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Macular Degeneration Basic Research

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.

Research on Dry Macular Degeneration (Non-Neovascular AMD):

Patients who are affected have gradual loss of central vision due to death of photoreceptor and retinal pigmented epithelial (RPE) cells. Photoreceptors are the specialized cells that change light stimuli into impulses that travel to other cells in the retina and eventually to the brain. They are essential for vision but they can not function or survive without RPE cells. It is not known why photoreceptors and RPE cells die in patients with macular degeneration, but it is probably due to a combination of genetic mutations that make the cells more susceptible to damage and exposure to damaging stimuli in the environment.

1. Identification of genetic defects in patients with macular degeneration
It is important to identify the cause(s) of cell death so that specific treatments can be developed. One strategy is to identify the genetic defects that occur in patients with macular degeneration and then develop genetically engineered animal models that can be studied in detail. There are some forms of macular degeneration that occur in young patients due to a mutation in a single gene. Examples are Best's disease and Stargardt's disease, and elucidation of the functions of the gene products involved in these relatively uncommon, but genetically straightforward diseases, and determining how dysfunction of the gene product results in retinal degeneration could lead to treatments for these diseases and new insights relevant to AMD. Dr. Kang Zhang in the laboratory of Dr. Don Zack is performing linkage analysis using DNA samples from patients with Stargardt's disease and has identified a new genetic locus where a defect exists in some patients. Collaborative studies are underway to identify the gene in which the defect is located. Collaborative studies in the Zack and Campochiaro laboratories are aimed at identifying proteins that interact with the product of the Best's disease gene product to try and identify its function and other studies are aimed at identifying genes that are good candidates for other retinal degenerations. The laboratory of Dr. David Valle is using a completely different strategy to identify candidate genes. In a large collaboration, the AMD Genetics Study, DNA samples are being obtained from patients with age-related macular degeneration and their affected family members. These samples are being used in a search for genes with defects and for candidate gene analyses.

2. Environmental exposure
Drs. Sheila West, Barbara Hawkins, and their colleagues are performing epidemiological studies aimed at identifying environmental exposures that in combination with genetic defects increase the likelihood of macular degeneration. Macular degeneration is most common in patients over the age of 60. But it does not occur in all elderly patients, supporting the hypotheses that it only occurs in patients with susceptible genotypes (genetic defects that increase susceptibility to damage from particular environmental exposures). Identifying risk factors can provide information concerning what should be avoided to minimize your risk of AMD. Several studies have shown that smoking markedly increases the risk of AMD. All patients should be aware of this, because it is something that can be modified. While there is laboratory evidence suggesting a rationale for why light exposure might be a risk factor, studies by Dr. West and her colleagues have not substantiated this hypothesis. In the Salisbury Eye Study, Dr. West and her research team are seeking to identify other things in the environment that may increase the risk of AMD.

Many of the environmental exposures that increase risk for macular degeneration are thought to act by causing oxidative damage. This has led to the hypothesis that antioxidant vitamins may help to prevent macular degeneration. While vitamin manufactures would like patients to believe that this is a proven fact, it is not. However, the effect of antioxidants on the development of macular degeneration is being tested at the Wilmer Institute and other centers in the AREDS Study sponsored by the National Eye Institute.

3. Identification of downstream genes involved in dry AMD
Identification of genetic defects that occur in patients with macular degeneration is only the first step. It is necessary to determine how the genetic defects result in the death of photoreceptors and RPE cells. One way to identify genes that are involved is to determine which genes are "turned on" or "turned off" in the retina and RPE of patients with macular degeneration compared to patients who are the same age but do not have macular degeneration. Many of our patients have decided to donate their eyes when they die to contribute to research that will assist other patients with macular degeneration. RNA is isolated from the retina and retinal pigmented epithelium. Several approaches are being used to determine which genes are turned on or turned off in patients with AMD compared to similarly aged-patients without AMD.

4. Neurotrophic factors
Neurotrophic factors are proteins that are normally produced by cells in the body that help to keep the producing cells or neighboring cells alive. Some retinal degenerations may be due to a deficiency of neurotrophic factors, but even those that aren't may be helped by pharmacologic doses of one or a combination of neurotrophic factors. It is important to know how neurotrophic factors work so their effects can be maximized or mimicked by other treatments. A collaborative study between the Zack and Campochiaro laboratories is investigating which neurotrophic factors stimulate intracellular signaling in which retinal cells. The Campochiaro and Zack laboratories are using genetically engineered mice to determine if sustained expression of neurotrophic factors can prevent retinal degeneration. Dr. Janet Sunness is studying the natural history of a form of dry macular degeneration called geographic atrophy, information that is needed for future clinical trials. The long-term objective of these studies is to develop treatments to prevent cell death resulting in gradual loss of vision in patients with macular degeneration.

5. Transplantation of photoreceptor and/or retinal pigment epithelial cells
Another approach is to replace dead or dying cells by transplantation. There are many large technical hurdles that must be overcome for this approach to be viable. One obstacle is to determine the best approach to obtaining and maintaining cells for transplantation and the conditions necessary for functioning after transplantation.

Research on Wet (Neovascular) Macular Degeneration:

The wet form of macular degeneration is due to growth of abnormal blood vessels beneath the retina; a process referred to as choroidal neovascularization (CNV).

1. Pathologic studies
It is not known why abnormal blood vessels grow, but deposits of material in between the RPE and Bruch's membrane (Bruch's membrane is a complex 5 layer extracellular matrix structure that separates the blood vessels of the choroid from the RPE) referred to as large "soft drusen" predispose to CNV. Studies in the laboratory of Dr. Richard Green have demonstrated that diffuse thickening of Bruch's membrane often precedes CNV and that when CNV occurs, it is often due to penetration of Bruch's membrane in multiple locations. The Green laboratory has published numerous clinico-pathologic correlations that have helped us to understand what is happening at the cellular level when we see certain features in eyes with macular degeneration.

The laboratory of Dr. Jerry Lutty has developed a new technique through which choroidal flat mounts are prepared from eyes donated after death by patients with macular degeneration and similarly-aged patients without macular degeneration. These studies have shown unexpected changes in choroidal vessels from patients with AMD that are being intensely investigated.

2. Identification of molecular signals involved in abnormal blood vessels growth
The Campochiaro and Zack laboratories are using genetic engineering in mice to investigate the effects of various growth factors in the retina. Studies to date suggest that vascular endothelial growth factor plays an important role as a stimulator of abnormal blood vessel growth in the eye, while fibroblast growth factor does not. This suggests that vascular endothelial growth factor, but not fibroblast growth factor, provides a good target for intervention. These studies have also led to the development of useful animal models. Another model of CNV in which Bruch's membrane is ruptured with a laser in mice, has been useful to explore the role of individual gene products in CNV.

3. Development of drugs that inhibit abnormal blood vessel growth
The Campochiaro and Lutty laboratories are investigating the effect of various drugs on abnormal blood vessel growth in the eye. Antagonists of integrin avb3 partially inhibits retinal neovascularization, while a kinase inhibitor that blocks phosphorylation by protein kinase C, vascular endothelial growth factor receptors, and platelet-derived growth factor receptors dramatically inhibits both retinal and choroidal neovascularization. Clinical trials are being organized to test the ability of these agents to inhibit CNV in patients with macular degeneration.

Dr. Sheila West on the Link Between Smoking and Eye Disease in Women - 7/23/2014

Dr. Pradeep Ramulu and Colleagues Study Relationship Between Vision Loss and Work Status - 7/18/2014

Wilmer Resident Receives Lindstrom Research Grant - 7/11/2014

Four Wilmer Researchers Receive BrightFocus Foundation Awards - 7/10/2014

Dr. Michael Repka Part of Team Researching Telemedicine and ROP - 6/27/2014

Dr. M. Valeria Canto-Soler and Colleagues Featured on WBAL-TV - 6/24/2014

Dr. M. Valeria Canto-Soler and Colleagues Use Human Stem Cells to Create Light-Sensitive Retina in a Dish - 6/10/2014

Wilmer's Division of Ocular Immunology Announces "Living With Uveitis" Support Group - 6/10/2014

Dr. Neil Bressler to Speak on Diabetic Retinopathy at National Eye Health Summit and Webcast - 6/10/2014

Dr. Donald Zack Receives a Research to Prevent Blindness Nelson Trust Award for Retinitis Pigmentosa - 6/9/2014

Dr. Michael Boland Leads Study on Effectiveness of Automated Telecommunication-Based Reminders on Adherence to Glaucoma Medication Dosing - 6/4/2014

Dr. Christina Prescott Discusses Summer Eye Protection on Fox 45 News - 6/1/2014

Dr. Jonathan Song Discusses Treatment Options for Pediatric Cataracts - 5/23/2014

Johns Hopkins' Jordan Green Discusses His Work at Wilmer's Translational Tissue Engineering Center - 5/21/2014

Longtime Wilmer Employee Lillie Alston Honored by Hopkins - 5/19/2014

Dr. Richard Semba: Diets Rich in Antioxidant Resveratrol Fail to Reduce Deaths, Heart Disease or Cancer - 5/12/2014

Dr. Neil Miller Explains Eye Twitching in The Wall Street Journal - 5/12/2014

Dr. Hendrik Scholl Receives ARVO Award - 5/7/2014

 

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