Inhibition of HSV-1 Associated Ocular Neovascularization by Antiangiogenic Agents
Konstantin G. Kousoulas, Ph.D.
Louisiana State University, Department of Pathobiological Science
Deborah E. Sullivan
Tulane University, Microbiology & Immunology
Project (December 1, 2010 - April 30, 2015)
Herpes simplex virus-1 (HSV-1) infects approximately 90% of humans worldwide. HSV-1 infection and subsequent replication induce inflammation and neovascularization in the cornea of the eye leading to corneal blindness. In the United States, HSV infection is the leading cause of infection-induced blindness, and 20,000 new cases are reported each year. The most common treatment for ocular herpes infection is a combination of steroids and antiviral drugs such as triflurothymidine; however, treatment with corticosteroids increases the risk of glaucoma and cataracts, necessitating continued research for better interventions for this disease.
Cyclin-dependent kinases (CDKs) are involved in cell cycle control and regulation of transcription and are required for herpesvirus transcription and replication. It was recently shown that the CDK inhibitors 5,6- dichlorobenzimidazole (DRB) and flavopiridol (FP) reduce HSV-1 replication; however, there is no published data on the effect of FP on HSV-1 infection of the cornea or in preventing HSV-1 associated ocular neovascularization and its consequences.
We have recently discovered that FP and DRB reduced HSV-1 corneal neovascularization in a mouse model to levels observed in animals treated with the gold-standard anti-herpetic trifluridine/trifluorothymidine (TFT). The beneficial effects of FP and DRB appear to be due to inhibition of multiple steps in the angiogenic pathway, as well as reduced viral replication. Thus, the use of CDK9 inhibitors as viable pharmacological agents in the treatment of HSV-1 corneal neovascularization should be further evaluated. Commercialization analysis of this invention by Foresight Technologies, LLC stated “There is a clear need for new treatments for HSV-1 induced corneal neovascularization, and the compounds being pursued by Professor McFerrin may offer a viable new approach. That one of the compounds, flavopiridol (FP) is in clinical trials for treating leukemia may offer an advantage in accelerating some clinical trials for HSV-1 therapy in the future.”