R01EY032238

Soft Drusen in Rhesus Macaques as a Nonhuman Primate Model of Early Age-Related Macular Degeneration - Project Summary

Age-Related Macular Degeneration (AMD) is the leading cause of vision loss in the elderly, but current treatments target advanced stages when interventions may be limited by irreversible cell loss. Soft drusen are the initial and hallmark feature of AMD, but their pathogenesis is unclear and the development of treatments is limited by the lack of good animal models.

Unlike most laboratory animals, nonhuman primates (NHPs) possess a true macula and spontaneously develop soft drusen resembling early human AMD. Prior studies of NHP drusen have been observational, cross-sectional, and qualitative, owing to the high costs of maintaining aged animals, limited longitudinal imaging capabilities, and lack of next-generation sequencing (NGS) and bioinformatics support.

We recently surveyed a unique colony of geriatric rhesus macaques at the California National Primate Research Center (CNPRC) and found a 30.6% prevalence of drusen. Using high-resolution multimodal in vivo imaging, we precisely measured drusen progression over 2 years, with histological and ultrastructural correlates demonstrating lipid accumulation resembling human soft drusen.

Similar to cardiovascular diseases, AMD shares epidemiologic risk factors such as high-fat diets, susceptibility genes in lipid metabolism, and deposits similar to atherosclerotic plaques with lipoprotein accumulation, lipid oxidation, and complement-based inflammatory responses. Recent pilot studies suggest that high-dose oral atorvastatin can cause drusen regression in some AMD patients, but human studies are limited by the heterogeneity of AMD phenotypes and variability in subject diets and serum lipid concentrations.

In this study, we plan to establish a new, unique cohort of aged rhesus macaques with soft drusen and perform:

1) Detailed ophthalmic characterization using spectral-domain optical coherence tomography (SD-OCT) to precisely measure retinal layers and track drusen volume, and fundus autofluorescence (FAF) to measure RPE lipofuscin.
2) Metabolic profiling to measure fasting plasma metabolites, lipoproteins, and apolipoproteins.
3) Whole-genome sequencing to identify genetic variants in animals with drusen that may be shared with human AMD.

Next, we will establish the impact of a "Western-style" high-fat/sugar (HFS) diet and high-dose atorvastatin on drusen progression and RPE health over 2 years, and determine possible correlations with dietary fats and serum lipids.

Finally, we will employ NGS-based single-cell RNA-sequencing (scRNA-seq) to determine the gene expression profile in macular RPE cells with and without soft drusen, exposure to HFS diet, or treatment with high-dose statin, followed by immunohistochemistry of contralateral eyes to evaluate and validate identified gene sets or pathways, as well as complement and other immune pathways.

Together, these studies will not only establish a highly valuable and unique cohort of aged rhesus macaques with soft drusen suitable for translational studies but also explore the role of dietary lipids, oral statins, RPE gene expression, and immune pathways in this NHP model of early AMD.

Davis University Of California

1) TO SUPPORT EYE AND VISION RESEARCH PROJECTS THAT ADDRESS THE LEADING CAUSES OF BLINDNESS AND IMPAIRED VISION IN THE U.S. THESE INCLUDE RETINAL DISEASES, CORNEAL DISEASES, CATARACT, GLAUCOMA AND OPTIC NEUROPATHIES, STRABISMUS, AMBLYOPIA, AND LOW VISION AND BLINDNESS REHABILITATION. 2) TO INCREASE UNDERSTANDING OF THE NORMAL DEVELOPMENT AND FUNCTION OF THE VISUAL SYSTEM IN ORDER TO BETTER PREVENT, DIAGNOSE, AND TREAT SIGHT-THREATENING CONDITIONS, AND, TO ENHANCE THE REHABILITATION, TRAINING, AND QUALITY OF LIFE OF INDIVIDUALS WHO ARE PARTIALLY-SIGHTED OR BLIND. 3) TO SUPPORT A BROAD PROGRAM OF BASIC VISION RESEARCH THROUGH GRANTS AND COOPERATIVE AGREEMENTS, TO ENCOURAGE HIGH QUALITY CLINICAL RESEARCH, INCLUDING CLINICAL TRIALS, OTHER EPIDEMIOLOGICAL STUDIES, AND HEALTH SERVICES RESEARCH, TO ENCOURAGE RESEARCH TRAINING AND CAREER DEVELOPMENT IN THE SCIENCES RELATED TO VISION, AND TO SPONSOR SCIENTIFIC WORKSHOPS IN HIGH PRIORITY RESEARCH AREAS TO ENCOURAGE EXCHANGE OF INFORMATION AMONG SCIENTISTS. 4) SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENCOURAGE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.867 - Vision Research

National Eye Institute (NEI) [HHS - NIH]

Davis, California 95616 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 448% from $590,988 to $3,241,037.