NRTIs hold promise for preventing or treating AMD

Reviewed by Jayakrishna Ambati, MD

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.

NRTIs already are used in patients with hepatitis B and human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS).

Dr. Ambati, the DuPont Guerry III Professor of Ophthalmology, vice chairman for research, Department of Ophthalmology, and founding director, Center for Advanced Vision Science, University of Virginia, Charlottesville, VA, 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 that are endogenous, leading to cell death.

“In trying to understand these mechanisms, we found that Alu RNAs activate the inflammasome, leading to interleukin-mediated cell death,” Dr. Ambati said. “Several other groups have replicated and extended this work.”

Undiscovered MOA

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,” Dr. 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.

Dr. Ambati and fellow researchers were the first to show 10 years ago that active complement exists in eyes with dry AMD, Now, they have shown complement-induced retinal degeneration can be blocked by NRTIs.

Smoking factor blocked

Smoking factor blocked

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,” Dr. Ambati said.

To help track NRTI use and AMD incidence in humans, Dr. 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,” Dr. Ambati said.

Work is underway to commercialize these findings about NRTI by Inflammasome Therapeutics Inc., which has licensed this technology, Dr. Ambati said.

Jayakrishna Ambati, MD

E: JA9QR@hscmail.mcc.virginia.edu

Dr. 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 Dr. Ambati delivered at the 2016 Retina Subspecialty Day prior to 2016 American Academy of Ophthalmology meeting.