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.”
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.