruch’s membrane; detergent treatment to eliminate debris accumulated within Bruch’s membrane, followed by ECM ligand coating; and resurfacing Bruch’s membrane with a cell-deposited matrix. The first two methods showed limited improvement in attachment and early survival. Long-term survival was not demonstrated. The last method improved long-term cell survival more than 200%. However, from a therapeutic standpoint, resurfacing submacular Bruch’s membrane with the cell-deposited ECM was problematic owing to the inability to solubilize ECM components in a manner compatible with clinical application. These studies demonstrate the need for development of a method to improve long-term cell transplant survival in AMD patients.

Bovine corneal endothelial cells (BCECs) secrete an extracellular matrix that supports rapid attachment, growth, and differentiation of RPE. During BCEC-ECM formation, in addition to basal secretion, BCECs secrete ECM components into the overlying medium, including collagens, proteoglycans, and entactin/nidogen. Secretion of ECM components into the overlying medium is most abundant in early passage cells and exceeds basal ECM deposition in quantity. Since soluble ECM can affect cell shape and metabolism in addition to stimulating production of ECM molecules, the presence of these proteins suggests that conditioned medium (CM) harvested from BCEC cultures (BCEC-CM) could be a source of cell-supporting soluble proteins and, if effective, could lead to development of an adjunct to cell-based therapy for AMD. Currently, we are characterizing the behavior of RPE cells transplanted onto Bruch’s membrane of aged and AMD donor eyes cultured in BCEC-CM or CM vehicle by using a previously characterized human submacular Bruch’s membrane bioassay.