631 lines
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HIV drugs show promise for “dry” AMD
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December 22, 2014
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<a href="/about/news-and-events/news?topic=246" hreflang="en">Age-Related Macular Degeneration</a>
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<img src="https://www.nei.nih.gov/sites/default/files/styles/small/public/news/amd-hiv.jpg?itok=u0mpNHub" alt="Degenerated RPE cells from mice with geographic atrophy are shown at left. Treating the mice with NRTIs protected the RPE cells. Photos courtesy of Jayakrishna Ambati, M.D." width="395" height="195">
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<p>Degenerated RPE cells from mice with geographic atrophy are shown at left. Treating the mice with NRTIs protected the RPE cells. Photos courtesy of Jayakrishna Ambati, M.D.</p>
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<p>A class of medications long used to curb HIV infection shows promise as a therapy for age-related macular degeneration (AMD), suggest findings from an NIH-funded study. These mainstay HIV drugs, called nucleoside reverse transcriptase inhibitors (NRTIs), may eventually be repurposed to treat a host of other inflammatory disorders, too.</p><p>The study broke new ground by showing that NRTIs block inflammation, said Jayakrishna Ambati, M.D., vice chair of the Department of Ophthalmology and Visual Sciences at the University of Kentucky. Dr. Ambati’s lab led the study, which was published in <em>Science.</em></p><p>In mice, the NRTIs stavudine and zidovudine prevented the progression of geographic atrophy, also known as dry AMD. AMD is a leading cause of blindness among people age 60+ worldwide, and approximately 90 percent of people with AMD have geographic atrophy. There are currently no FDA-approved treatments for geographic atrophy.</p><p>AMD involves deterioration of the retina, the light-sensitive tissue at the back of the eye. The most severe damage occurs in the macula, a small area of the retina that is needed for sharp, central vision. In geographic atrophy, there is a gradual breakdown of the nerve cells in the macula and the supporting cells beneath it, called retinal pigment epithelial (RPE) cells.</p><p>NRTIs are believed to halt the progression of HIV infection by derailing reverse transcription, the process by which the virus converts its own genetic information (RNA) into DNA within the host’s immune cells, forcing those cells to become factories that produce new copies of the virus.</p><p>Initially, the University of Kentucky researchers hypothesized that the ability of NRTIs to halt reverse transcription could be leveraged to prevent RPE cell death. Their reasoning: RPE cell death appears linked to an overabundance of genetic material called <em>Alu</em> RNA. Like HIV, Alu also relies on reverse transcription to reproduce. Since NRTIs are therapeutic for HIV, perhaps NRTIs would also block the effects of <em>Alu</em> RNA on the retina.</p><p>The researchers introduced <em>Alu</em> into the eyes of healthy mice to induce RPE cell death, a model of geographic atrophy. Next, daily oral administration of the NRTI stavudine was given to the mice for six days and the investigators found that it prevented RPE cells from dying in 5 of 6 mice compared with 0 of 6 mice receiving a control treatment. They also tested twice daily abdominal injections of zidovudine for six days and found that it prevented RPE death in 8 of 9 treated mice versus 0 of 8 control mice.</p><p>Surprisingly, the researchers found that the protective effect of NRTIs was independent of their ability to prevent reverse transcription. Instead, NRTIs blocked the inflammasome, a large protein complex that promotes inflammation. For this reason, the investigators theorize that NRTIs could have similar benefits for other inflammatory disorders, including neovascular AMD, also called wet AMD, a disease in which leaky blood vessels develop around the macula to cause blindness. Although several effective drugs for neovascular AMD exist, they are given by regular injections into the eye and can become less effective with time.</p><p>“We welcome the identification of anti-inflammatory compounds, especially those that can selectively control a disease process,” said Grace Shen, Ph.D., director of the retinal diseases program at the National Eye Institute, which funded the study in part.</p><p>However, “much work remains to be done. Results obtained from the mouse model of AMD have important limitations, such as the fact that mice do not have a macula. We will not know whether NRTIs are an effective treatment for AMD in people until clinical trials demonstrate such a benefit,” she said.</p><p>The planning for two multicenter clinical trials testing NRTIs approved for treating HIV is already underway, Dr. Ambati noted. One trial will assess an orally administered NRTI while the other will test the effects of injecting the drug directly into the eye. If NRTIs prove effective in people, they could be available for use in AMD and potentially other inflammasome-related disorders in a few years, he said.</p><p>Funding for the study included several NEI grants to Dr. Ambati’s lab (EY018350, EY018836, EY020672, EY022238, and EY024068).</p><p><strong>Reference: </strong>Fowler <em>et al.</em> “Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity.” Science, 21 November 2014. <a href="http://science.sciencemag.org/content/346/6212/1000">DOI: 10.1126/science.1261754</a> <a href="https://pubmed.ncbi.nlm.nih.gov/25414314/">Pubmed</a></p>
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