Repurposed HIV Drugs Show Early Success in Treating Geographic Atrophy

Learn about how an international research team studying a form of dry age-related macular degeneration (AMD) discovered that two drugs used to treat human immunodeficiency virus (HIV), the virus that can lead to AIDS can block the retinal pigment epithelium (RPE) degeneration found in AMD.

What: An international research team studying geographic atrophy, a form of dry age-related macular degeneration (AMD), has shown that, in mice and possibly in humans, two drugs used to treat human immunodeficiency virus (HIV), the virus that can lead to AIDS, and safer chemically modified close counterparts of the drugs, can block the retinal pigment epithelium (RPE) degeneration found in AMD.

Where: Narendran S, et al. Nucleoside Reverse Transcriptase Inhibitors and Kamuvudines Inhibit Amyloid-β Induced Retinal Pigmented Epithelium Degeneration. Signal Transduction and Targeted Therapy, April 14, 2021.

BrightFocus Connection: Related research by coauthor Bradley Gelfand, PhD, on vascular components of AMD is being supported by a Macular Degeneration Research (MDR) grant. He is an assistant professor of ophthalmology at the University of Virginia (UVA) School of Medicine in Charlottesville, VA. Additionally, senior author Jayakrishna Ambati, also of the UVA medical research faculty, is a past MDR grantee.

Why It Is Important: Chronic inflammation has long been recognized as a key contributor to diseases of aging. The build-up under the retina of tiny, fatty protein deposits known as drusen is a common, early sign of AMD. Within these drusen, inflammatory components known as amyloid-beta oligomers, or AβOs, are linked to the progression to geographic atrophy (GA), an irreversible and currently untreatable form of late-stage dry AMD.

For other degenerative diseases of aging such as Alzheimer’s, inhibiting the inflammation caused by these AβOs is a treatment strategy now in development. However, developing such treatments for AMD requires identifying the targets and pathways of AβO-induced RPE degeneration, and then finding drugs that inhibit their function.

In this study, researchers including Dr. Gelfand used genetically modified mice to show that AβOs fuel inflammation by activating key components of the immune system known as inflammasomes. The team also showed that P2RX7, a mediator of inflammasome activation, is key to AβO induced RPE degeneration.

Next, in mice, the team tested the ability of four inflammasome-inhibiting drugs to block the RPE degeneration caused by AβOs. The drugs included two nucleoside reverse transcriptase inhibitors (NRTIs), which are commonly used to treat HIV by inhibiting viral replication. They also studied derivatives of those HIV drugs known as kamuvudines, which retain the anti-inflammatory properties of their HIV-fighting counterparts but lack their toxicity and ability to inhibit reverse transcriptase.

In their report, the authors concluded that their findings “provide a strong impetus to explore these modified NRTIs as possible drug candidates for treating geographic atrophy,” particularly because these drugs are relatively safe.