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Soft drusen in rhesus macaques as a nonhuman primate model of early age-related macular degeneration

Award Number: R01EY032238
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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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 share 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, and 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Vision Research	000	5	10/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $672,319 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Vision Research	000	5	1/17/2025	NON-COMPETING CONTINUATION	$672,319
														Subtotal = $672,319

Issue Date FY: 2024 ( Subtotal = $659,117 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Vision Research	000	4	1/3/2024	NON-COMPETING CONTINUATION	$659,117
														Subtotal = $659,117

Issue Date FY: 2023 ( Subtotal = $684,798 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Vision Research	001	3	3/8/2023	NON-COMPETING CONTINUATION	$68,481
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Vision Research	000	3	1/5/2023	NON-COMPETING CONTINUATION	$616,317
														Subtotal = $684,798

Issue Date FY: 2022 ( Subtotal = $633,815 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Vision Research	001	2	1/28/2022	NON-COMPETING CONTINUATION	$45,739
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Vision Research	000	2	1/6/2022	NON-COMPETING CONTINUATION	$588,076
														Subtotal = $633,815

Issue Date FY: 2021 ( Subtotal = $590,988 )
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Vision Research	000	1	12/28/2020	NEW	$590,988
														Subtotal = $590,988

Grand Total All Awards = $3,241,037

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Soft drusen in rhesus macaques as a nonhuman primate model of early age-related macular degeneration

Award Number: R01EY032238

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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