The USF Health Byrd Alzheimer’s Center contributed to a new international study in Nature Medicine suggesting there is reason to reevaluate the concept of “typical” Alzheimer’s disease. The study examined the largest and most diverse population in the world to date using tau-positron emission tomography scans (tau-PET scans), an advanced neuroimaging technique.

Amanda Smith, MD, professor of psychiatry and behavioral neurosciences and clinical research director at the Byrd Alzheimer’s Center, USF Health Morsani College of Medicine, was among the Alzheimer’s Disease Neuroimaging Initiative (ADNI) coauthors for the Nature Medicine paper. As one of more than 60 ADNI sites across the U.S. and Canada, the Byrd Alzheimer’s Center shares PET and MRI images, cognitive tests, blood biomarkers and other research data used by scientists worldwide to improve the understanding of Alzheimer’s disease.

Amanda Smith, MD, is director of clinical research at the USF Health Byrd Alzheimer’s Center.

Alzheimer’s disease is characterized by toxic accumulation of the protein tau (as well as abnormal amyloid protein deposits), leading to the death of nerve cells in the brain.

The recent study, led by researchers from McGill University and Lund University, delineates four distinct patterns (subtypes) of tau pathology in Alzheimer’s disease — each distinguished by where in the brain toxic tau deposits originate and spread. The researchers showed that over time each pattern of tau accumulation correlates to different clusters of symptoms with different prognoses for the affected individuals.

For the past 30 years, many researchers have described the development of tau pathology in Alzheimer’s using a single model, despite recurring cases that do not fit that model.

The current findings help explain why different patients may develop different symptoms, Dr. Smith said.

“In the clinic where we assess hundreds of patients with Alzheimer’s disease, we know that not everyone presents with the same symptoms. Many people present with typical short-term memory loss. Some can remember but exhibit very prominent language problems. Others may have visual difficulties that cause them to not see, or to misinterpret, what is front of them,” she said. “Although advanced Alzheimer’s tends to look the same, individuals don’t necessarily fit neatly into one category (of symptoms) earlier in the disease process.”

The recent tau-PET scan findings have implications for how disease progression is staged, and ultimately helping with the discovery of individualized treatments.

Byrd neuroscientists are working to develop both anti-amyloid and anti-tau antibodies – drugs to stop or delay Alzheimer’s disease, which yet has no disease-modifying therapies. In addition to more precisely detecting the early presence of disease and monitoring its progression, the latest neuroimaging techniques help researchers see whether their investigational drugs can remove the damaging Alzheimer’s-associated proteins from the brain.

PET scans of the brains of Alzheimer’s patients, showing patterns of both amyloid and tau. CREDIT: Dean Wong, MD, PhD, Ayon Nandi, MS, and Hiroto Kuwabara, MD, PhD | Johns Hopkins Medicine

“The increasing degree of specificity provided by neuroimaging studies may advance our ability to accurately target treatments for individuals with abnormal tau in the brain – and that’s not just limited to Alzheimer’s disease,” Dr. Smith said. “While amyloid is unique to Alzheimer’s, toxic tau is found in other cognitive disorders, including certain frontotemporal dementias and chronic traumatic encephalopathy.” (CTE is brain degeneration linked to repeated head trauma, including concussions in athletes.)

Dr. Smith leads clinical trials at the USF Health Byrd Alzheimer’s Center that involve brain imaging of a wide range of older adults – from study participants with no symptoms (presymtomatic) or very minor memory difficulties, to those diagnosed with mild cognitive impairment or various stages of Alzheimer’s dementia.

Current trials include Alzheimer’s Disease Initiative 3, the AHEAD Study, and the Trial-Ready Cohort for the Prevention of Alzheimer’s Dementia (TRC-PAD).  For information on these and other clinical studies, please visit health.usf.edu/medicine/byrd/clinical-trials, or call 813-974-4904.

The new office will allow the previously separate offices to combine resources and elevate their research efforts to improve health care for all Floridians

TAMPA, Fla (Nov. 30, 2020) — Tampa General Hospital and USF Health today announced the creation of a joint TGH-USF Health Office of Clinical Research to strengthen and expand current jointly conducted clinical trials, including translational studies that bridge laboratory discoveries and benefit patient care.

Both organizations are working to create Florida’s leading academic medical center dedicated to outstanding patient care, education and research. The restructuring will allow TGH and USF Health to combine resources and work together more seamlessly to initiate, operate and coordinate clinical trials looking at new ways to prevent, detect and treat disease.

“We already have established and invested in a strong foundation for clinical research,” said Tampa General President and CEO John Couris. “Combining the efforts of TGH and USF Health is the next step to elevate the world-class research we do to push forward to the edge of scientific discovery.”

“The joint office will allow for expansion of that portion of our clinical research portfolio occurring at TGH and to conduct that research with greater efficiency,” said Charles J. Lockwood, MD, MHCM, senior vice president of USF Health and dean of the USF Health Morsani College of Medicine.  “A robust research portfolio is a core component of all academic medical centers – and clinical trials are an essential part of what we do to advance the science leading to evidence-based health care. We expect this joint office to streamline the clinical trial process, thereby providing greater opportunities for both hospitalized patients and outpatients to participate in leading studies investigating new treatments.”

The joint TGH-USF Health Clinical Research Office will build upon the success over the last seven months of researchers and research staff at both institutions working to collaboratively launch about 35  COVID-19 clinical trials investigating a range of diagnostics, antiviral and anti-inflammatory medications, treatment protocols, vaccines and surveillance registries. Several, such as the joint studies testing Regeneron’s combination monoclonal antibody therapy in sick people or those exposed to the virus, are part of larger national clinical trials.

Including those COVID trials, TGH and USF Health now are working together on about 350 research studies. In July, TGH and the University of South Florida signed a new clinical affiliation to further solidify one of the largest academic medical centers in Florida and build upon their longstanding relationship and commitment to improving health care in Tampa Bay.

Clifton Gooch, MD, professor and chair of neurology at USF Health, was appointed co-vice president of Clinical Trials and Translational Research, and Rachel Karlnoski, PhD, was named executive director of the joint TGH-USF Health Office of Clinical Research.

This move to better align joint clinical research includes new leadership appointments:

• Clifton Gooch, MD, and Abraham Schwarzberg, MD, were named as co-vice presidents of Clinical Trials and Translational Research for the joint office. Dr. Gooch is professor and chair of the Department of Neurology at the USF Health Morsani College of Medicine and Tampa General Hospital Endowed Chair in Neurology. Schwarzberg is senior vice president of network development and chief of Oncology at TGH.

• Following a national search, Rachel Karlnoski, PhD, director of clinical research operations for USF Health, was selected to fill the new role of executive director of research. Karlnoski will report to Gooch and Schwarzberg for the oversight of all clinical studies involving both USF Health and Tampa General Hospital. She retains the position directing clinical research operations for USF Health, which she had held since 2018. For all USF Health trials except those based at TGH, Karlnoski continues reporting to Stephen Liggett, MD, vice dean for research at USF Health.

The administrative research changes will not affect USF Health’s participation in clinical studies with Moffitt Cancer Center, James A. Haley Veterans’ Hospital or other community and academic partners. Nor will the changes affect TGH’s partnership in clinical studies with Moffitt Cancer Center, TeamHealth, the Florida Orthopedic Institute, or other private practice physician partners.

From designing 3D printed test swabs, to researching antibody responses and engaging in leading clinical trials, USF Health scientists rapidly team up to help fight COVID-19

While the world waits for therapies to reduce death rates and a widely available vaccine to prevent COVID 19, team science at USF Health and other academic medical centers continues to take on an unprecedented sense of urgency.

Globally, scientists across disciplines are publicly sharing their ideas, expertise and data like never before – all singularly focused on finding solutions to a highly contagious and potentially life-threatening new virus known as severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2.

Since the pandemic began, the number of studies posted by researchers worldwide to open-access repositories like bioRxiv and medRxiv has skyrocketed. These preprints – papers written after a study concludes but made available before peer review – let scientists disseminate their findings more quickly and obtain instant feedback on their work. Researchers also continue to identify and share viral genome sequences, protein structures, and COVID-19 related epidemiological and clinical data through online databases.

Meanwhile, thousands of clinical trials have been launched as academic medical centers, hospitals and laboratories join forces with government and industry in the search for optimal diagnostics and therapies. At USF Health, more than 65 COVID-19 related laboratory, clinical and epidemiological projects are underway or in final stages of the approval process. These represent unique research efforts by the faculty of all four USF Health colleges, as well as joint efforts with pharmaceutical firms and biotechnical and software companies. Many of the patient-related studies are conducted by USF Health faculty physicians at Tampa General Hospital.  USF Health is also working with Tampa General to create a biorepository that collects, processes and stores health data and residual specimens from patients who test positive or negative for COVID-19 to use in future biomedical research.

“The need for rapid and accurate basic and clinical results has never been greater. The scientific community has risen to the challenge of a lifetime and continues to push forward,” said Stephen Liggett, MD, associate vice president for USF Health Research and vice dean for research in the Morsani College of Medicine. “Without a doubt we are still in the early stages of understanding this new coronavirus – in knowing who should be tested and how often, and which tests work best; in knowing how to treat patients and how effective vaccines will be in conferring immunity.”

//www.youtube.com/watch?v=8LWaITfItQA

View the interview with Stephen Liggett, MD, associate vice president for research at USF Health, who discusses how the COVID-19 pandemic has changed research here.

USF faculty and student researchers have been quick to mobilize their talent and resources, Dr. Liggett said. “They want to do whatever they can to find answers — both to help fight this pandemic and to prepare for future outbreaks.”

How are some key scientific areas contributing to the pandemic response?  Below are just a few examples provided by USF Health scientists:

Epidemiology:  Containing the spread of the virus

From the start, epidemiologists have been at the forefront of efforts to understand how fast and why SARS-CoV-2 is spreading. Also known as disease detectives or virus hunters, epidemiologists and the models using data they gather are instrumental in tracking and predicting the patterns of disease transmission in populations, said Thomas Unnasch, PhD, distinguished professor in the USF College of Public Health and codirector of the Center for Global Health Infectious Disease Research. Their work had been critical for both guiding policymakers’ plans to curb the pandemic and helping evaluate whether countermeasures to contain the virus are working.

“We’ve been hunkered down in the midst of a pandemic wildfire and testing only the symptomatic people most likely to be infected” — largely to prevent surges of sick patients from overwhelming the health care system, Dr. Unnasch said. “We’re still missing about 90 percent of the population with COVID-19 infections exhibiting mild or no symptoms.”

USF College of Public Health’s Thomas Unnasch, PhD, oversees the COVID-19 symptom surveillance network for Tampa Bay.

Dr. Unnasch oversees a symptom-based surveillance network launched in mid-April to help identify and map COVID-19 hotspots across the Tampa Bay region. USF College of Public Health researchers worked with the Hillsborough, Pinellas, Pasco and Polk County Health Departments to create the Tampa Bay symptom surveillance survey, adapting existing COVID-19 surveillance technology developed by the Puerto Rico Sciences Trust and deployed in Puerto Rico and, more recently, the Boston area through Harvard University.

The anonymous survey asks Tampa Bay residents questions about potential exposure and symptoms consistent with COVID-19. The information collected, which drills down to the zip code level, is provided to the local health departments and hospital groups.

Surveillance – a tool commonly used by public health agencies to identify and prevent the spread of HIV, tuberculosis, anthrax and other infectious diseases – can help fill in the gaps created by limitations inherent in a complex society, such as a lack of uniform testing, Dr. Unnasch said.

COVID-19 cases in Pinellas and Hillsborough County broken down by zip code, as tracked and entered by the Hillsborough County Health Department on April 16, 2020. Pasco and Polk counties have since been added to the symptom surveillance system.

“So far the only way to prevent the disease is to prevent transmission of the virus. That has meant everyone doing the right thing — staying at home, social distancing face masks, and hygiene,” Dr. Unnasch said.  “As we reopen our communities, surveillance can help us do that safely by detecting clusters of new cases early at a very targeted level, so we can stomp out the embers before they reignite COVID-19 outbreaks.”

Real-time mapping of suspected COVID-19 hotspots can be used to strategically direct Tampa Bay’s public health resources to specific areas where testing, contact tracing and isolation are most likely needed, he said.

“The more data we get and the more accurate the information, the more powerful the tool will be.”

Biostatisticians: Keeping the bias at bay

The data collected by epidemiologists or other health researchers can be fed into mathematical models that predict how fast COVID-19 infections may spread or the number of deaths expected in an overall population. At the community/clinical level, predictive models can help hospitals and medical staff triage patients and allocate limited health care resources (like ICU beds or ventilators) by estimating the risk of people being infected or having a poor disease outcome.

While they can be useful to prepare for worst-case scenarios, predictive models have differed widely in their forecasts – and sometimes they can cause more harm than benefit in guiding policy or clinical decisions, said Ambuj Kumar, MD, MPH, director of the Research Methodology and Biostatistics Core, USF Health Office of Research.

Dr. Kumar, a biostatistician and associate professor of internal medicine, points to a recently published systematic review analyzing studies of prediction models for the diagnosis and prognosis of patients with COVID-19. This review concluded that all 31 clinical models were poor quality, at high risk of bias, and their reported performance was likely overly optimistic.

Ambuj Kumar, MD, MPH, directs USF Health’s Research Methodology and Biostatistics Core.

Methodologist/biostatisticians like Dr. Kumar are trained to recognize the issues and complications arising from the analysis of human health data. They play a key role in any team designing and executing a model, providing the statistical methodology needed to draw meaningful conclusions or make predictions. These data scientists help reduce bias in selecting sample populations, observing or reporting findings, and measurement. They are attuned to factors that can interfere with an accurate estimate of cause-and-effect.

Requiring frequent updates, projections are only as good as the model’s underlying assumptions and the reliability and standardization of the data applied to the model, Dr. Kumar said.

For instance, the commonly cited Institute for Health Metrics and Evaluation model assumes social distancing and other strong voluntary measures to control viral spread will stay in place, but predicting how people will behave as the U.S. reopens in phases is tricky. And, the death data relied upon by many models may be confounded a lack of consistency in the way COVID-19 deaths are reported and counted by hospitals and health departments. (Public health experts have suggested that deaths are undercounted.)

Predictive modeling uses existing data and reasonable assumptions to forecast how an infectious disease spreads in the real world. As more data becomes available, it triggers adjustment of the model, resulting in different outcomes.

Many people understandably want to know now what to expect during this pandemic: How many more cases? How long will it last? When can I safely return to work, or school? Will there be a second wave?

But, many uncertainties about testing, immunity, susceptibility and treatments still influence the variables that make up the algorithms forecasting COVID-19 outcomes, Dr. Kumar said. As the reliability and accuracy of rapidly accumulating data improves, so should the models, he added.

“Predicting the future is particularly challenging when we’re dealing with a virus new to the entire world,” Dr. Kumar said.  “Whether you’re battling COVID-19 or another crisis, you can’t compromise on the systematic, standardized approach needed to create a useful model, or study. If you want accurate results, there’s no substitute for good, rigorous science.”

Virology:  Studying how SARS-CoV-2 works

To develop effective therapies and vaccines to combat COVID-19, scientists need to understand how the virus functions, including its interaction with human immune response. That’s the role of virologists like Michael Teng, PhD, associate professor of internal medicine in the USF Health Morsani College of Medicine.

Dr. Teng has spent many years working with the National Institutes of Health and other groups on research and development of a vaccine for respiratory syncytial virus, or RSV. While RSV was discovered over 60 years ago, researchers continue to work on a vaccine for this common respiratory virus that infects virtually every child by age 2.

Like many other scientists, USF Health virologist Michael Teng, PhD, quickly pivoted from his usual research activities to respond to the new global health threat.

Scientists and companies now testing a myriad of SARS-CoV-2 vaccines in the pipeline have benefited from the extensive RSV research, Dr. Teng said. “They’ve learned a lot from RSV about what works and what pitfalls to avoid in vaccine development.”

Like many other scientists, Dr. Teng quickly pivoted from his usual research activities to respond to the new global health threat. In mid-March his laboratory studied the durability and effectiveness of the 3D-printed nasal swabs successfully created for COVID-19 testing by a team at USF Health Radiology and its innovative 3D Clinical Applications Division, directed by  associate professor Summer Decker, PhD.  Faculty with expertise  in anatomy and infectious diseases as well as radiology contributed to the effort. The ambitious 3D design, modeling and printing project teamed USF Health with Formlabs, a 3D printer manufacturer, and Northwell Health, the largest hospital system in New York, the pandemic’s U.S. epicenter.

An integral part of coronavirus test kits that detect the RNA virus’s genetic code, swabs were in extremely short supply as the pandemic escalated. The slender, flexible device collects a sample from the nasal passages or throat, and that sample goes into a test tube containing transport media for preservation until the specimen is processed by a hospital or commercial laboratory. Using RSV as a proxy for a SARS-CoV-2, synthetic respiratory tract mucous (made by USF Health’s Sophie Darch, PhD), and a World Health Organization recipe for transport media, Dr. Teng demonstrated that the 3D-printed alternative swabs worked as well as conventional commercial swabs to safely collect enough of the sample, without leeching into transport media or interfering with the nucleic acid test’s ability to detect virus particles.

Top:  A USF Health Radiology-led team successfully designed, tested and produced a prototype 3D printed nasopharyngeal swab in record time. As of late May, more than 50,000 of the nasal swabs had been mass produced and were being used worldwide by health care providers to alleviate bottlenecks in COVID-19 testing. Bottom: Jonathan Ford, PhD, a biomedical engineer in USF Health Radiology, holds a cube of the 3D diagnostic nasal swabs.

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The 3D printed swabs, fabricated with FDA-approved, nontoxic materials, also passed performance benchmarks when clinically validated in hospitalized patients undergoing COVID-19 screening at Tampa General Hospital and Northwell Health sites. (A larger-scale multisite clinical trial, led by USF Health Infectious Disease Division Director Kami Kim, MD, is further evaluating the performance of the investigational 3D swabs for diagnostic testing.) Meanwhile, several hundred hospitals and academic medical centers across the country, many state governments, and international agencies and health care facilities are already using the USF-patented swabs to alleviate bottlenecks in COVID-19 testing.

The team worked late nights, taking only about a week from swab prototype design and bench testing to the start of clinical validation. “That’s an incredibly fast turnaround time,” Dr. Teng said.

Dr. Teng is also a coinvestigator for a Morsani College of Medicine-College of Public Health project led by Dr. Kim, which is working to find and map epitopes, the parts of SARS-CoV-2 proteins recognized by the immune system. Antibodies are made by the immune system in response to a threat from a specific virus, bacteria and other harmful pathogen. Some epitopes are associated with protective antibody responses that neutralize (inactivate) a virus when that pathogen is recognized by the immune system again. Others may actually lead to a harmful immune response when a person is exposed to the same virus a second time. The USF Health team wants to identify specific epitopes triggering strong protective antibodies to help researchers design vaccines that mimic a beneficial immune response against COVID-19.

“The data we gather may also be useful in screening (convalescent) plasma for specific antibodies that may best be used to treat critically ill COVID-19 patients,” Dr. Teng said.

Thomas McDonald, MD, USF Health professor of cardiovascular sciences, is investigating whether genetic, physiological or medication-interaction factors may contribute to racial and ethnic disparities in COVID-19 infection rates and cardiovascular complications.

A coronavirus “pseudotype” created by Dr. Teng’s laboratory is being used by the team working on finding neutralizing antibodies and a second USF Health team investigating what factors may affect who suffers worse COVID outcomes.

The second team, led by Thomas McDonald, MD, professor of cardiovascular sciences at the USF Health Heart Institute, wants to know if socioeconomic differences alone account for racial and ethnic disparities in who gets sicker and dies from COVID-19, or if genetic, physiological, or even medication-interaction factors contribute to disproportionate infection rates and cardiovascular complications.

Human pluripotent stem cells grown in Dr. McDonald’s laboratory are prodded to become lung, immune, and heart cells in a petri dish. The stem cells come from blood samples donated by many patient volunteers of different ages, genders and races, as well as various pre-existing cardiovascular conditions. These tissue samples will be infected with the COVID-19 proxy virus engineered by Dr. Teng.

The substitute virus combines the well-studied vesicular stomatitis virus (VSV) with an outer shell containing the spike protein on the surface of SARS-CoV-2 that allows the coronavirus to enter human cells. This non-replicating virus is “a sheep in wolf’s clothing,” invading cells like the COVID-19 virus without harming scientists working with the pathogen, Dr. McDonald said. VSV also expresses the same enzyme, luciferase, that gives fireflies their glow. When hit with a chemical, this “firefly luciferase” lights up the virus so researchers can trace how much invades cells and which cell types are vulnerable.

“With a machine we can image the range of light, which is the level of infection coming out of the cells,” Dr. Teng said.

For the Dr. Kim-led study evaluating the ability of different serum antibodies to block the virus from entering human cells, less light would indicate that the antibodies protected against infection, he added.

Luciferase, the same enzyme that gives fireflies their glow, is helping USF Health researchers track how much proxy COVID-virus invades human cells and which cells are most vulnerable.

Structural biology: A key to drug discovery

Unraveling the structure of viral proteins and identifying the receptors they use to enter cells can help guide discovery and design of potential antiviral treatments.

Yu Chen, PhD, is a USF Health associate professor of molecular medicine with a background in structural biology and biochemistry. Dr. Chen applies his expertise in structure-based drug design using advanced techniques — including X-ray crystallography and molecular docking — to help develop inhibitors (drug compounds) that target bacterial enzymes causing resistance to certain commonly prescribed antibiotics such as penicillin.

Now he’s turned his attention toward looking for new or existing drugs to stop SARS-CoV-2.

Yu Chen, PhD, an associate professor of molecular medicine who has expertise in structure-based drug design, has turned toward looking for new or existing drugs to stop SARS-CoV-2.

One way to do this would be to block the virus’s main protease, known as M^pro, an enzyme that cuts out proteins from a long strand that the virus produces when it invades a cell. Without it, the virus cannot replicate. Dr. Chen works with colleagues at the University of Arizona College of Pharmacy (Jun Wang, PhD) and the USF Department of Chemistry (James Leahy, PhD) on this project.

“M^pro represents a promising target for drug development against COVID-19 because of the enzyme’s essential role in viral replication and the absence of a similar protease in humans,” Dr. Chen said. Since people do not have the enzyme, drugs targeting this protein are less likely to cause side effects, he explained.

This winter, an international team of scientists shared their description of the complex crystal structure of M^pro and in April published their discovery of its inhibitors, a half-dozen leading drug candidates identified by targeting the viral enzyme. Taking advantage of the breakthrough, Dr. Chen and other scientists worldwide hope to add more candidates to the drug discovery pipeline soon.

Together with the scientists from University of Arizona, Dr. Chen has found that several known protease inhibitors, including an FDA-approved hepatitis C (HCV) drug boceprevir and an investigational veterinary antiviral drug GC376, showed potent inhibition of the viral protein, and were more active than the previously identified inhibitors. Dr. Chen and his doctoral student, Michael Sacco, have recently determined the first structure of GC376 bound by M^pro, and characterized the molecular interactions between the compound and the viral enzyme.  Their paper describing these results will soon be published in the prestigious scientific journal Cell Research.

Generated by X-ray crystallograhy, this image depicts the overall structure of the COVID-19 virus’s main protease (Mpro), which plays a key role in viral replication. Dr. Chen and colleagues recently found two new protease inhibitors that offer promise in blocking the drug target. –Photo courtesy of Yu Chen.

Dr. Chen and colleagues are also looking for small molecules that can effectively stop the M^pro enzyme from working or last long enough in the body to kill the COVID-19 virus.

The researchers use the latest computer software to visualize and predict how different drug candidates (M^pro inhibitors) bind with the viral proteins. This 3D structural analysis of “binding hotspots” can help in designing and chemically modifying other types of protease inhibiting-drugs with improved activity against SARS-CoV-2, Dr. Chen said.

The most potent antiviral compounds would be tested in human respiratory cell cultures growing the virus. Only then can a drug candidate move to animal models, and, eventually, human trials.

Genomics: Linking genetic variations to outcomes

Why do some individuals get so ill from the COVID-19 virus, while others barely notice symptoms? Why do certain countries and populations have higher death rates than others? Age, underlying medical conditions, socioeconomic and environmental factors play a role – but genetic variation, both in the virus itself and the humans it invades, are likely part of the equation.

“This virus has swept across the world, and some differences in immune response, virulence and disease outcomes of people infected with SARS-CoV-2 could be due to various strains of the virus yet to be defined,” USF Health’s Dr. Liggett said.

Differences in immune response, virulence and disease outcomes of people infected with SARS-CoV-2 could be due to various strains of the virus not yet defined, Dr.  Liggett says.

Sequencing all genes that make up the COVID-19 virus — not just certain sections of the virus’s genome — will be key to uncovering genetic changes that could make a difference in patient susceptibility and outcomes, Dr. Liggett said. More than a decade ago, a team led by Dr. Liggett sequenced for the first time all known genomes of the human rhinovirus, providing a framework for antiviral treatments or vaccine development for this common respiratory virus implicated in asthma flare-ups.

“All parts of a virus’s genome work together for its existence, reproduction and infectivity,” he said. “So, to sequence only one part would be like looking at just the spark plugs, instead of the whole engine, when your car is not running well.”

The data gathered so far indicates that SARS-CoV-2 mutates slowly in the population. Most people have only 10 or so genetic variations in the 30,0000 nucleotide viral genome compared to the reference standard, Dr. Liggett said. “This may be a good sign that antibodies developed from an infection, a vaccine, or derived from an infusion, will provide long-lived immunity. This lower level of mutations also allows us to track a viral strain, potentially knowing how a community became infected.”

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Noting where genetic variation does not occur is also important, since this may represent a “soft-spot” in the virus’s genome that cannot tolerate change because it is so vital, he added. “That might offer a clue about where to target a vaccine or therapy.”

As for human genetic variations that might influence whether certain individuals or subgroups of patients with COVID-19 fare better or worse, Dr. Liggett says the scientific community understands many human genes responsible for mounting an immune defense against this SARS-CoV-2 virus, and other respiratory viruses.

“With enough samples and epidemiology, we may be able to identify patients at genetic risk for serious, life-threatening outcomes,” he said. “However, it will be extremely challenging to find those needles in this big haystack.”

Clinical Trials: Testing treatments that attack on several fronts

As clinicians cared for more patients, one thing became increasingly clear – COVID-19 is more than a respiratory disease that injures the lungs.

It can strike many cell types and organs throughout the body including the brain, heart, blood vessels and kidneys; destroy taste and smell; cause life-threatening blood clots; and trigger a dangerous inflammatory cytokine storm. People with weakened immune systems are more vulnerable to severe illness – including the elderly and those with heart or lung diseases, diabetes, obesity or other underlying medical conditions. Black and Latino populations are disproportionately more likely to die from the virus. And while children are largely spared, a rare inflammatory pediatric syndrome with cardiac complications has been associated with COVID-19.

USF Health, working with Tampa General Hospital, had been at the forefront of a wide range of COVID-19 clinical trials in the Tampa Bay region.

Physicians and scientists are exploring many possible treatments to increase survival and improve prognoses for critically ill patients. Some target the virus itself or human cellular pathways that the virus exploits to replicate. Others aim to prevent collateral inflammatory damage in the human host. A disease affecting so many parts of the body will need drugs, or combinations of drugs, to attack on several fronts, said USF Health infectious disease physician-scientist Dr. Kim.

In the Tampa Bay region, USF Health, working with Tampa General Hospital, is at the forefront of a wide range of COVID-19 clinical trials. Creating drugs from scratch can take years, so several trials are investigating medications already prescribed for other infectious or inflammatory diseases to determine their effectiveness against SARS-CoV-2. For instance, Dr. Kim is local lead investigator for a multisite randomized controlled trial testing the safety and effectiveness of sarilumab in blocking acute lung damage in hospitalized COVID-19 patients. Sarilumab, approved for treating rheumatoid arthritis, is a monoclonal antibody targeting the proinflammatory cytokine receptor interleukin 6. Another trial will evaluate the ability of nitazoxanide, originally developed as an antiparasitic drug for gastrointestinal infections, to prevent respiratory virus replication in health care workers.

Dr. Kim is also working with Tampa General’s laboratory to analyze and validate the reliability of commercial tests that test patient blood samples for antibodies, proteins that provide evidence of past COVID-19 infection and recovery.

Kami Kim, MD, director of the Division of Infectious Disease and International Medicine at USF Health, leads a study evaluating the accuracy of antibody testing.

The accuracy of the antibody testing – different from the nasopharynx swab or saliva tests used to diagnose a current active infections – is important because it can give health officials a clearer picture of how widely COVID-19 has spread in the community and the extent of asymptomatic cases. Based on past experience with other coronaviruses like SARS and MERS, a positive SARS-CoV-2 antibody test would typically indicate some level of immunity. Researchers like Dr. Kim want to confirm that and hope to define the concentration of antibodies needed to confer immunity as well as how long that immunity lasts.

(In late May, the Centers for Disease Control and Prevention released new guidelines cautioning that some antibody tests have high false positive rates, and more definitive data is needed before they can be used to make decisions about returning to work, school or other public places.)

“We need to know if people who have the antibodies are actually protected against another infection,” Dr. Kim said. “It’s not yet clear… but, preliminary data indicates that a fairly large proportion of those people who recover from COVID-19 infection will have what are the protective (neutralizing) antibodies.”

SARS-CoV-2 shares genetic and some clinical similarities with the first SARS virus (SARS-CoV) — which caused a smaller scale global outbreak and has not re-emerged since the last reported case in 2004. But the new coronavirus is both more highly contagious and more apt to spread asymptomatically.

Based on past experience with other coronaviruses like SARS and MERS, a positive SARS-CoV-2 antibody test would typically indicate some level of immunity. Scientists are working to figure out how much immunity and how long it lasts.

“It’s the thing that has kept all of us in public health and infectious diseases up at night – a completely new pathogen that explodes before we had a real chance to get a handle on what was happening,” Dr. Kim said. “We’re learning more as we go, but teamwork is essential. No one will be able to solve all the pieces of this pandemic puzzle by themselves,” she added.

It will take time for scientists to fully understand the COVID-19 virus and how genetics, the environment, medications, lifestyle and public health measures impact the course of the disease.

“COVID-19 has essentially shut down the entire world,” added Dr. Kim, who as a clinical infectious diseases fellow at the University of California San Francisco in the 1980s witnessed firsthand the devastating consequences of the domestic HIV/AIDS epidemic. “A lesson we need to learn is the importance of maintaining preventive public health infrastructures — not only in our local communities, but globally, so that we can efficiently combat any future pandemics.”

Cardiothoracic surgeon Dr. John Dunning and team performed the transplantation of  donor lung kept “breathing” in human-like conditions

For all the advances in organ transplantation, most organs are still transferred from donor to recipient in a cooler packed with ice. The clock begins ticking as soon as the donor organ is recovered – and in the case of a heart or lung, for instance, a transplant is usually no longer viable after four to six hours.

Now, the USF Health Heart and Lung Transplant Program at Tampa General Hospital (TGH) has become the first in the state to use or formally study the sophisticated organ transplant system designed to keep donor lungs and hearts healthier longer and increase the number of transplants.  TGH is also assessing the Organ Care System (OCS ), manufactured by medical device company TransMedics Inc., for use in extending the life of donor livers.

//www.youtube.com/watch?v=oKmStWSZifk

Video footage courtesy of TransMedics, Inc.

The first lung transplant in Florida using this system was performed Oct. 22, 2019 by a team led by John Dunning, MD, professor of cardiothoracic surgery at the USF Health Morsani College of Medicine and surgical director for Health and Lung Transplantation at TGH. (The FDA has already approved the OCS technology for lung transplant, but its use for hearts and livers is still investigational.)

TGH is among the top 10 busiest transplant centers in the nation, having now performed more than 10,000 transplant operations.

The new OCS technology – often referred to as “lung in a box” or “heart in a box” — allows the donor organ to keep functioning almost as if it were still inside the human body while it is transported to the hospital in a portable sterile machine equipped with probes and tubing. During a process called normal temperature perfusion, the organ is oxygenated and nourished with continuously circulating blood. The flow of blood prompts the heart to continue beating, the lungs breathe with a puff of ventilator air, and the liver produces bile. A touch-screen tablet lets surgeons assess the fitness of organs right up to the time they arrive in the operating room for transplant.

“We can maintain the organs for longer periods, which means we can retrieve them from a wider geographic area,” Dr. Dunning said. “And the condition of the organs at the time of transplant is better,” compared to the conventional method.

Dr. John Dunning, USF Health professor of cardiothoracic surgery at Tampa General Hospital, led the first Florida lung transplant using the OCS technology.

The conventional way involves covering the organ with preservation solution in a plastic bag and putting it on ice in a cooler, but this cold storage can limit tissue survival time, especially over long distances.  The OCS uses a different approach, transporting the organs at a warmer, near-normal body temperature.

The process has been shown to reduce the risk of rejection in lung transplants, and organs in some cases become healthier after being placed in the high-tech OCS machines.  For example, a potential donor who is on a ventilator in a hospital might develop fluid in their lungs as a side effect.  But this can clear up when the lung is placed in the OCS.  This improvement means more organs not considered healthy enough for donation in the past are likely to become medically suitable for transplantation to treat end-stage heart, lung or liver disease.

“We can actually monitor their function on the machine and see their function improving prior to transplantation,” Dr. Dunning said.

Each year, the number of patients on the waiting list continues to be much larger than both the slower growing number of donors and transplants. The U.S. Health Services & Resources Administration estimates 20 people die each day waiting for a transplant. Health professionals hope that new preservation technology like the OCS can safely reduce the dire shortage of lungs, hearts and other organs for transplantation, in part by making organs previously excluded due to age, oxygenation complications and other donor selection criteria acceptable.

Traditionally donor lungs come from deceased patients declared brain dead. But the OCS also allows lung transplants from patients after cardiac (circulatory) death, which could potentially expand the donor pool by 20 to 30 percent.

Dr. Dunning is Florida principal investigator for a multicenter post-approval study known as the OCS Lung TOP registry, which will track both the survival and outcomes of patients who receive transplants of OCS-preserved organs and the quality of the organs themselves. He is also among a handful of lead investigators from academic medical centers nationwide participating in a pivotal clinical trial to evaluate the safety and effectiveness of the OCS for heart transplantation after circulatory death.

His team searches beyond the hallmark Alzheimer’s disease proteins for alternative treatments

//www.youtube.com/watch?v=Hbl6gGddYpM

In his laboratory at the USF Health Byrd Alzheimer’s Center, neuroscientist David Kang, PhD, focuses on how different types of proteins damage the brain when they accumulate there. In the case of Alzheimer’s disease, decades of good science has zeroed in on amyloid and tau, as the two types of hallmark proteins driving the disease process that ultimately kills brain cells.

Dr. Kang and his team investigate molecular pathways leading to the formation large, sticky amyloid plaques between brain cells, and to the tau neurofibrillary tangles inside brain cells –including the interplay between the two proteins. But, he is quick to point out that amyloid and tau are “not the full story” in the quest to understand how normally aging brains go bad.

“Our goal is to understand as much of the entire Alzheimer’s disease process as possible and then target specific molecules that are either overactive or underactive, which is part of the drug discovery program we’re working on,” said Dr. Kang, professor of molecular medicine and director of basic research for the Byrd Alzheimer’s Center, which anchors the USF Health Neuroscience Institute.

Neuroscientist David Kang, PhD, (third from left)  stands with his team in his laboratory at the Byrd Alzheimer’s Center, which anchors the USF Health Neuroscience Institute.

Attacking dementia from different angles 

Dr. Kang’s group takes a multifaceted approach to studying the biological brain changes that impair thinking and memory in people with Alzheimer’s, the most common type of dementia, as well as Lewy body, vascular and frontotemporal dementias.

That includes examining how damaged mitochondria, the energy-producing power plants of the cell, contribute to pathology in all neurodegenerative diseases. “Sick mitochondria leak a lot of toxins that do widespread damage to neurons and other cells,” Dr. Kang said.

Dr. Kang’s team was the first to identify how mutations of a gene, called CHCHD10, which contributes to both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), cause both mitochondrial dysfunction and protein pathology called TDP-43. Their findings on the newly identified mitochondrial link to both neurodegenerative diseases were published in Nature Communications in 2017.

The role of selective degradation in ridding cells of abnormal proteins, old or damaged organelles (including mitochondria) and other debris is another key line of research pursued by Dr. Kang and colleagues.

A single stained nerve cell | Microscopic image courtesy of Kang lab

“We believe something more fundamental is going wrong in the brain during the aging process to tip the balance toward Alzheimer’s disease – beyond what we call proteinopathy” or deposits of malformed proteins like toxic amyloid and tau, said Dr. Kang, whose work is bolstered by nearly $8 million in grant funding from the National Institutes of Health (NIH), the Veterans Administration (VA merit awards) and the Florida Department of Health.

“I think one of the fundamental things happening is that the (cellular) plumbing system isn’t working to clear out all the accumulating junk,” he said. “That’s why we’re looking at the protective clearance mechanisms (autophagy and mitophagy) that would normally quickly remove misfolded proteins and dysfunctional mitochondria.”

Unfortunately, pharmaceutical trials to date have yielded no effective treatments for Alzheimer’s disease, the sixth leading cause of death in the U.S.  Most clinical studies have centered on developing medications to block or destroy the amyloid protein plaque formation, and a few have targeted the tau-containing neurofibrillary tangles. The five Alzheimer’s drugs currently available may provide temporary relief of symptoms, such as memory loss and confusion. But, they do not prevent or delay the mind-robbing disease as toxic proteins continue to build up and dismantle the brain’s communication network.

Lesson learned: The critical importance of intervening earlier

Some scientists argue that the “amyloid hypothesis” approach is not working. Dr. Kang is among those who maintain that amyloid plays a key role in initiating the disease process that leads to brain atrophy in Alzheimer’s – but that amyloid accumulation happens very early, as much as 10 to 20 years before people experience memory problems or other signs of dementia.

Early detection and treatment are key, Dr. Kang says, because as protein plaques and other lesions continue to accumulate in the brain, reversing the damage may not be possible.

“One reason we’ve been disappointed in the clinical trials is because so far they have primarily targeted patients who are already symptomatic,” Dr. Kang said. “Over the last decade we’ve learned that by the time someone is diagnosed with early Alzheimer’s disease, or even mild cognitive impairment, the brain has degenerated a lot. And once those nerve cells are gone they do not, for the most part, regenerate… The amyloid cascade has run its course.”

As protein plaques and other lesions continue to accumulate, becoming apparent with MRI imaging, reversing the damage may not be possible.  So, for anti-amyloid therapies – or even those targeting downstream tau – to work, patients at risk of Alzheimer’s need to be identified and treated very early, Dr. Kang said.

USF Health is recruiting healthy older adults with no signs of memory problems for a few prevention trials. A pair of Generation Program studies will test the effectiveness of investigational anti-Alzheimer’s drugs on those at high genetic risk for the disease before symptoms start. And, the NIH-sponsored Preventing Alzheimer’s with Cognitive Training (PACT) study is examining whether a specific type of computerized brain training can reduce the risk of mild cognitive impairment and dementias like Alzheimer’s disease in those age 65 and older.

To accelerate early intervention initiatives, more definitive tests are needed to pinpoint biomarkers that will predict Alzheimer’s disease development in genetically susceptible people. Dr. Kang is hopeful about the prospects.  His own team investigates how exosomes, in particular the lipid vesicles that shuttle proteins and other molecules from the brain into the circulating bloodstream, might be isolated and used to detect people at risk of proteinopathy.

“I think within the next five years, some type of diagnostic blood test will be available that can accurately identify people with early Alzheimer’s brain pathology, but not yet experiencing symptoms,” he said.

Graduate research assistant Yan Yan, a member of Dr. Kang’s research team, works at a cell culture hood.

Searching for alternative treatment targets

Meanwhile, Dr. Kang’s laboratory continues searching for other treatment targets in addition to amyloid and tau — including the enzyme SSH1, which regulates the internal infrastructure of nerve cells, called the actin cytoskeleton. SSHI, also known as slingshot, is needed for amyloid activation of cofilin, a protein identified by the USF Health neuroscientists in a recent study published in Communications Biology as a possible early culprit in the tauopathy process.

“Cofilin is overactive in the brains of Alzheimer’s patients so if we can inhibit cofilin by targeting slingshot, it may lead to a promising treatment,” Dr. Kang said.

Ultimately, as with other complex chronic diseases, Alzheimer’s may not be eliminated by a single silver-bullet cure.  Rather, Dr. Kang said, a combination of approaches will likely be needed to successfully combat the neurodegenerative disorder, which afflicts 5.8 million Americans.

“I think prevention through healthy living is definitely key, because brain aging is modifiable based on things like your diet as well as physical activity and brain exercises,” he said.  “Also, we need to focus on earlier diagnosis, before people become symptomatic, and develop next-generation drugs that can attack the disease on multiple fronts.”

Xingyu Zhao, PhD, a research associate in the Department of Molecular Medicine, is among the scientists in Dr. Kang’s laboratory studying the basic biology of the aging brain.

Fascinated by how the brain works — and malfunctions

Dr. Kang came to USF Health in 2012 after nearly 20 years as a brain researcher at the University of California San Diego, where he earned M.S. and PhD degrees in neurosciences and completed NIH National Research Service Award fellowships in the neuroplasticity of aging.

As an undergraduate Dr. Kang switched from studying engineering to a dual major in science/psychology. He began focusing on neurosciences in graduate school, he said, because tackling how the brain works and malfunctions was fascinating and always challenged him.

“With every small step forward, we learn something else about the basic biology of the aging brain,” said Dr. Kang, “It’s not just helpful in discovering what therapeutic approaches may work best against Alzheimer’s disease – we’re also learning more about other neurodegenerative conditions affecting the brain.”

In addition to leading day-to-day research operations at the Byrd Center and helping to recruit new Alzheimer’s investigators, Dr. Kang holds the Mary and Louis Fleming Endowed Chair in Alzheimer’s Research and serves as a research neurobiologist at the James A. Haley Veterans Haley Veterans’ Hospital.

He has authored more than 50 peer-reviewed journal articles on brain aging and Alzheimer’s disease research. A member of the NIH Clinical Neuroscience and Neurodegeneration Study Section since 2016, he has served on multiple national and international editorial boards, scientific panels and advisory boards.

Dr. Kang sits next to a computer monitor depicting stained microscopic images — a single neuron (far left) and the two hallmark pathological proteins for Alzheimer’s disease, tau tangles (center) and amyloid plaques (right).

Some things you may not know about Dr. Kang

• His parents were Presbyterian missionaries in Africa, so he spent nine years of his early life (third through 10^th grade) in Nigeria.
• Dr. Kang practices intermittent fasting, often forgoing breakfast and eating only within an 8-hour window. Animal studies indicate the practice may contribute to lifespan and brain health by improving cellular repair through the process of autophagy, he said. “Autophagy really kicks your cells’ plumbing system into gear to clear out all the waste.”

-Video and photos by Allison Long, USF Health Communications and Marketing

A Jan. 31 open house highlighted services and resources of the Morsani Center’s expanded Clinical Research Center – for the benefit of faculty investigators and patients.

As USF Health’s overall research portfolio grows, the space, services and resources dedicated to clinical trials have also expanded.

Last fall, the Clinical Research Center (CRC), where USF Health faculty conduct clinical trials testing new ways to diagnose, treat and prevent human disease, moved from the first to the fourth floor of the Morsani Center for Advanced Healthcare.  The relocation and reconstruction nearly tripled the size of the center’s footprint to 4,500 square feet – a much-needed expansion since last year USF Health attracted a record $14.7 million in clinical trial revenue, up 133 percent over the last five years ($6.3 million in FY 2013-14).

USF Health leaders, faculty and staff will officially celebrate the launch of the new CRC on Jan. 31 with an open house for clinical investigators and staff, both those who currently use the center, and those faculty interested in finding out more about the space, technology and the on-site CRC team to support clinical trials.

USF Health neurologist Derrick Robertson, MD, a leading clinical investigator at the Morsani Center-based Clinical Research Center, speaks with a patient participating in a multiple sclerosis continuation drug trial.

The following are just some of the services and resources offered by the new and expanded CRC:

• Five examination rooms and six infusion rooms designed for patient comfort, with reclining chairs, televisions and computer work stations.
• A laboratory equipped to store, process and monitor specimens, and an area for secure investigational drug/product storage.
• Highly trained team of nurse managers, research nurses, study and regulatory coordinators to support study investigators.
• Open space equipped with computers, phones and other business amenities to accommodate faculty investigators and their departmental research staff.
• Support by the Office of Clinical Research to assist with business operations and/or financial services at all stages of non-federally sponsored clinical research studies.

Dr. Robertson reviews patient study-entry criteria with Carrie Downey (left), DO, a neurology fellow specializing in multiple sclerosis, and Angela Aungst, MPH, assistant director of MS clinical research.

USF Health has significantly upgraded its laboratories, equipment and other research infrastructure over the last several years – and clinical research growth continues to be a vital component of that investment.

Stephen Liggett, MD, associate vice president for research at USF Health and vice dean for research at the Morsani College of Medicine, attributes the growth to increased interest and training in clinical research by USF Health physicians as well as the dedication of administration and a top-notch team of CRC staff.

Faculty currently conduct 315 active trials — sponsored by industry, biopharma or foundations – testing new drugs, devices or other therapies for conditions ranging from Alzheimer’s disease and congestive heart failure to Parkinson’s disease, multiple sclerosis, and more.

Dr. Liggett expects clinical research activity to be even stronger in 2019.

“As an academic medical center, we are committed to understanding and solving the vexing clinical problems that elude us,” he said. “Rigorous clinical research encourages translational research, moving basic science discoveries in model systems to investigations focused on improving patient care and outcomes.”

USF Health neurologist Derrick Robertson, MD, one of the CRC’s top users, advocates for more faculty to take advantage of the center’s highly trained on-site support team and resources to conduct safe, controlled and compliant clinical trials.

Clinical research coordinator Brittany Harvey works in the new laboratory space at the Clinical Research Center.

Dr. Robertson, director of the USF Multiple Sclerosis Center, and his team participate in several trials testing new treatments for multiple sclerosis. He was the Tampa Bay region’s lead investigator for clinical studies of the intravenous medication ocrelizumab, which in 2017 became the first FDA-approved drug to slow progressive disability in a particularly aggressive form of multiple sclerosis called primary progressive MS.

“USF was one of the top-enrolling sites in the country, and our patients were part of the science that led to that game-changing drug getting approved.  The Clinical Research Center played a key role in facilitating that,” said Dr. Robertson, who continues ongoing studies of the MS drug, known commercially as Ocrevus.

In addition to the Morsani Center-based CRC, faculty lead clinical trials at Tampa General Hospital, the USF Health Neuroscience Institute (Byrd Alzheimer’s Institute and Center for Parkinson’s Disease and Movement Disorders), the South Tampa Center for Advanced Healthcare, the Hillsborough County Health Department, and the USF All Children’s Research Institute.

Ray Schneider (right), MS team research coordinator for the Department of Neurology, assesses the gait of a patient during a walk down one of the CRC hallways.

The volume of clinical trials at USF Health has climbed steadily over the last several years.

Stephen Liggett, MD, (right) associate vice president for research at USF Health, speaks with Charles Lockwood, MD, (center) senior vice president for USF Health and Morsani College of Medicine dean, and Kevin Sneed, PharmD, dean of the USF College of Pharmacy, during a tour of the new CRC space.

The CRC tripled in size and expanded resources with its recent relocation to remodeled space on the Morsani Center for Advanced Healthcare’s fourth floor.

-Photos by Torie M. Doll and graphics by Cynthia Greco, USF Health Communications and Marketing

USF researchers and clinicians heard valuable ideas for connecting with community groups and recruiting more minorities for clinical trials when they attended a community advocacy workshop earlier this month.

The program was an exercise offered by USF Health WE-CARE, an initiative that aims to improve health outcomes among minority populations by increasing minority enrollment and participation in research.

“We are going to cast a broad net to all groups to make sure we are making every attempt we can to capture people and introduce them to your research,” said Kevin Sneed, PharmD, dean of the USF Health College of Pharmacy, senior vice president of USF Health, and director of WE-CARE (Workgroup Enhancing Community Advocacy and Research Engagement).

“We have to build trust and co-create solutions. And we need all of you, the researchers and the community, to shorten the bridge that will get us together and make sure we’re communicating.”

Dr. Kevin Sneed welcomes attendees at the WE-CARE, CAM workshop.

WE-CARE is helping build part of that bridge by connecting clinical researchers with community groups in hopes that more minorities will enroll in research. Clinical trials have historically lacked participation by people from minority populations, skewing research results to reflect presumed outcomes for predominately white and male populations. While African-Americans, Latinos, Asians and mixed sub-groups make up almost 40 percent of the U.S. population, current clinical trial demographics do not reflect that same diversity – non-whites account for less than 5 percent of clinical trial participants.

This narrow pool of DNA variants equates to limited samples for researchers to study as they develop new treatments, and thus limit information on the true effectiveness and on the risks of these treatments in minorities.

WE-CARE, CAM workshop panelists.

Part of the WE-CARE mission is to act as a resource for reviewing research studies and guiding researchers in potential ways of adjusting their effort to incorporate more minorities in their studies. Researchers can submit an abstract to WE-CARE, which goes to the group’s review board and, if approved, WE-CARE will help connect with Tampa Bay area community groups to help with recruitment.

“We can help you find people from underserved, underrepresented groups here in the Tampa Bay area,” Dr. Sneed said to the audience that included many researchers from USF Health and Moffitt Cancer Center.

Both Dr. Sneed and program panelists – made up of leaders from community advocacy groups and non-profit organizations from across the Tampa Bay area – urged researchers in the audience to remain cognizant of the patient’s perspective and to always consider them as individuals.

“The number one thing you can do is to buy into their humanity first,” Dr. Sneed said.

The Nov. 2 workshop was the second event hosted locally aiming to advance clinical research by increasing minority enrollment. About three years ago, a similar workshop was hosted, inspired by and in partnership with 50 Hoops, a national effort for outreach focused mostly on increasing minority male enrollment in clinical trials for prostate cancer. The recent workshop hosted by WE-CARE is based on the CAM model (Community Advocacy Matchmaking) designed by 50 Hoops.

Another concern voiced at the workshop was lack of follow through, and that if researchers want more minority enrollment they will have to engage far more frequently.

“Report back,” Dr. Sneed urged everyone researcher in the room.

“The number one complaint (I hear) is that researchers came into a community, collected, and never came back into the community to give an update. They never heard the result of anything.”

Photos by Eric Younghans, video by Torie Doll, story by Sarah Worth.

The time between diagnosis and the beginning of symptomatic treatment is critical in the effort to find a cure for Parkinson’s disease (PD). A paper published in npg Parkinson’s Disease, a Nature Partner journal, notes too many early PD patients wait too long before seeking medical attention, or start taking symptomatic medications before they are required, thereby dramatically shrinking the pool of candidates for clinical trials.

Parkinson’s disease is a disorder of the central nervous system that affects movement. Symptoms include tremors, stiffness, and slow and small movements. The pace of progression varies among patients, making the months following diagnosis crucial to researchers studying the disease’s progression.

Robert Hauser, MD

“The critical time of about one year from when the patient can be diagnosed with early PD based on mild classic motor features until they truly require symptomatic therapy can be considered the Golden Year,” said lead author Robert A. Hauser, MD, director of the Parkinson’s Disease & Movement Disorder Center, based at the USF Health Neuroscience Institute. “It is during this early, untreated phase, that progression of clinical symptoms reflects the progression of the underlying disease.”

Dr. Hauser says that in order to determine whether or not a potential disease slowing therapy is actually working, clinical researchers must be able to compare the therapy to a placebo without interference from symptomatic treatment. Otherwise, they won’t know if the therapy is slowing the disease’s progression or if they are just seeing the effects of symptomatic treatment.

This requires patients to seek assessment soon after they notice the onset of tremor or slow movement. In addition, physicians should consider referring patients to clinical trials soon after diagnosis and delay prescribing symptomatic medication until it’s needed. If a patient waits until symptomatic treatment is necessary, the opportunity to participate in these crucial clinical trials is lost.

The Healthcare Imaginarium for Exponential Technologies, or HIETs is the brainchild of visionary College of Pharmacy Dean Kevin Sneed

Kevin Sneed, PharmD, (standing right) dean of the USF College of Pharmacy, spoke about how exciting new technologies would be integrated into the college’s currriculum starting this fall.

TAMPA, Fla. (Feb. 22, 2018) — USF Health’s Pharmacy Dean Kevin Sneed, PharmD, announced this week several key initiatives intended to integrate advanced technologies into the student curriculum and to keep the college at the cutting-edge of innovation in education, research and patient care. He spoke Feb. 20 to a gathering of business and community leaders, as well as students, faculty and staff.

“We want our USF College of Pharmacy to remain relevant not only today, but for the next 25 years,” Dr. Sneed said.  “Right from the beginning, our mission has been to revolutionize health through innovation and empowerment… Now is the time to reimagine what education will be moving into the future.”

The initiatives are part of a newly created Healthcare Imaginarium for Exponential Technologies or HIETs.   They include the introduction in fall 2018 of virtual reality content to supplement existing curriculum and help make the learning experiences of USF pharmacy students more immersive and life-like than textbooks, online content and traditional videos.

Many of those gathered used mobile device technology to record the event.

Students will put on special eyewear to view computer-generated images they could interact with. So for instance, they might experience in 360-degree, three-dimensional context the growth of plaques in coronary arteries and what happens when a stent is inserted to clear a clogged artery.  In yet-to-be-developed ways, virtual reality technology may also seamlessly combine pharmacology with physiology to simulate the effects of treatment. For example, students could visualize in real-time the action on smooth muscle airways when a bronchodilator drug is inhaled by an asthma patient. Such advanced technology could also be harnessed by health professionals as a more engaging way to educate patients about their diagnoses and care, Dr. Sneed said.

The College of Pharmacy plans to work with MediaLab 3D Solutions, a Tampa-based digital content creator, and BioLucid, a digital health company recently acquired by Sharecare, to develop a combination of virtual, augmented and mixed reality content.

USF pharmacy student Natalie Dehaney demonstrates how virtual reality technology allows students to visualize what happens inside the body when a patient experiences atrial fibrillation. She can trigger and replay the simulation of electrical conduction in the heart. 

MediaLab CEO Bruce VanWingerden said the project will be the first time the company, which works with major corporations, has ventured into academia. “This is an exciting opportunity to work with Dr. Sneed and his staff to really look at different ways to present in a new and exciting fashion information that can be difficult to convey,” VanWingerden said. “We want to take all the innovative technology and make it easy to use to further the educational process.”

Laysa Mena, a student delegate for the College of Pharmacy, describes herself as a “visual learner” who absorbs more by seeing than reading. “So I feel implementing virtual reality with our curriculum would be very beneficial and give us a better appreciation of how drugs work in the body,” she said.

Dr. Sneed announced a key initiative known as the Botanical Medicinal Research Consortium, which will team USF researchers and clinicians with local companies to conduct evidence-based  clinical research on whether non-euphoric forms of cannabis may benefit patients with certain diseases.

Another key initiative, known as the Botanical Medicinal Research Consortium, or BMRC, will bring together researchers and clinicians in USF’s colleges of pharmacy and medicine, the university’s Center for Drug Discovery & Innovation, and businesses in Tampa Bay and beyond to conduct rigorous studies on the safety and effectiveness of medical cannabis and other plant derivatives.

Many unanswered questions remain about the potential of cannabinoids, the active chemical found in the plant and elsewhere, to treat various diseases or conditions like chronic pain. The USF College of Pharmacy wants to take the lead in conducting top-quality research on medical cannabis and find the correct noneuphoric formulations that may benefit patients and their overall health, Dr. Sneed said.

Mark Kindy, PhD (left), professor of pharmaceutical sciences, is the College of Pharmacy’s liaison for the Botanical Medicinal Research Consortium, and Kevin Olson, PharmD, MBA, assistant professor of biopharmaceutics and clinical research, is the liaison for the Entreprenerial Academy, a collaboration with the Muma College of Business. 

“Plant-derived compounds are the future of medicine, and we’re looking forward to collaborating with the University of South Florida in this area,” said Garyn Angel, chief strategy officer for ANANDA Scientific, a company that produces nonpsychoactive and nonabusive oral cannabinoid health products. “Evidence-based clinical research is needed for cannabinoids to enter Western medicine.”

Dr. Sneed also announced that the BMRC would collaborate with the UCLA Cannabis Research Initiative at the UCLA Semel Institute for Neuroscience and Human Behavior, one of the first academic programs dedicated to investigating cannabis to lead public policy and public health decisions.

Other HIETs initiatives include:

• With the College of Engineering, USF Pharmacy will work to advance personalized medicine that tailors therapy based on an individual’s genetic makeup. As the technology of medicine and drug development continues to shrink down to the nanoscale, USF has also started a Pharmaceutical Nanotechnology master’s program to teach students how to deliver medications in new, more precise ways.

• The College of Pharmacy will join forces with the Muma College of Business to create an Entrepreneurial Academy that inspires innovation and start-up companies.  The aim is to help pharmacists think like entrepreneurs so they can better enhance heath care outcomes and cost-effectiveness.

• Clinical trials: Through its WE-CARE program (Workgroup Enhancing Community Advocacy and Research Engagement), the College of Pharmacy partners with key stakeholders to increase participation of minority and medically underserved populations in clinical trials.  The program seeks to ensure that all communities have access to genomic clinical research as technology advances.

-Photos by Torie Doll, USF Health Communications and Marketing

//www.youtube.com/watch?v=8EGW58Uq-Yk

Patients have always been the center of the yearly scientific symposium hosted by the Friedreich’s Ataxia Research Alliance (FARA) and the University of South Florida Ataxia Research Center.

But, for the 8^th annual symposium held Sept. 15 at USF’s Gibbons Alumni Center, patients took on an even more prominent role. The panel discussion in which they share their stories about living with the rare, but devastating, progressive neurodegenerative disease, including patient participation in clinical trials, was moved up in the program format.

The 8th annual scientific symposium hosted by FARA and USF was held in the USF Gibbons Alumni Center.  More than 750 in the FA community listened to the latest perspectives on ataxia research from patients and scientists, in person and internationally via live-stream.

And this year, led by FARA spokesperson Kyle Bryant as moderator, the four patient panelists were the ones driving the conversation with leading researchers from academia and industry who sat onstage beside these young adults to discuss the latest advances in the search for effective treatments and, ultimately, a cure.

More than 250 attendees gathered at the USF Gibbons Alumni Center for the symposium, which was also live-streamed and viewed worldwide by those in the FA community, over 500 people in eight countries. The symposium “Understanding Energy for a Cure” kicked off a series of events in Tampa Bay to raise awareness about FA, culminating Sept. 17 with the FARA Energy Ball gala, which this year raised $2 million to benefit innovative ataxia research.

The patient panel, moderated by FARA spokesperson Kyle Bryant (far left), helped drive the conversation with leading researchers. Participants were, from left, Alex Fielding, Sean Baumstark, Alison Avery and Anna Gordon.

“My parents and sister never really let me believe that Friedreich’s ataxia was going to stop me,” said panelist Alison Avery, 22, diagnosed with Friedreich’s ataxia at age 18, who is interning with the National Football League’s social responsibility department in NYC following college graduation. “It may have changed the way that I do certain things, but right now I’m living on my own in New York City, and that’s something not everyone would do, whether or not they have FA.”

Alison participates in the “Cardiac MRI and Biomarkers in Friedreich’s Ataxia” study at Children’s Hospital of Philadelphia and another evaluating the relationship between exercise performance and neurological/cardiac status and overall functioning in children and adults with FA. “I’m excited to be able to share my perspective on being involved in different research studies,” she said. “I feel like that’s something more people should know, especially the researchers — about how patients actually feel about trials and studies.”

USF System President Judy Genshaft said USF has made neurosciences, including ataxia research, a high institutional research priority.

Friedreich’s ataxia typically strikes in childhood or adolescence and leads to a progressive loss of coordination and muscle strength, eventually robbing young people of their energy and ability to walk. While the neurological symptoms are most visible, FA is a multisystem disease that can adversely affect cardiac function, metabolism, vision, hearing and the skeletal system. There is currently no approved treatment for FA.

“Throughout the history of this event, the one constant has been how incredibly motivating and inspiring it is to hear from patients and their families who never fail to share one valuable message: ‘Live life to its fullest despite the challenges of Friedreich’s ataxia,’” said USF System President Judy Genshaft in her symposium welcome remarks.

FARA Executive Director Jennifer Farmer introduced the patients and provided insights on their participation in studies and clinical trials.

The USF Health Morsani College of Medicine is one of 10 sites in the international FARA Collaborative Clinical Research Network, all working to discover treatments that can attack FA on different fronts and improve the quality of life for patients.

“We’ve made this a high research priority within the institution,” President Genshaft said. “Over the last 20 years FARA’s international collaborative of researchers has increased the pace in the fight against FA. Today more than 20 drugs are in the treatment pipeline and ongoing studies are working toward the discovery of new therapies… We have every reason to be hopeful, but we do know there is more work to be done.”

Theresa Zesiewicz, MD, professor of neurology and director of the USF Ataxia Research Center, presented promising preliminary results from two clinical trials conducted at USF, among other sites. – Photo by Kent Ross

Theresa Zesiewicz, MD, professor of neurology and director of the USF Ataxia Research Center, updated attendees on the center’s initiatives.

“We started out at USF with one clinical trial eight years ago, and now we have five or six clinical trials and each (investigational) drug works differently,” Dr. Zesiewicz said. “Some drugs work to increase frataxin (the protein depleted in those with FA), some drugs work on inflammation, some work as strong antioxidants. So, there may not be one magic bullet to stop this disease; rather, it may require a cocktail of therapies, a conglomerate of different compounds to help delay or stop the disease process.”

David Lynch, MD, PhD, (center) lead investigator for the FA Natural History Study at Children’s Hospital of Philadelphia, responds to a patient question. He was joined in the discussion of clinical trials by Martin Delatycki, PhD, (far left) of Murdoch Children’s Research Institute, Melbourne, Australia.

Some promising preliminary results for two clinical trials conducted at USF, among other sites, were announced by lead investigator Dr. Zesiewicz. Both studies were done in collaboration with FARA.

• EPI-743 Safety and Effectiveness Study: The Phase 2 open-label extension study, sponsored by Edison Pharmaceuticals, tested the effectiveness of the potent antioxidant EPI 743 primarily on vision, and secondarily, on neurological function in adult patients with FA. After two years of study and a year of data analysis, the researchers found that patients taking EPI-743 from the study’s start demonstrated markedly less disease progression than would be expected in the natural history of the disease. The improvement in neurological function was dose-dependent, and although the last 18 months of the study were open-label, patients and investigators were blinded to the drug dose allocation. Additional studies of EPI-743 are planned in pediatric patients and those with point mutations.

FARA President Ron Bartek thanked everyone in the room, including researchers, pharmaceutical partners and patients and their families, for working together to advance discoveries to “slow, stop and reverse” Friedreich’s ataxia.

• Retrotope RT001 Phase 1/2: The randomized double-blind, placebo-controlled trial evaluated the safety, tolerability and early effectiveness of the stabilized fatty acid RT001 in adult patients with FA. In the small, 28-day study, researchers found that the drug was safe, well tolerated at high doses and rapidly absorbed to target levels, with early signs of effectiveness. Earlier this year, the FDA granted Retrotope orphan drug designation for RT001 in FA.

The scientist and physician panelists at the symposium covered four areas of FA research:

• Basic and Discovery Science: Helene Puccio, PhD; Marek Napierala, PhD; and Jordi Magrane, PhD
• Drug Development and Advancing Treatments: Mark Payne, MD; and Barry Byrne, MD, PhD.
• FA Biomarkers: Kimberly Lee Lin, MD; Angel Martin, PhD student; and Christophe Lenglet, PhD.
• Clinical Trials and Translating Treatments to Improved Care: Martin Delatycki, PhD; and David Lynch, MD, PhD.

The researchers discussed their scholarly work, progress beyond their laboratories and its relevance to advancing treatments. They also emphasized their passion for FA science and personal commitment to patients.

Scientists participating in the Basic and Discovery Science panel discussion were, from left, Jordi Magrane, PhD, of the Brain and Mind Research Institute, Weill Cornell Medical College; Marek Napierala, PhD, of the University of Alabama; and Helene Puccio, PhD, of the Institute of Genetics and Molecular and Cellular Biology, University of Strasbourg.

Moving from treating symptoms to slowing and stopping progression to reversing disease is “not an overnight event,” said David Lynch, MD, PhD, lead investigator for the FARA Natural History Study at Children’s Hospital of Philadelphia. “So, in 15 years we may look back and talk not about the advance but about the 15 advances from each of 15 clinical trials superimposed on top of one another, eventually leading to that four letter word — cure.”

Answering patient questions on drug development and advancing treatments were physician-scientists Barry Byrne, MD, PhD, (left) of the University of Florida College of Medicine; and R. Mark Payne, MD, of Indiana University School of Medicine.

Despite the challenges, the researchers agreed that the steadfast determination and resilience of patients and their families energizes them to keep working toward a cure.

“Everything we do is for the patients, and we are all in this together trying to find a treatment and cure for Friedreich’s ataxia,” said USF’s Dr. Zesiewicz. “That’s the only reason we’re here.”

Participants in the FA BioMarkers panel discussion were, from left, Kimberly Lee Lin, MD, of Children’s Hospital of Philadelphia; Christophe Lenglet, PhD, of the Institute for Translational Neuroscience, University of Minnesota; and Angel Martin, a PhD candidate at Duke University.

Alison Avery, second from right, credits her family — sister Laurel Avery (left) and parents Paul and Suzanne Avery — with “never really letting me believe that Friedreich’s ataxia is going to stop me.”

Dr. Zesiewicz with members of the USF Ataxia Research Center, one of 10 sites in the international FARA Collaborative Clinical Research Network. – Photo by Kent Ross

Photos by Eric Younghans and video by Sandra C. Roa, USF Health Communications and Marketing