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