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Macular Degeneration Basic Research
The research component of the Wilmer Macular Degeneration Center consists of a large group of scientists and clinician/scientists who are performing investigations relevant to macular degeneration. Several independent laboratories are participating in a macular degeneration program project that is partially supported by the Foundation Fighting Blindness. The following is a synopsis of the laboratory research at the Wilmer Institute related to macular degeneration.
Macular degeneration is divided into "dry" and "wet" forms. The dry form refers to the degeneration or atrophy that occurs from cell death and the "wet" form refers to the growth of abnormal blood vessels beneath the retina and the scarring that results from it.
Dr. Valeria Canto-Soler and her team have been conducting studies which will contribute to a better understanding of the mechanisms underlying retinal degenerative diseases and the development of therapeutic treatments for them. Within this context, they are working toward the development of human induced pluripotent stem cell (hiPSC) technology that could be used for the study and treatment of retinal dystrophies. Over the past three years, her lab has devoted their efforts to the development of systems which will unfold the full potential of hiPSC for clinical applications. They are now entering the phase of utilizing their system to model retinal diseases and testing its potential for the development of therapeutic treatments.
Dr. James Handa continues his research into the impact of cigarette smoking, as well as examining the role of oxidized fat, on AMD. His lab has found that cigarette smoke generates both oxidative stress and unwanted inflammation. The oxidative stress is generated mainly from the mitochondria, the battery of the cell, after it is damaged. In terms of oxidized fat, Dr. Handa’s focus is on determining how it generates inflammation. Instead of activating complement, a specific arm of inflammation that is linked to AMD risk, they have found that oxidized fat impairs the control networks of complement. In other words, specific regulators of complement become reduced, enabling enhanced complement activation when cells are exposed to oxidized fats.
Dr. Handa’s work in developing a novel microsurgical system continues in collaboration with the computer scientists and biomedical engineers. They have continued to optimize the “smart instruments” and have integrated these instruments with an audio alert system that can warn the surgeon when the force exceeds a specific strength. They have tested this system on a number of surgeons, who have responded favorably and Dr. Handa and his colleagues have been working on imaging tacking systems that can follow movements. They believe that this is important because it will serve as the foundation for developing a system that will quantitatively describe the movement of surgery. This will enable them to better determine what distinguishes an excellent from an average surgeon that is based on objective, rather than subjective indicators. These finding will aid in training surgeons, both current and new, in new techniques.
One approach to prevent or treat dry AMD is to improve one’s ability to handle oxidative stress. The laboratory of Dr. Peter Campochiaro has developed mouse models in which oxidative damage causes degeneration of photoreceptors. Using these models, Dr. Campochiaro is identifying treatments that help the retina to withstand the oxidative stress and prevent retinal degeneration. Dr. Campochiaro has also developed animal models in which abnormal blood vessels grow under the retina just as occurs in patients with wet AMD. These models were used to determine that vascular endothelial growth factor (VEGF) plays an important role in the growth of abnormal blood vessels. When tested in patients with wet AMD, three different drugs that block VEGF (Lucentis, Avastin, and Eylea) were found to reduce leakage in the retina and improve vision. Dr. Campochiaro is testing several other new drugs that may have better effects that are longer-lasting and given by injections under the skin rather than injections in the eye. In a complementary approach, Dr. Campochiaro and his colleagues are developing nanoparticles that when injected into the eye may release drugs for three months or more, decreasing the need for frequent injections.
Dr. Justin Hanes, the director of the Center for Nanomedicine at Wilmer, has collaborated with Dr. Peter Campochiaro on a key paper where they describe their joint development of a new treatment for AMD, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, and other neovascularization-related eye diseases. Additionally, Dr. Hanes was senior author of work that enhanced understanding of the behavior of drug delivery nanoparticles within the eye. Dr. Hanes has also founded a company focused on developing better and longer-lasting treatments for various eye diseases with Drs. Campochiaro and McDonnell. That start-up company, GrayBug, won the 2013 Invest Maryland Challenge in the Life Sciences category, beating out 68 other companies in the category.
Dr. Gerard Lutty is applying regenerative medicine to complications in blood flow to the retina that results from the death of retinal and choroidal blood vessels, which is at the heart of AMD as well as other diseases. His team is using vascular progenitor cells derived from human iPs cells (a type of cell derived from adult cells) to develop novel treatments for ischemic retinopathies (diseases in which there is insufficient blood flow to the cells of the retina). The early results suggest that they may be able to deliver therapeutic genes and repair damaged blood vessels in a living animal. In particular, Dr. Lutty has found that mast cells, immune cells in skin that cause itching in allergic reactions, are activated and increased in number in AMD choroid. When activated, they release growth factors that drive neovascularization and enzymes that destroy the tissue. This is a major discovery because the release of growth factors and enzymes can be stopped by topical drugs that are already approved by the FDA.
Dr. Shannath Merbs and Dr. Jiang Qian have been working on the DNA methylation changes in age-related macular degeneration (AMD). Great effort has been made to determine the molecular basis of this disease. For example, genome-wide association studies (GWAS), which compare genetic variations in large numbers of individuals with disease to matched populations without disease, have identified several genetic factors associated with AMD. Despite these efforts, many of the factors that determine risk in this complex disease remain unknown, leading to an interest in non-genetic factors that contribute to, or serve as risk factors for, disease. They recently identified a large number of methylation sites in blood samples that are associated with AMD patients. These sites have the potential to be used as biomarkers for future study and potentially even serve as clinically useful diagnostic and/or prognostic markers and therapeutic targets for AMD.
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