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Nucleoside reverse transcriptase inhibitors

Potent antiviral agents show promise for treating AMD

Sean Henahan

Posted: Wednesday, December 14, 2016

Jayakrishna Ambati MD

Jayakrishna Ambati MD

 

Nucleoside reverse transcriptase inhibitors (NRTIs), a class of agents perhaps better known for the antiretroviral treatment of HIV disease and hepatitis, appear to offer potential benefits in the treatment of retinal vascular disease, according to Jayakrishna Ambati MD, Professor and Vice Chair for Research of the Department of Ophthalmology, University of Virginia, USA.

Dr Ambati’s lab has been studying the pathophysiology and molecular basis of geographic atrophy (GA) and retinal pigment epithelium (RPE) degeneration for more than a decade. These studies revealed that in GA there is a reduction in an enzyme called DICER1. One function of DICER1 is the catabolisation of a toxic substance called Alu RNA. Eyes with GA were shown to have reduced DICER1 levels and an accumulation of Alu RNA transcripts, associated with the death of RPE cells.

“How does this occur? It appears that this activates an important immune platform, the NLRP3 inflammasome, a multi protein complex, implicated in a variety of ageing diseases, including age-related macular degeneration (AMD), Alzheimer’s disease, atherosclerosis and arthritis. The inflammasome churns out active cell death molecules including IL18, IL1beta, leading to RPE cell death,” Dr Ambati told a session of the 34th annual meeting of the American Society of Retina Specialists in San Francisco.

In an effort to develop inhibitors of inflammasome, researchers made the serendipitous observation that NRTIs have a previously unknown mechanism of blocking the inflammasome. In-vitro and in-vivo work showed that these agents had potent inhibitors of inflammasome and could potentially block RPE death.

The researchers then created altered versions of the antivirals that eliminated the reverse transcriptase effects while still blocking Alu RNA toxicity. The new class of drugs, known as Kamuvudines, appear to block the inflammasome without causing the mitochondrial toxicity seen in response to NRTIs. The modified NRTIs block inflammasome activation at the level of a channel called P2X7, which has been implicated by way of gene polymorphisms in AMD.

“Of course Alu RNAs are only one of the molecular stressors that accumulate in human GA. There are many others – complement activation, amyloid beta deposition, iron overload, cigarette smoking. All of these culminate in a common element the inflammasome. Our work showed that NRTIs and Kamuvudines offer near complete protection of the RPE in animal studies,” he reported.

Clinical trials based on this work are in the early planning stages. Pharmaco-epidemiological research looking at large databases of patients who received NRTIs for HIV disease and hepatitis B provide a hopeful note, with a 30-40% reduction in dry and wet AMD among patients compared with controls, he noted.

Jayakrishna Ambati: ja9qr@virginia.edu

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