SiRNA structural optimization

Rhode Island Hospital, Providence RI

Investigators

Linked publications & trials

Abstract

Human papillomaviruses (HPVs) are a major cause of anogenital and head and neck neoplasms and malignancies.[unreadable] Unfortunately, no specific antiviral therapies for HPV infection or HPV-induced malignancies have been identified.[unreadable] This U19 proposal is submitted as project by Alexander in a consortium proposal entitled siRNA Microbicides. The goal of this[unreadable] research consortium is to develop native and chemically modified siRNAs as effective means for blocking[unreadable] transmission of HIV, HSV2 and HPV. In project by Alexander, we hypothesize that chemically modified single-stranded[unreadable] boranophosphate-backbone short interfering RNAs (siRNAs) are superior to native siRNAs for potent and durable[unreadable] gene silencing, and that anti-HPV E6/E7 single-stranded boranophosphate-backbone siRNAs (ssBP-siRNAs) can be[unreadable] used to effectively block HPV viral replication and proliferation of HPV-transformed cells. By combining chemical[unreadable] modifications shown individually to increase siRNA silencing potency and duration, we will create ssBP-siRNAs,[unreadable] designed for topical delivery, that block episome replication in HPV-infected cells and induce irreversible growth[unreadable] arrest in HPV16-transformed cells. Anti-HPV16 ssBP-siRNAs identified by us will be tested in project 3 using novel[unreadable] cell culture and transgenic mouse models of HPV infection.[unreadable] Project 3 will also supply optimized ssBP-siRNAs to projects by Ramratnam and Herold to allow comparison of ssBP-siRNAs with[unreadable] conventional siRNAs for targeting expression of macaque CCR5, murine focal adhesion kinase, and murine nectin-1.[unreadable] To allow immediate work optimizing ssBP-siRNA delivery to vaginal mucosa, we will supply existing highly active[unreadable] ssBP-siRNAs to Core B (Formulations). The vaginal mucosal uptake and activity of formulated ssBP-siRNAs will be[unreadable] assessed quantitatively in project 3.[unreadable] At the conclusion of this study, we will have developed anti-HPV16 E6/E7 ssBP-siRNAs as effective topical[unreadable] microbicides for prevention of HPV infection and HPV-induced malignancies. We will also have created high potency[unreadable] ssBP-siRNAs active against other consortium targets, and forwarded these ssBP-siRNAs for microbicidal testing in[unreadable] laboratory models of viral infection.