Topical Nitric Oxide Therapy to Treat Cervical Neoplasias and Prevent HPV-Associated Cancers

The goal of this research was to develop a nitric oxide-releasing vaginal suppository for self-administration to treat cervical neoplasias, eradicating HPV-18 infection and inhibiting disease progression to cancer. The suppository contains our proprietary NO-releasing drug, NVN1000, with demonstrated in vitro antiviral efficacy against HPV-18. We developed five prototype formulations using excipients determined to be compatible with NVN1000 and appropriate analytical methods. Post 12-week stability data, a lead prototype was selected, although it requires refrigeration to maintain stability. Our collaborators at the University of Alabama Birmingham established an NVN1000 dose (4 mg/mL) and application frequency (every other day) that successfully inhibits HPV-18 replication inhuman raft cultures while minimizing cytotoxicity. Immunoblot data show increased p53 levels and p53 stabilization via phosphorylation, corroborating decreased E6 activity/levels post NVN1000-treatment. However, the exact mechanism of action(e.g., inhibition of association of E6 with p53) was not discerned. RNA sequence data show reduced transcription of E6 mRNA, but no increase in p53 transcription and overall support pleiotropic effects of NVN1000 on HPV-18-infected cells.