Sunday, June 8, 2025
6/8/2025
A new molecular therapy against ocular herpes - Herpes simplex virus type-1 (HSV-1) is a herpesvirus known to cause long-term morbidities in the eye and serious vision problems. In our previously funded period, we discovered the high efficacy, unique mode of action, pharmacokinetics, safety, and superior antiviral properties of BX795 against HSV-1 in the eye. Our findings provided a new understanding of host protein targets involved in HSV-1 infection of the cornea. Through extensive transcriptomic and proteomic analyses of BX795, we uncovered a novel cell cycle regulatory mode of action with broader scientific implications beyond its antiviral properties. Due to our extensive studies, BX795 shows strong promise as a new topical antiviral for ocular herpes, and it can now be pursued for Phase 1 clinical studies. However, our studies also revealed an interesting challenge: BX795 failed to synergistically enhance other clinically relevant drugs, specifically nucleoside analogs like ACV and TFT, commonly used for ocular HSV- 1 infections. To address the scientific curiosity about whether a functional analog of BX795 can exhibit synergism with existing antivirals, we utilized our omics data, conducted in silico L1000 assay-based CMap predictions, and identified another small molecule, GW8150, as the closest functional analog of BX795. Our preliminary data demonstrated high efficacy, low toxicity, and, to our satisfaction, strong synergy with ACV and TFT. Thus, GW8150 presents a valuable new tool to study the pathways contributing to HSV-1 infection in the eye, understand why synergy was absent in BX795, and offer a potential candidate for topical or oral antiviral development. To achieve our goals, we have defined three specific aims for the competitive renewal period: first, to determine GW8510's antiviral action and its impact on corneal cells by analyzing Omics data and identifying interactions with corneal cell proteins and changes in cell proteomes; second, to assess the therapeutic benefits of topically delivered GW8510 in murine models of ocular HSV-1 infection, establishing it as a potent candidate for further development as an FDA approved antiviral for ocular indications; and third, to investigate GW8510's synergistic abilities in reducing ocular HSV-1 infection, potentially in combination with clinically approved drugs, with the aim of enhancing antiviral efficacy, improving treatment options, and exploiting transcriptomics and proteomics analyses to uncover the specific targets and pathways that underpin this synergistic antiviral action. Post-treatment corneal, as well as retinal health and associated vision functions, will be examined to determine the benefits (and/or any toxic effects) of drug administration. By completing these specific aims, we aim to gain valuable insights into ocular antiviral mechanisms, new proviral pathways targeted by GW8510, and develop more effective strategies to combat HSV-1 infections in the eye. This research holds promise for advancing our understanding and treatment of ocular herpes, improving patient outcomes, and contributing to the development of novel ocular antiviral therapies.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).