Twelve days later, UAB Professor Emeritus Timothy Ness posted plans on ClinicalTrials.gov for an exploratory COVID-19 outpatient study to test Matalon’s hypothesis and prevent worse clinical outcomes. His quick reaction is another example of how nimble UAB researchers have been during the COVID-19 pandemic.

In the Physiological Reviews paper, the researchers noted that all those comorbidities feature elevated levels of the extracellular protease plasmin. Plasmin is able to nick proteins at amino acid sequences called furin sites. For many viruses, this nicking increases their infectivity. Both SARS and MERS – the two virulent coronaviruses that are related to the COVID-19 virus – “have evolved an unusual two-step furin activation for fusion, suggestive of a role during the process of emergence into the human population,” the researchers wrote.

They noted that the COVID-19 virus, SARS-CoV-2, has a furin site on its spike protein, the vital protein for viral attachment to a lung cell. The researchers proposed that plasmin may cleave that site in the spike protein to increase its infectivity and virulence, and they hypothesized that, “the plasmin system may prove a promising therapeutic target for combating COVID-19.”

Ness already knew there is an inexpensive, commonly used drug – tranexamic acid, or TXA – that targets plasmin by inhibiting its conversion from the inactive precursor, plasminogen, to the active protease, plasmin.

TXA is approved by the U.S. Food and Drug Administration for treatment of heavy menstrual bleeding because having lower plasmin levels allows better clotting. TXA has a long track record of safety and is commonly given off-label. At UAB Hospital, TXA is used as a standard of care for orthopedic and cardiac bypass surgeries; it is commonly used for hemorrhaging trauma patients and has been used for spinal surgery, neurosurgery and corrective jaw surgeries. It is being studied for use in cesarean section surgeries.

For the clinical trial, Ness and colleagues have started a double-blind study, giving either TXA or a placebo pill to COVID-19 outpatients who were recently diagnosed. Patients also receive an anticoagulant. The overall goal of the exploratory study is to assess the safety and efficacy of five days of TXA versus placebo. Enrollment is ongoing.

Ness and colleagues hypothesize that the TXA treatment will reduce the infectivity and virulence of the virus, as measured by reduced need for hospitalization within a week if a patient’s condition deteriorates. Adults 19 years old and older are eligible, and all patients – whether in the control group or the TXA group – receive standard care as directed by their primary caretakers.

To learn more about the study, “TXA and Corona Virus 2019 (COVID19) in Outpatients,” patients and physicians can contact Dr. Timothy Ness at tness@uabmc.edu. Patients who have recently tested positive for COVID-19 can call 205-934-6777 to see if they qualify for the study.

Other principal investigators for the trial are Dr. Sonya Heath, professor in the UAB Department of Medicine Division of Infectious Diseases; Dr. Brant Wagener, associate professor and Sadis Matalon, distinguished professor, both in the UAB Department of Anesthesiology and Perioperative Medicine. Ness is professor emeritus in that department.

Authors of the Physiological Reviews paper, “Elevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility,” are Hong-Long Ji and Runzhen Zhao, University of Texas Health Science Centre at Tyler; Michael A. Matthay, University of California, San Francisco; and Matalon.

Matalon said the paper has been widely noticed. “Since its publication online, it has been downloaded 26,565 times and cited 55 times,” he said.

At UAB, Matalon holds the Dr. Alice McNeal Endowed Chair in Anesthesiology, and he is a Distinguished Professor and vice chair for Research.

(Courtesy of Alabama NewsCenter)

The pilot projects will yield payoffs down the road from the knowledge UAB researchers gain. Preliminary data from the pilots will form the basis for new grants and contracts, including pursuit of the $2 billion COVID-19 grant support being offered by the National Institutes of Health.

“The number of high-quality proposals we received made the decision on which ones we could fund very difficult,” said Kent Keyser, Ph.D., associate vice president in the Office of Research, who managed the second round and led the review process. “These projects, together with the 14 projects funded in May by the UAB School of Medicine, show once again that UAB is at the forefront in fighting COVID-19. We are grateful for the philanthropic support that made the program possible.”

The 10 projects have 27 principal investigators or co-investigators, and they come from a broad swath of the UAB School of Medicine, as well as an investigator from the UAB School of Public Health, Department of Epidemiology.

The School of Medicine departments represented by these investigators include:

• The Department of Medicine and its divisions of Pulmonary, Allergy and Critical Care Medicine; Gerontology and Geriatric Medicine; Infectious Diseases; Gastroenterology; Preventive Medicine; and General Internal Medicine.
• The Department of Pediatrics and its divisions of Pediatric Rheumatology, and Pediatric Pulmonary and Sleep Medicine.
• The departments of Anesthesiology and Perioperative Medicine; Radiology; Cell, Developmental and Integrative Biology; Microbiology; and Pathology.

The interactions of investigators from all these backgrounds fulfill part of UAB’s strategic plan, Forging the Future, with the objective of enhancing UAB’s institutional culture of collaboration and innovation.

The titles of the funded grants also show the diverse research at UAB:

• Clonal diversity of human antibodies to SARS-CoV-2 S-protein.
• Glucocorticoid treatment of COVID-19 cytokine storm syndrome.
• Therapeutics targeting COVID-19 entry into pulmonary epithelial cells.
• Immunotyping COVID-related acute respiratory distress syndrome.
• Circulating microbiota and microbial endotoxin drive uncontrolled immune activation of blood monocytes in COVID-19.
• Development of a tri-specific neutralizing antibody for the treatment of SARS-CoV-2 infection.
• Individual- and area-level risk factors for COVID-19 disparities in the Deep South.
• Exploratory study of the effect of tranexamic acid treatment on the progression of COVID-19 in outpatients.
• Molecular mechanisms underlying the pathogenesis of acute respiratory distress syndrome in critically ill SARS-CoV-2-infected patients.
• Neutrophils as a driving mechanism of acute respiratory distress syndrome and death in COVID-19 patients.

“We are deeply grateful to our local and national philanthropic partners for quickly responding with critical support needed to accelerate UAB’s COVID-19 research efforts,” said Jessica Towns, UAB School of Medicine’s executive director of Development. “Through our recent Day of Caring and ongoing fundraising initiatives, we have seen tremendous generosity from the community. This support provides significant resources and encouragement to our scientists, faculty, staff and students during this challenging time.”

Although the first round of pilots was advertised to the School of Medicine, the projects included funding for Sue Feldman, R.N., Ph.D., in the UAB School of Health Professions, to ensure scalability of the UAB helpbeatcovid19.org website to broader communities, including translating the site into Spanish. Helpbeatcovid19.org is a geographical symptom tracker, driven by crowdsourced, consumer-generated data to monitor and visualize COVID-19 symptoms across the United States with a focus on hard-to-reach communities in Alabama. Helpbeatcovid19.org also provides valuable research data for use by researchers across the entire UAB campus. Helpbeatcovid19.org is the precursor to Healthcheck, which is part of the GuideSafeTM platform of tools being used for returning to campus operations.

(Courtesy of UAB)

AdCOVID is designed to express the receptor binding domain of the SARS-CoV-2 virus spike protein, a key immune target that is essential for the virus to bind to cells and initiate infection. By focusing the immune response to this portion of the viral spike protein, AdCOVID elicited a strong systemic antibody response against the receptor binding domain in mice, achieving serum IgG antibody concentrations greater than 800 micrograms per milliliter just 14 days after administration of a single intranasal dose. In addition, AdCOVID stimulated serum viral neutralization titers of 1:320 by Day 28, two-times higher than the titer recommended by the U.S. Food and Drug Administration for investigational convalescent plasma as a treatment for severe COVID-19.

In a separate study with UAB, a single intranasal dose of AdCOVID stimulated a 29-fold induction of mucosal IgA in bronchoalveolar fluid of vaccinated mice. This level of IgA antibody stimulation is well above that associated with protection from disease in clinical studies of other mucosal vaccines. Frances Lund, Ph.D., lead UAB investigator for preclinical testing of the AdCOVID vaccine candidates, said, “The potent stimulation of mucosal IgA immunity in the respiratory tract may be crucial to effectively block infection and transmission of the SARS-CoV-2 virus, given that the nasal cavity is a key point of entry and replication for the SARS-CoV-2 virus.”

“Stimulation of immunity at this level just 14 days after a single dose is impressive for any vaccine, and is particularly notable for a potential coronavirus vaccine,” said Lund, the Charles H. McCauley Professor and chair of the UAB Department of Microbiology. The Lund lab did the preclinical testing in collaboration with the labs of Troy Randall, Ph.D., professor of medicine in the UAB Division of Clinical Immunology and Rheumatology; Kevin Harrod, Ph.D., professor in the UAB Department of Anesthesiology and Perioperative Medicine; and three more UAB Department of Microbiology labs led by Rodney King, Ph.D., assistant professor, Todd Green, Ph.D., associate professor, and John Kearney, Ph.D., professor.

In other details from the collaborative preclinical work, Altimmune announced that the antibody responses were accompanied by a rapid recruitment of CD8+ T cells, CD4+ T cells, dendritic cells and natural killer cells in the respiratory tract. Increases in both germinal center and memory B cells, as well as T follicular helper cells, all associated in prior vaccine development research with the generation of long-lived antibody responses, were observed in regional lymph nodes and the spleen

Preclinical data for the antigen-specific T cell response are expected in coming weeks, along with additional immunogenicity readouts.

The Altimmune–UAB collaboration was announced March 30, and Lund made that work the highest priority for her group. “The goal,” she said in March, “is to get the data to Altimmune as rapidly as possible, so they will use the information gained from the preclinical study to design their clinical trial in people.

Intranasal dosing provides AdCOVID with the potential to be administered rapidly and without the need for needles, syringes or trained healthcare personnel. In addition, AdCOVID’s expected room temperature stability profile may allow for broad distribution of the vaccine without the need for expensive cold-chain logistics, such as refrigeration or freezing.

UAB has extensive experience in conducting clinical studies of vaccines and has participated in studies sponsored by the Vaccine Evaluation and Trial Unit, part of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

At UAB, Randall holds the William J. Koopman Endowed Professorship in Rheumatology and Immunology, Harrod holds the Benjamin Monroe Carraway, M.D., Endowed Chair in Anesthesiology, and Kearney holds the Endowed Professorship in Immunology.

(Courtesy of UAB)

“We will screen the Scripps Calibr repurposed library of compounds to determine if any licensed drugs have activity against Sars-Cov-2, the virus that causes COVID-19,” Whitley said. “If there are any that are active, we will plug them into my National Institutes of Health U19 grant and, specifically, the coronavirus project.”

In 2019, Whitley’s Antiviral Drug Discovery and Development Center at UAB was awarded a five-year, $37.5 million grant from the National Institute of Allergy and Infectious Diseases Centers of Excellence for Translational Research to study and develop treatments for high-priority infections. These include the coronaviruses that caused SARS and MERS, with the addition now of the novel coronavirus that causes COVID-19. The antiviral drug center is also seeking treatments for influenza viruses; flaviviruses like dengue, West Nile virus and Zika; and alphaviruses, such as Venezuelan equine encephalitis virus and chikungunya. Remdesivir, an investigational drug developed by Whitley for MERS and now produced by Gilead Sciences, is currently being tested in hospitals for treating COVID-19 patients.

In Birmingham, the screening of the ReFRAME compounds will be done at Southern Research’s state-of-the-art High-Throughput Screening Center, which has advanced robotic equipment and a well-trained staff with the capacity to run a wide variety of assay types.

Southern Research is a nonprofit scientific research organization, and its board is chaired by UAB President Ray Watts, M.D.

Compounds that show activity in the Southern Research screening would then be further tested by Whitley’s collaborators on the NIH U19 grant. Mark Denison, M.D., professor of pediatrics at Vanderbilt University Medical Center, would study a compound’s medicinal chemistry and mechanism of action. Ralph Baric, Ph.D., professor of microbiology and immunology at the University of North Carolina-Chapel Hill, would study preclinical cellular and animal models.

“COVID-19 is an unprecedented public health crisis that will only be brought fully under control by effective medical therapies,” said Peter Schultz, Ph.D., president and CEO of Scripps Research, La Jolla, California. “Repurposing drugs that have already been approved for use in humans, or compounds for which we have ample safety data, offers the most rapid path to finding an antiviral drug or drug combination that is effective against COVID-19.”

Shortly after the initial COVID-19 outbreak began in China, Calibr began sharing the ReFRAME library and conducting joint experiments with other research teams at Scripps Research and collaborating institutions worldwide. Support comes from the Bill & Melinda Gates Foundation.

“In the case of COVID-19,” said Arnab Chatterjee, vice president of Medicinal Chemistry at Calibr, “we could leverage this important resource, along with Calibr’s expertise in drug development and discovery, to collaborate with some of the world’s leading virology labs and quickly identify potential medicines.”

Schultz says that, while the results of the collaborations are still preliminary and need to be confirmed, they have already identified a number of compounds that show varying degrees of activity against the virus. The researchers hope to soon begin testing the drugs in cellular and animal models, including testing combinations of drugs that work by two different mechanisms for enhanced effectiveness.

At UAB, Whitley holds the Loeb Eminent Scholar Chair in Pediatrics.

(Courtesy of UAB)

“We are eager to collaborate with Altimmune on this important project,” said Frances E. Lund, the Charles H. McCauley Professor and Chair for the UAB Department of Microbiology. “The expertise and infrastructure at UAB will be invaluable to the rapid progression of this vaccine into clinical studies,” she added.

Six UAB labs will work together on this urgent collaboration with Altimmune. “This project will be our highest priority for the group in the next few months as the goal is to get the data to Altimmune as rapidly as possible, so that they will use the information gained from the preclinical study to design their clinical trial in people,” Lund said.

In addition to Lund’s lab, the labs are led by Troy Randall, Ph.D., professor of medicine in the UAB Division of Clinical Immunology and Rheumatology; Kevin Harrod, Ph.D., professor in the UABDepartment of Anesthesiology and Perioperative Medicine; and three more UAB Department of Microbiology labs led by Rodney King, Ph.D., assistant professor, Todd Green, Ph.D., associate professor, and John Kearney, Ph.D., professor.

“It is critical that the biotechnology industry and academic institutions work together to prevent the further spread of COVID-19, and UAB is an ideal partner to support us in this effort,” said Vipin K. Garg, Ph.D., president and chief executive officer of Altimmune. “UAB has an impressive track record of cutting-edge research in virology and immunology, as well as in the clinical development of vaccines. In fact, Altimmune was founded through a technology license from UAB in 1997. We are excited to collaborate with UAB in our efforts, and we look forward to addressing this crisis together.”

UAB also has extensive experience in conducting clinical studies of vaccines and has participated in studies sponsored by the Vaccine Evaluation and Trial Unit, part of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

Altimmune expects that the COVID-19 vaccine candidate will activate mucosal and cellular immune responses, as well as a strong antibody response in the blood, as was found for its influenza vaccine candidate, which uses the same proprietary intranasal vaccine technology. If the AdCOVID vaccine candidate is as stable as Altimmune’s influenza and anthrax vaccines candidates, that may allow inexpensive and efficient distribution of the millions of doses needed for widespread vaccination of populations.

At UAB, Randall holds the William J. Koopman Endowed Professorship in Rheumatology and Immunology, Harrod holds the Benjamin Monroe Carraway, M.D., Endowed Chair in Anesthesiology and Kearney holds the Endowed Professorship in Immunology.

(Courtesy of UAB)

MicroRNAs are found in animal and plant cells, where they help control gene expression. In previous work, Shalev found that miR-204 plays key roles in regulating insulin production and other critical beta-cell processes.

Now, in a study published in the American Journal of Physiology-Endocrinology and Metabolism, Shalev and colleagues report that miR-204, which is highly enriched in human beta cells, is released by dying beta cells. After that release, it becomes detectable in circulating blood.

Measurements using human blood samples showed that serum miR-204 was elevated in children and adults with early Type 1 diabetes, and in people with autoantibodies who are at risk for Type 1 diabetes, but it was not elevated in Type 2 diabetes or another autoimmune disease. Furthermore, serum miR-204 levels were inversely correlated with remaining beta-cell function in recent-onset Type 1 diabetes.

“Having a non-invasive, straightforward method sensitive enough to detect early beta-cell loss – especially prior to the diagnosis of Type 1 diabetes – is critical in order to allow for any therapeutic intervention to be started as early as possible in the disease process and ideally before the majority of beta cells has been destroyed,” Shalev said.

Shalev is a professor in the UAB Department of Medicine’s Division of Endocrinology, Diabetes and Metabolism, and she directs the UAB Comprehensive Diabetes Center.

Discovery of the biomarker was a step-by-step, hypothesis-driven process, starting from the observation that miR-204 had 108-fold higher expression in pancreatic islet beta cells as compared to pancreatic alpha cells.

The researchers first showed that miR-204 was released by cultured rat beta cells after induction of cell death by streptozotocin. Then they showed that killing of beta cells in mice given streptozotocin led both to diabetes, as expected, and to a massive increase in serum miR-204 levels.

Next, they showed that Type 1 diabetes-associated inflammatory cytokines, which induce beta cell death, caused release of miR-204 from both cultured rat beta cells and primary human pancreatic islets.

To test miR-204 in humans, they looked at serum from people receiving autologous pancreatic islet transplantations. It is known that islet transplantation is associated with massive beta-cell death shortly after the transplantation. The researchers found that miR-204 levels in serum rose sharply, 20 to 40 minutes after islet infusion.

The researchers next found that serum miR-204 was significantly elevated in children with recent-onset Type 1 diabetes. It was also elevated nearly threefold in adults with recent onset Type 1 diabetes and more than twofold in people with autoantibodies that put them at risk for Type 1 diabetes.

In contrast, it was not significantly elevated in people with Type 2 diabetes or people with the autoimmune disease rheumatoid arthritis. It was not significantly elevated in people who have had Type 1 diabetes for a long time and have lost most of their beta cells.

Serum miR-204, Shalev and colleagues found, correlated with remaining beta-cell function, as measured by the “gold standard” of mixed-meal stimulated C-peptide area under the curve. Serum miR-204 also showed good predictive diagnostic power in the context of early Type 1 diabetes, including the ability to differentiate adult recent-onset Type 1 diabetes from Type 2 diabetes. That is useful because adults with Type 1 diabetes are often misdiagnosed when first found to have diabetes.

Shalev says the study at UAB was highly interdisciplinary. Co-authors with her on the paper, “Serum miR-204 is an early biomarker of type 1 diabetes-associated pancreatic beta-cell loss,” are Guanlan Xu, Lance A. Thielen, Junqin Chen, Truman B. Grayson, Tiffany Grimes and Fernando Ovalle, Division of Endocrinology, Diabetes and Metabolism, UAB Department of Medicine; S. Louis Bridges Jr., Division of Clinical Immunology and Rheumatology, UAB Department of Medicine; Hubert M. Tse, UAB Department of Microbiology; Blair Smith, UAB Department of Surgery; Rakesh Patel, UAB Department of Pathology; Peng Li, UAB Department of Biostatistics; and Carmella Evans-Molina, Indiana University School of Medicine, Indianapolis, Indiana.

Support came from a National Institutes of Health Human Islet Research Network award and grant and from a JDRF grant.

At UAB, Shalev holds the Nancy R. and Eugene C. Gwaltney Family Endowed Chair in Juvenile Diabetes Research.

This story originally appeared on the University of Alabama at Birmingham’s UAB News website.

(Courtesy of Alabama NewsCenter)

“The O’Neal family has built a legacy in Birmingham, first in the city’s steel industry and now in the city’s future as a biomedical and technology hub,” said Ray L. Watts, M.D., president of UAB. “UAB’s National Cancer Institute-designated Comprehensive Cancer Center is among the pre-eminent cancer centers in the world, and we are proud and grateful that our cancer center will bear the O’Neal name.”

Members of the O’Neal family have been business and political leaders in Alabama for generations. Edward O’Neal was Alabama’s 26th governor, and his son Emmet served as the state’s 34th governor. Kirkman O’Neal was a pioneer in Birmingham’s burgeoning steel industry, founding in 1921 what was to become O’Neal Steel. The family now operates O’Neal Industries Inc., the nation’s largest family-owned group of metals service centers.

“We see this gift as an opportunity to give back in a meaningful way to a cause that is important to everyone,” said Craft O’Neal, chairman and CEO of O’Neal Industries and grandson of Kirkman O’Neal. “We hope the gift will be used in ways that will yield the greatest results, accelerating progress in research, treatment and prevention of cancer and, ultimately, eliminate cancer as a major public health problem.”

The gift and naming will be formally considered for acceptance by the University of Alabama System Board of Trustees at its February meeting.

“This gift will enhance the profile and impact of the cancer center as a premier national destination for those working to end cancer, and those fighting a personal battle with the disease,” said Selwyn Vickers, M.D., senior vice president and dean of the UAB School of Medicine. “It will have lifesaving results that can serve as a catalyst for further philanthropic investment, and we are grateful to the O’Neal family and O’Neal Industries for their leadership in the fight to end cancer.”

UAB’s cancer center was one of the original eight comprehensive cancer centers established by the National Cancer Act in 1971 and has been continuously funded for 46 years.

“We have made great strides in cancer treatment and prevention in the past several decades,” said Will Ferniany, Ph.D., CEO of the UAB Health System. “In the years ahead, the promise of proton therapy, precision oncology, advanced genomics and new therapeutics should reduce the burden of cancer on individual patients and their families, and on the health care system as a whole. The generous O’Neal gift will be a driving force that transforms cancer care moving forward.”

UAB is the only National Cancer Institute-designated cancer center in its four-state region. It also maintains joint ventures with Russell Medical Center and North Alabama Medical Center and manages the Deep South Network for Cancer Control, an outreach into underserved communities in Alabama and Mississippi. The UAB Health System maintains a Cancer Community Health Network in Alabama, Florida, Georgia and Mississippi.

“This truly transformational gift will have a far-reaching impact on cancer research and patient care in our community, state and region,” said Michael J. Birrer, M.D., Ph.D., director of the center. “It strengthens our clinical operation, expands our cancer research efforts, helps translate discoveries into clinical trials, and further establishes the center as a leader in cancer research and care in the nation. The impact of this gift not only will be felt in the cancer center but will be an economic driver for Birmingham and Alabama.”

The O’Neals’ extended family has been touched by cancer. Kirkman’s son and successor, Emmet, Craft’s father, died from emergency surgery associated with colon cancer, and his daughter Libby O’Neal White was a breast cancer survivor. Her husband, David White, succumbed to cancer, as did Craft O’Neal’s mother, Mary Anne, and his brother Kirk. Additional members of the O’Neal and White families have both survived and lost their lives to cancer.

“The O’Neal and White families know too well the devastating effects of cancer, and together we were motivated by the opportunity to play a role in extending the lives of those with cancer in the region, while honoring our family members who have been afflicted by the disease,” O’Neal said.

The O’Neal Comprehensive Cancer Center at UAB is home to more than 400 scientists and physician-scientists and is involved in more than 200 clinical trials of new, promising therapeutics, many using therapies that were developed at UAB. The center treats an estimated 5,000 new patients each year.

The gift will enhance patient access and overall patient care, according to Birrer. It also will expand research efforts, potentially tripling the number of clinical trials conducted at UAB. The gift will help recruiting efforts of additional investigators and provide leverage for new grant funding.

O’Neal Industries and its shareholders have a deep history of philanthropy with UAB. Craft O’Neal is a longtime member of the cancer center’s advisory board, and over the years, O’Neal Industries and family members have supported departments across UAB, including the Comprehensive Cancer Center, the Collat School of Business, the Department of Neurology, the School of Nursing, the Comprehensive Diabetes Center and UAB Athletics.

“Our company has a nearly 100-year history here, and that will continue,” O’Neal said. “We believe in giving back to the community that has been so good to us. UAB is the economic engine of Birmingham and, to a large extent, the state of Alabama. My hope is that others will see the exciting developments at the cancer center and want to invest in its future and that of our city as well.”

Industries represents a family of six companies with a global reach. There are 80 separate business locations, including 15 international facilities on four continents, employing more than 3,200 people.

“My grandfather’s and father’s generations of O’Neal employees laid the foundation for the success we enjoy today,” O’Neal said. “This success enables us to give back in all the communities in which we are located, and do even bigger things here at our headquarters in Birmingham. I hope each of our employees, loyal customers and supportive suppliers will take pride in this gift, because without their contributions to our success, we would not be able to give back in such a meaningful way.”

(Courtesy of Alabama NewsCenter)