Document text
Principal Investigator: Jason W. Botten
Organization: CELDARA MEDICAL, LLC
Fiscal Year: 2022
Award: $290,738
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
Accelerating emergence and re-emergence of a wide array of viral epidemics has been a deadly feature of the
21st century. Potent or even effective therapies are rarely available to combat these diseases, and in general,
the world remains unprepared to manage future outbreaks. The most recent outbreak of the Ebola virus resulted
in over 11,000 fatalities, more than 20,000 orphans, and economic costs of >$32B (Worldbank), and instilled
varying levels of fear in many more. But Ebola is not unique; in 2003 the global economic loss from the SARS
virus was ~$40B (WHO). In 2017, there were travel and pregnancy restrictions within the Americas due to the
Zika virus and its high correlation with the surge in the incidences of infant microcephaly. Currently, the world is
experiencing unprecedented hardship from the life-threatening COVID-19 (SAR2-CoV-2) pandemic, which has
already resulted in over 150,000 deaths worldwide, and for which there is no effective therapy or vaccine.
Unfortunately, this is neither the first nor the last time the world is expected to be in this plight, unless a broadly
acting first-line drug is available for rapid deployment. These outbreaks all resulted from RNA viruses, which
remain a major unaddressed disease class. Arenaviruses (e.g. Lassa fever virus and Junin virus), coronaviruses
(including SARS-COV-1, SARS-CoV-2, and MERS), and filoviruses (e.g. Ebola and Marburg viruses) are
enveloped RNA viruses that cause severe and often fatal human diseases. Despite the global impact and toll on
human lives, there are no effective treatment options or FDA-approved vaccines available to combat these
devastating infections and they are accordingly classified as NIAID Priority Pathogens and are also on the select
agent list of potential bioterrorism threats.
This proposal seeks to address this highly significant, unmet clinical need by developing a broad spectrum
antiviral agent (BSAA) that targets a fundamental host protein that is commonly subverted by multiple pathogenic
virus families but is not essential for the host. In particular, we propose to target the human ER-Golgi intermediate
compartment protein 53 kDa protein (ERGIC-53), a mannose-specific lectin that functions as an intracellular
cargo receptor to facilitate the anterograde transport of selected cellular glycoprotein ligands in the early exocytic
pathway. We have shown that ERGIC-53 is critically required for the propagation of arenaviruses, coronaviruses,
and filoviruses. In particular, ERGIC-53 i) associates with the envelope glycoproteins encoded by these viruses
as well as orthomyxoviruses and hantaviruses, ii) traffics to sites of virus budding, and iii) is incorporated into
viral particles. In the absence of ERGIC-53, viral particles containing the normal array and quantity of viral
structural proteins and genome are formed but are no longer infectious. Specifically, virions lacking ERGIC-53
are defective in their ability to attach to host cells. We have mapped the minimal domain within ERGIC-53 that
is required for controlling virion infectivity and shown that extracellular targeting of this region potently neutralizes
the infectivity of multiple pathogenic RNA viruses.
Herein, we have presented strong scientific rationale for targeting ERGIC-53 and proof of concept data that
extracellular targeting of ERGIC-53 is an effective antiviral target. Our development plan includes
collaborating with Lake Pharma, a company with a proven track record in antibody generation technology.
The successful development of potent antiviral monoclonal antibodies targeting ERGIC-53, would be
groundbreaking in the treatment of viral outbreaks. Due to its broad spectrum activity and the expected safety
of target modulation, ERGIC-53 targeting has the potential to be a first-line strategy against many RNA viruses.
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