Researchers at the Walker Eye Research Center, led by Nalini S. Bora, Ph.D., in collaboration with Puran Bora, Ph.D., are involved in understanding the etiopathogenesis of age-related macular degeneration (AMD) and uveitis using clinically relevant animal models. Translation of laboratory research into interventions that improve vision in the patients with these blinding ocular diseases is the current research focus at Walker Eye Research Center. Research performed at Walker Eye Research Center will bring the laboratory results from “bench to bedside” by developing new diagnostic and therapeutic strategies and would provide exciting opportunities for the prevention of vision loss associated with AMD and uveitis. Patients with ocular disease will be ultimate beneficiaries of our research.
Age-related macular degeneration (AMD)
AMD affects more than 30 million people worldwide. In the United States as well as in the state of Arkansas, AMD is the leading cause of irreversible blindness among the individuals over the age of 50. Approximately 1.8 million people in USA alone have AMD and it is projected that by 2020, roughly 2.9 million people will develop this disease. The state of Arkansas ranks third in the number of new AMD cases in the country. In AMD there is a progressive destruction of the macula leading to the loss of central vision. AMD patients cannot perform several daily tasks such as reading and driving. Clinically, AMD is classified into two forms, namely “dry” and “wet” AMD. The number of people affected by AMD is increasing because of increased lifespan. As the prevalence of AMD increases, the cost to manage and treat this disease grows as well.
Agents currently available for the treatment of human wet AMD have limited efficacy, require multiple administrations and are associated with a variety of ocular complications. Although these treatments reduce the rate of vision loss, they do not significantly improve the vision and are not cost effective. Although the dry form of AMD is more prevalent (approximately 85% of the cases) and a precursor to wet AMD, the fundamental processes driving dry-type AMD are poorly understood. Several agents to treat dry AMD are currently in the developmental stage. However, no effective treatment option is currently available. Therefore, more research is needed. Our laboratory is particularly interested in exploring the role of immunological, environmental and genetic factors in both the dry and wet AMD.
Choroidal neovascularization (CNV), the hallmark of wet AMD is responsible for the sudden loss of central vision and thus, has a profound impact on the quality of life. Our extensive pre-clinical studies published in peer reviewed journals with high impact factor have demonstrated that complement regulatory protein can prevent the progression of wet AMD in a mouse model. Importantly, these proteins can also inhibit already established experimental wet AMD. These findings are of great clinical relevance because our preclinical studies mimic frequent clinical presentation in humans where a patient presents with an active disease. We believe that complement regulatory protein may have potential to treat human AMD in future. Furthermore, we have explored the effect of nicotine and alcohol consumption on the development of CNV since smoking and chronic alcoholism are two environmental risk factors that have been strongly associated with human AMD, with cigarette smoking being the strongest environmental risk factor. Smoking and heavy alcohol consumption are devastating social problems. Over 100 billion dollars are spent each year to manage these social issues. Our results suggest that nicotine and alcohol consumption exacerbates experimental wet AMD pathogenesis.
One of the greatest obstacles to the development of effective treatments for dry-type AMD is the lack of animal model systems that can facilitate a better understanding of this disease and provide a convenient means to test candidate therapeutics. Recently, we reported that aged mice lacking CD46 spontaneously develop cardinal features of human dry AMD. CD46 (membrane cofactor protein; MCP), is the major regulatory protein of the complement system. We are quite excited that we have such a relatively straight-forward model for dry AMD. In our laboratory, we are utilizing this mouse model system in the investigation of dry AMD pathology and in analyzing potential targets to which complement-mediated therapy could be applied. It is difficult to study AMD in human subjects. Therefore, genetically engineered mice could provide critical tools for understanding and treating dry-type AMD.
Uveitis is an inflammatory disease of the eye, responsible for up to 20% of all blindness. Most uveitis patients present at an age where they are in the most active period of their working life. This age distribution makes uveitis an ocular disease with important socioeconomic impact.
The most common form of human uveitis is anterior uveitis of unknown (i.e. idiopathic) etiology. IAU is an autoimmune disease where an immune response affects only the anterior segment of the eye. Visual complications such as glaucoma, cataract or retinal edema associated with IAU lead to the permanent loss of vision which has long lasting impact on the quality of life. The management of patients with IAU remains a significant challenge because no specific treatment is available for this disease. IAU is treated symptomatically only using non-specific therapies such as steroid and immuno-suppressive agents. Unfortunately, these treatment modalities do not address the underlying mechanisms and are associated with adverse side effects. Prolonged immunosuppression results in increased morbidity.
Experimental autoimmune anterior uveitis (EAAU) is a convenient and reliable animal model of human IAU. For the past several years we are using EAAU animal model to understand the etiopathogenesis of IAU. We have extensively characterized this animal model and have published our findings in peer reviewed journals with high impact factor. Our current studies focus on defining the role of regulatory T cells (Tregs) in idiopathic AU. These studies have clinical relevance as Tregs may potentially be used as cellular therapeutic tool for idiopathic AU. Recently, we identified and characterized a peptide that represents one of the uveitogenic epitope of disease causing antigen essential for the induction of IAU in animals. Our discovery is significant and crucial for the development of peptide based immunotherapy for idiopathic AU. Such immunotherapeutic approach would open the door for developing innovative interventions for human idiopathic AU with fewer side effects.
Gene therapy for AMD and Uveitis
We are using cutting edge techniques to identify mutation in gene(s) responsible for the induction and progression of AMD and uveitis. The goal of this research is to delineate the genes involved and the specific roles they play in causing these ocular diseases.
The data obtained from our animal studies will support and justify the use of gene therapy for restoration of vision in human subjects. Once we have identified defective gene(s) in AMD and uveitis patients, we will next test other family members to see if they also carry the defective gene. This will identify the family member(s) at risk for the development of these diseases. Additionally, our study will provide information regarding how to manage these individuals before they develop the disease.