A Target and Screening System for the Identification of therapeutic candidates against secondary viral infections in cancer and immunocompromised diseaes
Description:
A target and
screening system for the identification of therapeutic candidates against
secondary viral infections in cancer and immunocompromised
diseases
Docket # 12-2771
Researchers in the
molecular biology department at Princeton University, together with researchers
in the department of microbiology and immunology, School of Medicine, University
of Nevada, Reno have developed a unique monocycle screening system which will
allow for the large scale monocyte culture for biochemical studies or high
throughput screening for therapeutics.
As a particular example this system has been developed and demonstrated
as a model for studying human
cytomegalovirus reactivation.
In collaboration
with the University of Nevada, Reno a viral protein, LUNA has been identified
which regulates the ability of human cytomegalovirus to reactivate from a
dormant state. The LUNA protein plays a role in the switch from dormant
infection to reactivation. By blocking LUNA, the
virus would be prevented from undergoing reactivation. Therapeutics against LUNA
would be able to prevent reactivation of virus in immunocompromised hosts and
therefore effectively prevent the development of life threatening disease for
those suffering from cancer, AIDS or during organ transplantation. Additionally
by preventing the reactivation of CMV from its dormant state, no active
replication would take place thus limiting the risk of developing a
drug-resistant mutant.
Nature of potential commercial
application
Most antivirals target the active replicating state. For CMV, three
anti-viral therapies targeting the active state are used, Valganciclovir,
Ganciclovir and Foscarnet. However, these therapeutic approaches still carry a
significant risk of developing drug-resistant virus strains, in addition to
their toxic burden. Gancyclovir resistance, for example, occurs in up to 10% of
lungs transplant recipients. The reality is that HCMV drug resistance is on the
rise and the current regime of anti-viral drugs is ill equipped to handle this
increasing burden. Without the development of better anti-CMV therapies, CMV
will only continue to negatively impact the long-term quality of life of all
immunocompromised patients.
Since LUNA targeted therapeutics are less likely to develop
resistance they could quickly out compete current CMV anti-virals. It is also possible that anti-LUNA
therapeutics could be used in combination with other CMV anti-virals to prevent
resistance development as they have done with HIV anti-virals. Either way, anti-LUNA drugs would be
able to command a significant share of the $300 million per year CMV anti-viral
market.
A second
avenue for commercial development is the monocyte suspension system itself. Since monocytes can be infected by a
number of different pathogens this
system can be adapted and used as a screen against a large number of
diseases, which currently lack effective therapeutics. Following our success with LUNA, the
monocyte suspension system can serve as the launching pad for a company focused
on developing therapeutics for the treatment of diseases of inflammatory and
infectious origin. In order to surmount present obstacles to therapeutic
development, we developed a method for maintaining freshly isolated human
monocytes in the laboratory in a state similar to their status in the blood
stream. These cells can be cultured in this state for up to 30 days post
isolation. The suspension system is flexible enough to allow for large-scale
culture for biochemical studies or high-throughput screening
for therapeutics.
As mentioned above the monocyte suspension system has been validated as a model
for studying HCMV reactivation.
Applications:
·
Identification of new anti-virals for secondary infections
related to cancer, transplant and immunocompromised patients
·
Identification of new therapeutic candidates for
inflammatory diseases
·
Screening
system offers a potential launching pad for startup focused on new therapeutic
development
Advantages:
·
Use of stable monocytes ¿In vitro¿ for high-throughput
screening
·
Provides a high-throughput screening method for evaluating
monocyte secretion, migration and differentiation outcomes.
·
Provides a comprehensive solution for screening
therapeutics against all identified
monocyte functions
Background
Basic
research continually highlights the roles the immune response plays as both a
cause and regulator of cancer. Additionally, current cancer treatments weaken
immune function leading to secondary infections, which often prove fatal.
However, translating this information into new therapeutic directions has been
limited by the ability to reduce such complex system responses into testable in
vitro models. A prominent experimental roadblock is the monocyte. Monocytes, an
important white blood cell population, are quintessential for the control of
bacterial, viral, and parasitic infection. However, monocytes can also become
infected by a number of pathogens, thus short-circuiting the immune response to
an infection. In addition, over-stimulation of monocytes can lead to chronic
inflammation contributing to the development of inflammatory diseases such as
rheumatoid arthritis, multiple sclerosis, and atherosclerosis. Until recently,
the study of human monocytes has been hindered by the inability to maintain the
cells outside the body without their immediate differentiation into other cell
types.
Publications:
Hargett D., Shenk T., Experimental
human cytomegalovirus latency in CD14+ monocytes, PNAS, November 16,
2010, Vol 107., No. 46, pg 20039-20044.
Lisa R. Keyes, Soland M, Hargett D.,
Bego MG., Rossetto CC, Almeida-Porada G., and St. Jeor S., HCMV protein LUNA is
required for viral reactivation from latently infected primary CD14+ cells. PLOS ONE, 2012, Pending
publication.
Inventors:
Danna Hargett is a research fellow in
the department of Molecular Biology at Princeton University. Her research interests are in the
pathogenesis of viruses that interact directly with immune cells, such as human
cytomegalovirus and understanding how these infections contribute to the chronic
inflammatory process.
Stephen St Jeor is a professor at the School of
Medicine, department of microbiology and immunology, University of Nevada, Reno.
His laboratory is interested in the pathogenesis of virus diseases. In the
overall area of virus pathogenesis we are interested in the regulation of human
cytomegalovirus latency and the pathogenesis of New World
Hantaviruses.
Intellectual property and technology
status:
Patent pending
Industrial collaborators or
entrepreneurs are sought for the further development and commercialization of
this technology.
Contacts:
Laurie
Tzodikov
Princeton
University Office of Technology Licensing ¿ (609) 258-7256¿
tzodikov@princeton.edu
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