Nucleoside reverse transcriptase inhibitors are broad-spectrum RPE protectants

Abstract

Purpose : Age-related macular degeneration (AMD) is the leading cause of legal blindness among people aged over 60 years especially in developed countries. AMD is a multifaceted disease with numerous potential environmental and molecular instigators contributing to retinal pigmented epithelial (RPE) death. We recently demonstrated nucleoside reverse transcriptase inhibitors (NRTIs), a widely used class of drugs to treat Human Immunodeficiency Virus-1 (HIV), possess anti-inflammatory activity by preventing NLRP3 inflammasome activation. The purpose of this study is to test whether NRTIs possesses the anti-inflammatory ability against these multiple toxic substances regarded as contributors to dry AMD.

Methods : To model RPE degeneration in dry AMD, wild-type mice were subjected to subretinal injection of Amyloid β (Aβ)1-40, poly(I:C) (pIC), iron (Fe (III)), cigarette smoke extract (CSE), paraquat, sodium iodate (NaIO₃) or Leu Leu OMe to induce lysosomal destabilization. NRTIs (lamivudine (3TC), stavudine (d4T), azidothymidine (AZT)) or NRTIs modified by alkylation which eliminates reverse transcriptase activity, were administered intraperitoneally or by intravitreous injection in wild-type male C57BL6/J mice. RPE degeneration was assessed by fundus photography and Zonula occludens-1 (ZO-1) staining of RPE flat mounts.

Results : Twice daily intraperitoneal administration of the NRTIs, at a dose equivalent to what is administered in humans, inhibited RPE degeneration in the mouse models of dry AMD caused by Aβ1-40, pIC, Fe (III) or paraquat. Further, one-time intravitreous injection of the NRTIs or modified NRTIs prevented the RPE degeneration induced by Aβ, pIC, Fe (III), CSE, paraquat, NaIO₃, Leu Leu OMe or Alu RNA.

Conclusions : The novel anti-inflammatory activity of NRTIs and modified NRTIs prevented RPE toxicity in eight models of dry AMD. Therefore NRTIs and modified NRTIs compounds may be well-suited for therapeutic protection of RPE in dry AMD.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.