The clinical component of the Center for Macular Degeneration Treatment and Research, whose basic science arm is the Ocular Cell Transplantation Laboratory, is staffed by the retina faculty, and includes the Low Vision Center and the Ophthalmic Diagnostic Imaging Center.  
  Treatment of Diabetic Macular Edema: Subthreshold Micropulse
Diode Laser Photocoagulation
  Neelakshi Bhaghat, MD  
  The goal of this clinical research project is to evaluate the efficacy of diode laser in the treatment of diabetic macular edema using subthreshold parameters.  
  Adjuvant 5-Fluorouracil and Low Molecular Weight Heparin in the Prevention of Proliferative Vitreoretinopathy  
  Neelakshi Bhaghat, MD  
  Dr. Bhagat has been involved in this clinical pilot study to evaluate the effect of 5-fluorouracil and low-molecular-weight heparin on the development of proliferative vitreoretinopathy in rhegmatogenous retinal detachments.  
  Retinal Dopamine: ERG Blue-Cone Response as a Biologic Marker of Decreased Brain Dopamine Levels in Cocaine-Withdrawn Patients  
  Monique S. Roy;  Alex Roy, MD  
  The “rewarding” effects of cocaine abuse are due primarily to its effects on the neurotransmission of brain dopamine (DA). Preclinical and clinical studies have shown that cocaine withdrawal is associated with decreased central DA. Since DA is found in high concentrations in the retina, retinal function in cocaine-withdrawn patients was examined using spectral Ganzfeld electroretinography (ERG). This laboratory found that patients had significantly reduced blue-cone ERG responses compared with those of matched normal controls. This finding was replicated in a second group of such patients and controls. The goal of the study is to determine whether ERG blue-cone responses may serve as biologic markers of decreased brain DA in cocaine-withdrawn patients. Results of the second study showed that low ERG blue cone response is associated with low CSF dopamine levels.  
  Proteinuria in African American Patients With Type 1 Diabetes  
  Monique S. Roy, MD  
  African Americans with type 1 diabetes are at high risk for end-stage renal disease. Factors associated with the presence of any proteinuria were examined in this group of individuals. Proteinuria and creatinuria were measured in both first-voided and 4-hour times urine specimens in African Americans with type 1 diabetes (n=717). Other evaluations included clinical interview, ocular examination, fundus photography, blood pressure, and glycosylated hemoglobin measurements. Of the 717 patients, 49.8% had any proteinuria. Frequency of any proteinuria increased significantly with age and duration of diabetes. Proteinuria appears to be common in this group of patients. Risk factors include male sex, systemic hypertension, poor glycemic control, and longer duration of diabetes.  
  Use of Eye Care Services by African American Patients With Type 1 Diabetes  
  Monique S. Roy, MD  
  This study was conducted over a 1-year period to determine the frequency of annual dilated eye examinations, health insurance status, frequency of visits to an ophthalmologist, reasons for lack of eye care, and factors that led to a dilated eye examination among African American patients with type 1 diabetes.  
  Risk Factors for Diabetic Retinopathy in African Americans  
  Monique S. Roy, MD  

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.

  Retinal Functional Abnormalities in the Early Identification of Progression
of Diabetic Retinopathy: A Prospective Study
  Monique S. Roy, MD  
  Diabetic retinopathy is the leading cause of new cases of blindness among Americans, aged 20 to 74 years. For patients with severe retinopathy, laser photocoagulation is beneficial in reducing the rate of severe visual loss. However, laser treatment is not always effective and may be associated with significant side effects. Thus, the early identification of patients with diabetes who are at risk for developing severe retinopathy might lead to early preventive treatment. Insulin-requiring diabetic patients with moderate retinopathy will be recruited over a 6- to 12-month period from the 5 clinics affiliated with the Department of Ophthalmology. Examinations will include PVF using the Fluorotron Master; ERG; and color vision testing using saturation neovascularization to establish a correlation between the scores obtained and retinal damage.  
  ERG Prospective Evaluation of Diabetic Retinal Neovascularization  
  Monique S. Roy, MD  
  Neovascularization of the retina and iris are major risks in diabetes and central retinal vein occlusion. To date, fluorescein angiography is the only successful modality for determining capillary dropout and venous staining, as prognosticators for laser surgery. Furthermore, the difficulties associated with angiography limit the number and frequency of tests. In this study, Dr. Roy is investigating the use of electroretinography to evaluate retinal discrimination, macroangiopathy, microalbuminuria, residual insulin secretion from serum C peptide levels, and serum glycosylated hemoglobin levels as measures of diabetic control. Patients are followed prospectively by retinal examinations every 6 months. PVF, ERG, and color vision testing are repeated 1 year following entry into the study. The end-point of the study is the development of severe retinopathy in either eye. Age- and sex-matched normal subjects will undergo ERG and color vision testing and serve as controls. Initially, patients are divided into 2 groups (normal and abnormal) according to (1) p-values, (2) ERG results, and (3) color vision data. Cumulative percent of eyes progressing to severe retinopathy by 18 months in the 2 groups will be compared. Statistical analysis, eg, Logistic Regression, will be used to determine which of the 3 retinal function tests is the best prognosticator of the progression to severe retinopathy. The ability to predict those patients progressing to the severe form of the disease can lead to studies of early treatment intervention.  
  Measurement of Macular Blood Flow Velocity in Patients With Sickle Cell Disease
Using Blue Light Entoptoscopy
  Monique S. Roy, MD  
  Decreased blood flow in the macular region of the retina is likely to be an early indication of sickle-cell retinopathy. Further, it is likely to be directly proportional to the extent of red blood cell heterogeneity in patients with sickle cell disease. The aim of this study is to measure macular blood flow in patients with sickle cell disease to determine whether blood velocity (as measured by the blue-field simulator) is decreased in this group as compared with age-matched controls. Additionally, we will determine whether there is an association between any such decrease and the extent of red blood cell heterogeneity, ie, polymerized hemoglobin-S content (as measured by the phthalate ester separation technique).  
  Digitization of the Foveal Avascular Zone in Sickle Cell Patients and Controls  
  Monique S. Roy, MD  
  The foveal avascular zone in patients with sickle cell hemoglobinopathy is being measured using image digitization and correlated with visual acuity loss and color vision deficiency.  
  Digitization of Geographic Atrophy Lesions in Patients with AMD  
  Monique S. Roy, MD  
  Geographic atrophy of the macular area in patients with macular degeneration is being evaluated using image digitization. The rate of visual loss associated with this atrophy is being followed over time and the results are being tabulated.  
  Color Vision Using Temporal Modulation Thresholds  
  Monique S. Roy, MD  
  The purpose of the study is to detect early color vision losses using a computerized color vision system developed by Ken Knoblauch (research investigator, Lighthouse, Inc, NY) and Robert Picardi (electronic engineer, NYU, NY). This newly developed system allows determination of temporal modulation thresholds for 2 color mixtures— red-green and blue-yellow. For a specific mixture of red and green, these 2 colors can be rendered equiluminous (similarly for blue-yellow) for individual observers, thereby correcting for individual differences in luminosity or luminosity losses due, for example, to lens opacities. This becomes particularly valuable when assessing patients with diabetes or older individuals for color vision losses thought to be caused by retinal disease.  
  Pigment Epithelium Removal and Transplantation  
  Marco A. Zarbin, MD, PhD  

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.

  Human Retinal Pigment Epithelium Wound Healing on Bruch’s Membrane  
  Marco A. Zarbin, MD, PhD  
  An alternative to RPE transplantation is to stimulate RPE ingrowth from the edge of the dissection bed. Human pathological studies indicate that RPE ingrowth following CNV excision in patients with AMD is incomplete and aberrant. An RPE wound healing model assay system was developed by creating small defects in Bruch’s membrane explants from cadaver eyes. The 3-mm defects remove the native RPE cells with the creation of 3 different surfaces: intact basement membrane, superficial surface of the inner collagenous layer (ICL), or deeper layers of the ICL. Results suggest that RPE basement membrane promotes RPE wound healing, and severe Bruch’s membrane damage hinders RPE resurfacing of localized defects in aged submacular human Bruch’s membrane. The poor RPE ingrowth observed on deep layers of the ICL mimics the histopathological findings in patients with AMD that have undergone CNV excision. The methods established in this model system to estimate the degree of RPE repopulation and to monitor ongoing ingrowth of RPE allow us to quantitatively assess RPE wound healing in response to potential therapeutic agents. We hope we can improve RPE wound healing by altering the substratum on which the cells must grow and/or by altering the cells themselves by treatment with substances known to stimulate proliferation and/or migration. These studies should lead to treatment for improved retinal survival and recovery of lost vision in patients with AMD after subfoveal CNV excision.  
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