The University of Colorado Anschutz Medical Campus and ARCA
biopharma, Inc. (Nasdaq: ABIO) today announced that the paper
entitled "Dynamic Regulation of SARS-CoV-2 Binding and Cell Entry
Mechanisms in Remodeled Human Ventricular Myocardium" (Bristow MR,
et al. https://doi.org/10.1016/j.jacbts.2020.06.007 was published
in JACC: Basic to Translational Science (JBTS), a member of the
Journal of the American College of Cardiology (JACC) family of
journals. The paper provides new information on mechanisms involved
in host cell binding and entry of the SARS-CoV-2 in the human
heart. Investigators affiliated with the Bristow Laboratory at CU
Anschutz Medical Campus, Cardiovascular Institute at the University
of Colorado School of Medicine and ARCA biopharma determined how
known and potential mechanisms responsible for COVID-19 infection
in the intact heart are altered by prior heart muscle disease, and
to what extent they are changed when damaged heart muscle improves
through a process called reverse remodeling.
COVID-19 infection occurs when SARS-CoV-2
infects host cells by binding to receptor sites on cell surface
membranes, then merging its viral membrane with host cell surface
and intracellular membranes to facilitate internalization, and
finally taking control over host cell RNA synthesis to replicate
virus. When heart muscle is damaged, enlarges and weakens (a
process termed "remodeling"), various myocardial cell constituents
change their expression, including some that may participate in
CoV-2 host cell binding and internalization. Foremost of those that
have been previously identified is angiotensin converting enzyme-2
(ACE2), which based on work performed in the Bristow Laboratory,
was first reported to be increased ("upregulated") at the protein
and enzyme activity levels in explanted remodeled human hearts in
2003 (Zisman LS et al, Circulation 108:1709-12). Shortly
thereafter, ACE2 was reported by others to be the receptor for
SARS-CoV binding to host cells (Li W et al, Nature 426:450-4,
2003), and recently, ACE2 was identified as the receptor for
SARS-CoV-2 cell binding (Hoffman et al, Cell 181:1-10, 2020).
However, it was not known if ACE2 upregulation in remodeled
explanted hearts was due to heart failure medications that can
affect ACE2 expression or was only found in late stage heart
failure and remodeling present in hearts obtained from cardiac
transplant recipients. Moreover, mechanisms or constituents other
than ACE2 that could participate in CoV2 host cell binding and
internalization had not been previously investigated in remodeled
human left ventricles (LVs).
In the JBTS reported study, 46 patients with
mild-moderate heart failure and remodeling from nonischemic dilated
cardiomyopathy and nonfailing, non-remodeled controls had RNA
extracted from interventricular septum endomyocardial biopsies.
From the extracted RNA, genes known to participate in CoV-2 host
cell binding and cell entry or who were possible candidates for
these processes had mRNA expression measured by two independent
platforms. The 46 dilated cardiomyopathy patients were then treated
for 12 months with beta-blocking agents to produce reverse
remodeling, measured by improvement in left ventricular ejection
fraction (LVEF), which occurred in 65 percent of the patients. Gene
expression in patients with reverse remodeling was then compared to
the 35 percent of patients whose LVEFs/remodeling did not change.
Importantly, the dilated cardiomyopathy patients were being treated
with inhibitors of the renin-angiotensin system prior to baseline
measurements and throughout the study, eliminating the possibility
that such therapy could have affected ACE2 expression.
At baseline, ACE2 myocardial mRNA expression was
markedly upregulated in the dilated cardiomyopathy patients, by
nearly two-fold. With reverse remodeling, ACE2 gene expression
normalized, and was unchanged in those with no remodeling
improvement. The behavior of ACE2 as well as the degree of baseline
expression was highly correlated with that of the natriuretic
peptide B gene, whose processed protein product BNP is considered
the gold standard biomarker for heart failure and remodeling. These
data indicate that the increased expression of ACE2 begins much
earlier than in end stage heart failure, that it is directly
related to the remodeling process and not to the administration of
heart failure therapy, and that by virtue of its potential for
increasing the amount of virus internalization into host cells
including cardiac myocytes, it is a likely a contributor to the
increased adverse outcomes of patients with underlying heart
disease who have COVID-19 infection.
ACE2 is a "protective" or counter-regulatory
enzyme that catalyzes the conversion of angiotensin-II to
angiotensin-(1-7), a peptide that mitigates abnormal cell growth,
blood vessel constriction and thrombosis (blood clots) mediated by
angiotensin-II, which is known to be elevated in COVID-19 patients
with clinically significant disease. However, the increased
expression of ACE2 in the remodeled heart means that its beneficial
effects may also predispose to increased cell infection by CoV-2.
Based on these observations, the paper concludes that an optimal
ACE2 targeted treatment for COVID-19 would consist of an agent that
blocks CoV-2 binding without diminishing or perhaps even increasing
ACE2 enzyme activity.
The study also examined the expression of
multiple proteases that facilitate cell entry through virus-host
cell membrane fusion, and found that none previously shown to be
involved in CoV or CoV-2 membrane coalescence were altered, and
that 11 additional expressed proteases were not upregulated in
remodeling. In contrast, the study found that integrin A5 subunit
(ITGA5), which binds to ACE2 and can mediate host cell
internalization of viruses, was upregulated in remodeled heart and
normalized its expression on reverse remodeling similar to ACE2.
The study concluded that the ITGA5 protein gene product or the a5b1
heterodimer is a candidate for facilitating CoV-2 binding and entry
in myocardial cells. Thus, in remodeled, intact human hearts one
(ACE2) and possibly two (ITGA5) myocardial cell components are
altered to favor enhanced infection by CoV-2, which may explain
COVID-19 increased adverse outcomes in patients with underlying
heart muscle disorders.
Michael Bristow MD, PhD, Director of
Pharmacogenomics at the Cardiovascular Institute, and ARCA’s
President and Chief Executive Officer commented, "These findings
add to the evidence that increased ACE2 expression contributes to
the increased adverse outcomes risk observed for COVID-19 in
patients with underlying myocardial disease. In addition, we
detected a possible additional route of CoV-2 binding and host cell
internalization that is upregulated in remodeled human ventricles,
involving integrin A5. This information sets the stage for the
development of diagnostic approaches to and therapeutic
manipulation of ACE2 for preventing CoV-2-host cell internalization
while preserving functional activity, and may identify a new target
for intervening in the cell infectious process."
About the University of Colorado School
of Medicine Cardiovascular InstituteThe University of
Colorado School of Medicine Cardiovascular Institute (CU-CVI) was
co-founded in 1998 by Dr. Bristow and Leslie Leinwand, PhD with the
mission of integrating cardiovascular research, treatment, and
discovery through a collaboration of the Anschutz Medical and
Boulder campuses. The CU-CVI is now Co-directed by Dr. Leinwand and
Peter Buttrick, MD, Division Head of Cardiology and Senior
Associate Dean for Academic Affairs at the CU School of Medicine,
who is a co-author on the JBTS paper.
The scientific goals of the Institute are to
understand the genetic basis and specific molecular mechanisms
responsible for heart muscle disease and heart failure and to
produce new diagnostic techniques and treatments for patients. By
integrating the effort of those committed to curing heart muscle
disease and heart failure, the collaborative nature of the
Institute encourages the sharing of findings and data, which
ultimately translate into improved treatments and therapies of
patients.
www.ucdenver.edu/academics/colleges/medicalschool/institutes/CardiovascularInstitute.
In work sponsored by the American Heart
Association the research team that worked on the current study is
now investigating the effects of CoV-2 on host cell entry and
internalization mechanisms in the intact heart of patients with
COVID-19 cardiac involvement.
About the University of Colorado
Anschutz Medical CampusThe University of Colorado Anschutz
Medical Campus is a world-class medical destination at the
forefront of transformative science, medicine, education, and
patient care. The campus encompasses the University of Colorado
health professional schools, more than 60 centers and institutes,
and two nationally ranked independent hospitals that treat more
than two million adult and pediatric patients each year.
Innovative, interconnected and highly collaborative, together we
deliver life-changing treatments, patient care, professional
training, and conduct world-renowned research. For more
information, visit www.cuanschutz.edu.
About ARCA biopharmaARCA
biopharma is dedicated to developing genetically targeted and other
precision therapies for cardiovascular diseases through a precision
medicine approach to drug development. ARCA is developing AB201
(rNAPc2) as a potential treatment for diseases caused by RNA
viruses, initially focusing on COVID-19. ARCA is also developing
GencaroTM (bucindolol hydrochloride), an investigational,
pharmacologically unique beta-blocker and mild vasodilator, as a
potential treatment for atrial fibrillation in heart failure
patients. ARCA has identified common genetic variations that it
believes predict individual patient response to Gencaro, giving it
the potential to be the first genetically targeted AF prevention
treatment. The U.S. FDA has granted the Gencaro development program
Fast Track designation and a Special Protocol Assessment (SPA)
agreement. For more information, please visit www.arcabio.com or
follow the Company on LinkedIn.
Safe Harbor StatementThis press
release contains "forward-looking statements" for purposes of the
safe harbor provided by the Private Securities Litigation Reform
Act of 1995. These statements include, but are not limited to,
statements regarding the ability of ARCA’s financial resources to
support its operations through the end of the third quarter of
2020, potential future development plans for AB201 and Gencaro, the
expected features and characteristics of AB201 or Gencaro,
including the potential for AB201 to treat COVID-19/CAC, the
potential for genetic variations to predict individual patient
response to Gencaro, Gencaro’s potential to treat AF, future
vaccines and/or treatment options for patients with COVID-19,
future treatment options for patients with AF, and the potential
for Gencaro to be the first genetically targeted AF prevention
treatment. Such statements are based on management's current
expectations and involve risks and uncertainties. Actual
results and performance could differ materially from those
projected in the forward-looking statements as a result of many
factors, including, without limitation, the risks and uncertainties
associated with: ARCA’s financial resources and whether they will
be sufficient to meet its business objectives and operational
requirements; ARCA may not be able to raise sufficient capital on
acceptable terms, or at all, to continue development of AB201 or
Gencaro or to otherwise continue operations in the future; results
of earlier clinical trials may not be confirmed in future trials;
the protection and market exclusivity provided by ARCA’s
intellectual property; risks related to the drug discovery and the
regulatory approval process; and, the impact of competitive
products and technological changes. These and other factors
are identified and described in more detail in ARCA’s filings with
the Securities and Exchange Commission, including without
limitation ARCA’s annual report on Form 10-K for the year ended
December 31, 2019, and subsequent filings. ARCA disclaims any
intent or obligation to update these forward-looking
statements.
CU Anschutz and School of Medicine Media
Contacts:Julia Milzer (CU Anschutz),
E: julia.milzer@cuanschutz.edu
C: 303.725.0733Chanthy Na (School of
Medicine), E: chanthy.na@cuanschutz.edu
ARCA biopharma Investor & Media
Contact:Derek Cole720.940.2163derek.cole@arcabio.com
A photo accompanying this announcement is available at
https://www.globenewswire.com/NewsRoom/AttachmentNg/af496e97-20da-420a-bf93-e51b3a3ed740
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