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microRNAs for Modulating Herpes Virus Gene Expression

Princeton University Invention # 07-2381

Researchers in the Molecular Biology department at Princeton University and the Simons Center for Systems Biology at the Institute for Advanced Study have developed an improved algorithm for the prediction of  mRNAs that are targeted by known microRNAs.  The algorithm was employed to identify the targets of cell-coded and virus-coded microRNAs in mRNAs encoded by herpesviruses. One of these predictions have been validated experimentally. These naturally occurring microRNAs target mRNAs that encode essential herpes virus-coded proteins.  Consequently, they would be expected to inhibit acute replication and pathogenesis of the herpes viruses and prevent the re-emergence of herpes viruses from latency.  These findings have many potential future uses in the treatment of herpes virus disease.

The miRNAs that have been identified are natural regulators of viral gene expression. As a consequence, inhibiting or augmenting these miRNA activities can be predicted to perturb viral replication and pathogenesis. Small inhibitory RNAs (siRNAs) that inhibit expression of the virus-coded mRNAs at the same site targeted by the naturally occurring miRNAs, and derivatives of the miRNAs and siRNAs that have been modified to enhance their efficacy, e.g., to extend their half life and/or enhance their entry into cells, are predicted to function as efficiently or even more efficiently than the naturally occurring miRNAs in the prevention and treatment of herpes virus disease. Finally, it is likely that artificial miRNAs, siRNAs and their derivatives that target all of the mRNAs or a subset of the mRNAs targeted by the naturally occurring miRNAs, but at a different site within the mRNAs than is targeted by the naturally occurring miRNAs, will also have therapeutic efficacy.

Naturally occurring miRNAs and their derivatives that recognize the same or similar target elements in mRNAs are expected to exhibit therapeutic efficacy that is superior to that of artificial miRNAs and their derivatives that target different sites in the same mRNAs. The first argument in support of this view is evolutionary: evolution selects for efficient function, and therefore, naturally occurring miRNAs would be expected to be optimized for a specific physiological outcome. The second argument is based on the observation that a single miRNA can regulate multiple targets.

Consequently, it is possible that cell-coded miRNAs controlling the function of a viral gene also control one or more additional viral or cellular genes that contribute to successful virus replication and spread. Individual miRNAs are known to sponsor multiple functional consequences that lead to a coordinated physiological response, so there is precedent for the view that a single naturally occurring miRNA could influence the dynamics of viral replication and pathogenesis by modulation of a set of virus-coded and cell-coded mRNAs.

Publications:

Murphy,E., Vanicek,J., Robins,H., Shenk,T., Levine, A.J., Suppression of immediate-early viral gene expression by herpesvirus-coded microRNAs: Implications for latency, PNAS, April 8, 2008, Vol. 105, 14, Pgs. 5453-5458.

Princeton University is currently seeking industrial partners to further the development and commercialization of this technology.

For more information on Princeton University invention # 07-2381 please contact:

                        Laurie Tzodikov

                        Office of Technology Licensing and Intellectual Property

Princeton University

                        4 New South Building

Princeton , NJ 08544-0036

                        (609) 258-7256

                        (609) 258-1159 fax

                        tzodikov@princeton.edu