Scientists have identified a group of drugs that may help stop a leading cause of vision loss after making an unexpected discovery that overturns a fundamental belief about DNA.
The drugs, known as Nucleoside Reverse Transcriptase Inhibitors, or NRTIs, are commonly used to treat HIV. The new discovery suggests that they may be useful against dry macular degeneration as well, even though a virus does not cause that sight-stealing condition.
A review of four different health insurance databases suggests that people taking these drugs have significantly reduced risk of developing dry macular degeneration, a condition that affects millions of Americans.
“We are extremely excited that the reduced risk was reproduced in all the databases, each with millions of patients,” said Jayakrishna Ambati, MD, a top macular degeneration researcher at the University of Virginia School of Medicine. “This finding provides real hope in developing the first treatment for this blinding disease.”
Targeting Macular Degeneration
The new discovery comes from Ambati; Fred H. Gage, Ph.D., of the Salk Institute for Biological Studies; and collaborators around the world. The work rewrites our understanding of DNA, revealing for the first time that it can be manufactured in the cytoplasm of our cells, outside the cell nucleus that is home to our genetic material.
The buildup of a certain type of DNA in the cytoplasm, Alu, contributes to macular degeneration, the researchers found. This buildup appears to kill off an important layer of cells that nourishes the retina’s visual cells.
Based on this discovery, the researchers decided to look at drugs that block the production of this DNA, to see if they might help prevent vision loss.
They analyzed multiple U.S. health insurance databases – encompassing more than 100 million patients over two decades – and found that people taking NRTIs were almost 40% less likely to develop dry macular degeneration.
The researchers are urging further study to determine if these drugs or safer derivatives known as Kamuvudines, both of which block a key inflammatory pathway, could help prevent vision loss from dry macular degeneration.
“A clinical trial of these inflammasome-inhibiting drugs is now warranted,” said Ambati, the founding director of UVA’s Center for Advanced Vision Science.
“It’s also fascinating how uncovering the intricate biology of genetics and combining it with big data archeology can propel insights into new medicines.”
Ambati, of UVA’s Department of Ophthalmology, previously determined that NRTIs may help prevent diabetes as well.
Age-related macular degeneration (AMD) is the predominant cause of blindness among the elderly in the industrially developed world.1 AMD is classified into atrophic (non-neovascular) and neovascular forms. Although this dichotomization is convenient, recent studies have identified significant overlap in the pathophysiological mechanisms driving disease initiation and progression of these ostensibly distinct clinical entities.2–4
Despite these similarities, they differ considerably in terms of treatment options. Although effective treatment with anti-vascular endothelial growth factor (VEGF) is available for neovascular AMD, no approved therapy exists for the atrophic form. Despite its efficacy in neovascular AMD, anti-VEGF therapy does not provide benefit for atrophic AMD.5 Therefore, a single therapy for both forms of AMD would be a welcome development.
Retinal pigment epithelium (RPE) degeneration and choroidal neovascularization (CNV) are the hallmark clinical features of atrophic and neovascular AMD, respectively.6 Azidothymidine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), possesses both anti-inflammatory and anti-angiogenic activities and has been shown to be effective in animal models of CNV and RPE degeneration.7,8
However, the systemic toxicity associated with AZT makes it less than ideal as a repurposing drug candidate for AMD.9 This toxicity is associated directly with its ability to inhibit reverse transcriptase, an activity necessary for its anti-retroviral function but unessential for its anti-inflammatory activity.10–12 Hence, identification of AZT analogs that lack the ability to inhibit reverse transcriptase and assessing the anti-inflammatory and anti-angiogenic properties of these analogs may help identify potential drug candidates for AMD.
Following oral administration, AZT is rapidly absorbed and metabolized. The predominant metabolite of AZT in humans, 5′-glucuronyl azidothymidine (GAZT), accounts for ∼70% of all excreted AZT and is inactive against retroviral replication.13,14 The aim of this study was to investigate if GAZT retains the anti-inflammatory and anti-angiogenic properties of AZT by assessing its efficacy in mouse models of geographic atrophy (GA) and CNV.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441363/
More information: Shinichi Fukuda el al., “Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration,” PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2022751118
