A2E, Lipofuscin, and Macular Pigments in a Primate Model of AMD
Age-related macular degeneration (AMD) is the most common cause of legal blindness in the elderly in developed countries, and is a leading cause of blindness worldwide. The typical American diet is low in nutritional factors that may reduce the risk or severity of AMD. The goal of this project is to determine whether being deprived of these nutrients has consequences for the development of AMD, and to determine the mechanisms by which this occurs. Results from these studies will provide direct evidence for the importance of these nutritional factors in maintaining retinal health and preventing advanced retinal disease, and may reveal new options for therapeutic intervention.
The goal of this project is to understand the long-term effects and impact that deprivation of nutritional factors known to be important for retinal health can have on development of macular degeneration. We have two specific aims for these studies. First is to quantify and correlate measurements of retinal health (fundus autofluorescence, FAF) with measurements of macular pigment (macular pigment optical density, MPOD) in vivo throughout the lifespan in animals fed normal diets and in aged animals fed diets deprived of carotenoids that are ,composed to form macular pigment. To satisfy this aim, we are performing FAF and MPOD retinal imaging in 40 monkeys fed normal diets throughout the lifespan. We then analyze these images to quantify the levels of autofluorescence and macular pigment across the macula and correlate these measurements to determine spatial relationships between the factors. The goal is to determine whether increased MPOD affects measurements of FAF, and if so, whether it does so in a spatially important way for macular and visual health. The second aim is to correlate the biochemical components of FAF and MPOD in tissue. To do so, we are collecting eyes from monkeys fed normal diets throughout the lifespan and processing them for biochemical and histological study. We have previously collected eyes from animals fed lifelong diets devoid of macular pigment and are performing biochemical and histological analysis on these tissues. The goal of these studies is to correlate measurements of the biochemical components of diet with the in vivo measures so as to confirm the cause of the relationships determined in Aim 1.
This proposal is unique because we are using two animal resources not available anywhere else in the world: an aging monkey resource and our cohorts of animals (now over 20 years old) that have been raised on life-long diets devoid of macular pigment. We also have built one of the most comprehensive and state-of-the-art retinal imaging and retinal function assessment labs for non-human primates in the world. Finally, we have the unique ability, unlike clinical studies, to perform correlative studies between in vivo measurements and biochemical and histological measurements obtained from the same tissue.
Upon completion, our studies will determine the relationship between nutritional factors involved in retinal health and the development of macular disease. These results can be expected to inform the field regarding diet supplements shown to minimize disease progression, identify targets for future therapeutic development, and ultimately provide critical data to aid in reducing the prevalence and impact of AMD.
About the Researcher
Over the last 15 years, my research has been focused on the evaluation of cell and gene therapies for retinal degenerative disease, and the translation of these therapies from small experimental animals into non-human primates. In collaboration with two biotech companies, we have succeeded in gaining FDA approval for two independent Phase I/II clinical trials. I continue this line of research as such, and I currently am the principal investigator on multiple projects involving translational studies involving cell or gene therapy-. Due to my success in this translational field, I was recently awarded the prestigious Carl Camras Translation Research Award at the Association for Research in Vision and Ophthalmology (2015). Over the past six years, my research has focused more heavily on the non-human primate as a model system for examining mechanisms of retinal disease and development and evaluation of prospective cell and gene therapies in this model.
As a young boy I used to spend summers and many weekends playing board and card games with my grandmother, to whom I was very close. She was diagnosed with wet AMD about 25 years ago, prior to any available therapeutic interventions. As various treatments were being evaluated and becoming available, my grandmother tried them, but it was already too late; she had lost a significant amount of her eyesight and the therapies were ineffective for her condition. I watched my independent grandmother become completely dependent on others for daily activities such as driving, grocery shopping, etc. It was particularly heartbreaking for her and myself to not be able to continue playing games with one another because her eyesight had been taken from her. Ultimately, my grandmother passed away in a tragic accident that never would have occurred if she could see.
Forevermore, I blame AMD for taking my beloved grandmother away from my family and me. This loss provides me with the motivation to learn and understand macular degeneration and to develop safe and effective therapies for this disease. I want to prevent other families from suffering a similar loss, perhaps prevent my parents from suffering the way my grandmother did, and prevent my children from experiencing the negative impacts of this disease on their loved ones.
Despite the negativity associated with this disease, I have a tremendous amount of hope for the development of a treatment and perhaps a cure for macular degeneration, and have been working toward this goal for the past 20 years. Foundation funding is a critical component in this process and contributions from donors are a critical reason this is possible. As such, I am extremely grateful for the generosity of the donors and for the trust the BrightFocus Foundation has placed in my research.
First published on: August 1, 2017
Last modified on: June 27, 2019