Loose DNA Snippets May Fuel Dry AMD

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Scientists at the University of Virginia have identified “junk” DNA in the cytoplasm of retinal cells as a possible driver of a molecular cascade that leads to geographic atrophy (GA) in patients with age-related macular degeneration (AMD). Furthermore, derivatives of a common anti-AIDS drug, AZT, appear to block the impact of this free-floating DNA and thereby prevent GA lesions from growing, the researchers found.^1,2

Known as Alu cDNA, these mole­cules were present in retinal pigment epithelium (RPE) cells of donor eyes of patients with GA, the researchers said. The Alu cDNA concentrates primarily along the periphery of the GA lesions.

HISTOLOGY. This image shows the Alu cDNA in the RPE at the edge of a GA lesion (red = Alu cDNA; blue = DAPI staining of the nucleus; green = autofluorescence of the RPE cells).

Why RPE cells die. In a series of experiments in rodents, the researchers found that the Alu cDNA triggers ac­tivation of an inflammasome, NLRP3, which then bathes cells in toxic cyto­kines.¹ This may explain why RPE cells die in patients with dry AMD.

These findings expand on those from an earlier study, in which the re­searchers published a dogma-toppling conclusion: Contrary to what has long been believed, production of cellular DNA is not always confined inside cell nuclei or mitochondria. Instead, in eyes with GA, small sections of what is usu­ally noncoding Alu RNA are released into the cytoplasm, where they cause production of complementary DNA.²

It is the extraneous Alu cDNA and a consequent release of mitochondrial DNA that trigger an inflammatory response leading to RPE cell degenera­tion, said study leader Jayakrishna Am­bati, MD, at the University of Virginia in Charlottesville. “You have this DNA that’s being made in the cytoplasm. It’s not supposed to be there. So when our body sees that, it turns on many of the same alarm pathways that it turns on when it sees viruses—that is, the in­flammasome,” Dr. Ambati said. “What’s evolved as a defense mechanism against pathogens has now been hijacked and turned against our own bodies.”

The AIDS connection. In a study published in 2014, the researchers found that this inflammatory pathway could be blocked by nucleoside reverse transcription inhibitors (NRTIs), which are used to treat HIV infection.³ Thus, they hypothesized that NRTIs might be reducing the incidence of dry AMD in patients who take them as AIDS thera­py, Dr. Ambati said.

They then analyzed data from four large, longitudinal health insurance databases and found that the use of NRTIs was associated with a 38% lower risk of GA (pooled adjusted hazard ratio, 0.616; 95% confidence interval, 0.493-0.770).²

Next steps. If an NRTI were to prove effective against GA, it would need to be in a less toxic formulation that does not have the potential serious side effects of antiretroviral drugs, Dr. Ambati said. “Those drugs are toxic from top to toe. Even the safer ones are not that pleasant. And certainly in an elderly population, you would have to be very careful.”

Buoyed by the “natural experiment” they uncovered in the insurance data­bases, Dr. Ambati said his group hopes to treat GA patients with a modified, less toxic NRTI from the Kamuvudine class in a clinical trial early this year.

—Linda Roach

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1 Fukuda S et al. Sci Adv. 2021;7(40):eabj3658.

2 Fukuda S et al. Proc Natl Acad Sci. 2021;118(6):e2022751118.

3 Fowler BJ et al. Science. 2014;346(6212):1000-1003.

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Relevant financial disclosures: Dr. Ambati—In­flammasome Therapeutics: O.

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