NIH researchers discover potential therapeutic target for degenerative eye disease

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A team of researchers from the National Institutes of Health (NIH) have uncovered the source of dysfunction in the process through which the cells in retina remove waste.

According to a news release, a report by scientists at NIH and Johns Hopkins University, Baltimore, details how alterations in a factor called AKT2 affect the function of organelles called lysosomes and results in the production of deposits in the retina called drusen, a hallmark sign of dry age-related macular degeneration (AMD).¹

Leading the research were Kapil Bharti, PhD, and Ruchi Sharma, PhD, co-head the Ocular Stem Cell & Translational Research (OSCTR) Section within NIH's National Eye Institute Intramural Research Program.¹

According to the researchers, the results of the study suggest drusen formation is a downstream result of AKT2-related lysosome dysfunction and points to a new target for therapeutic intervention.²

The researchers explained that lysosomes are like cells' garbage disposals, and they play a key role in maintaining the retina. Cells that make up the retinal pigment epithelium (RPE) provide oxygen and nutrients to the retina's energetically active neurons, while also collecting and processing the retina’s waste products through lysosomes. If the cells lose their ability to process the waste products, it leads to the formation of drusen. As AMD progresses, drusen increase in number and volume.

Despite extensive research, the formation of drusen remains a mystery.

In mice, the researchers were able to mold AKT2 expression levels in RPE. When they overexpressed AKT2, the lysosomes did not function normally, and the mice ultimately developed dry AMD symptoms such as RPE degeneration.

Moreover, the researchers saw similar features in RPE cells from human donors with AMD or in RPE cells generated from patient stem cells. The cells from donors who possessed a gene variant called CFH Y402H, which increases AMD risk, had relatively greater expression of AKT2, showed functionally defective lysosomes, and formed drusen deposits.²

The data form the study lays the groundwork for a potential future treatment for dry AMD, for which there currently is no treatment option. AMD is one of the most common causes of vision loss in the United States.

The study builds upon previous work published by Ruchi Sharma, PhD, also of the NEI Section on Ocular Stem Cell and Translational Research Section, who developed the AMD patient stem cell-derived RPE model (Sharma et al., 2021).³

References:

1. NIH researchers discover potential therapeutic target for degenerative eye disease. National Institutes of Health (NIH). Published July 26, 2024. Accessed July 30, 2024. https://www.nih.gov/news-events/news-releases/nih-researchers-discover-potential-therapeutic-target-degenerative-eye-disease

2. Ghosh S, Sharma R, et al. The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD. Nat Commun. 2024 Jul 21;15(1):6150. doi: 10.1038/s41467-024-50500-z.

3. Sharma R, et al. Epithelial phenotype restoring drugs suppress macular degeneration phenotypes in an iPSC model. Nat Commun. 2021 Dec 15;12(1):7293. doi: 10.1038/s41467-021-27488-x.