Nucleoside reverse transcriptase inhibitors (NRTIs) or their derivatives could one day be used to prevent or treat age-related macular degeneration (AMD), according to Jayakrishna Ambati, MD, of the University of Virginia in Charlottesville.
NRTIs are already used in patients with hepatitis B and human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS).
Ambati and colleagues previously have researched what causes the degeneration of the retinal pigmented epithelium. A few years ago, they showed how the reduction of an enzyme, called Dicer, leads to the accumulation of Alu repetitive transcripts, in turn leading to cell death.
"In trying to understand these mechanisms, we found that Alu RNAs activate the inflammasome, leading to interleukin-mediated cell death," said Ambati, the DuPont Guerry III professor of ophthalmology vice chairman for research in the department of ophthalmology, and founding director of the Center for Advanced Vision Science at the university. "Several other groups have replicated and extended this work."
As researchers focused on the development of inflammasome inhibitors, they made the serendipitous observation that NRTIs have a previously undiscovered mechanism of action that blocks the inflammasome. When this discovery was made, NRTIs already had been used in the clinic for 30 years for other treatments.
"Both NRTIs and modified NRTIs can block inflammasome activation," Ambati pointed out. "It's known that NRTIs have a potential cell toxicity because they cause mitochondrial toxicity. Modified derivatives don't have that toxicity."
Using animal models, researchers also have found that amyloid-beta deposits can cause retinal pigment epithelial degeneration that is blocked using NRTIs or modified derivatives of NRTIs. Additionally, the iron toxicity present in AMD is mediated by inflammasome activation. This also can be prevented by NRTIs.
Ambati and fellow researchers were the first to show 10 years ago that active complement exists in eyes with dry AMD, and now they have shown that complement-induced retinal degeneration can be blocked by NRTIs.
One last connection with NRTIs is cigarette smoking, a potent epidemiological risk factor for AMD. "Using cigarette smoke extract administered subretinally in mice, it was shown that this retinal toxicity too can be blocked by NRTIs," Ambati said.
To help track NRTI use and AMD incidence in humans, Ambati and fellow researchers performed an administrative claims analysis to analyze more than 50 million insurance beneficiaries from multiple health insurance databases. They focused on patients who had HIV or hepatitis B and who were over the age of 50. None of the patients had a prior diagnosis of AMD.
"We found that NRTI use by some 40,000 patients was associated with an about 50% relative risk reduction in the incidence of new AMD, both dry and wet," Ambati said.
Work is underway to commercialize these findings about NRTIs by Inflammasome Therapeutics Inc., which has licensed this technology, Ambati said.
This article originally appeared on our partner's website Ophthalmology Times, which is a part of UBM Medica. (Free registration is required.)
Disclosures
Ambati has financial interests with Allergan, Biogen, Inflammasome Therapeutics, iVeena Delivery Systems, iVeena Pharmaceuticals, and Olix Pharmaceuticals. This article was adapted from a presentation that Ambati delivered at the 2016 Retina Subspecialty Day prior to the 2016 American Academy of Ophthalmology meeting.