USF Health Morsani College of Medicine immunologist Kenneth Ugen, PhD, participated in a new study demonstrating how a synthetic DNA vaccine approach successfully protected against infection, brain damage and death caused by the mosquito-borne Zika virus in vivo.

Dr. Ugen, a professor in the Department of Molecular Medicine, was a co-investigator for the preclinical study, recently published in the journal Nature: npj Vaccines. David B. Weiner, PhD, executive vice president and director of the Vaccine Center at The Wistar Institute in Philadelphia, was the study’s lead author.

“The paper published presents a study demonstrating the ability of a gene-based vaccine against a Zika virus protein to successfully protect mice from infection with this virus and associated damage,” Dr. Ugen said.

In this multisite study, 100 percent of the animal models were protected from Zika after vaccination followed by a challenge with the Zika virus. In addition, they were protected from degeneration in the cerebral cortex and hippocampal areas of the brain, while the other cohort showed degeneration of the brain after Zika infection.

A microscopic image of the Zika virus.

The research was the first of its kind to analyze a vaccine in an animal model that is susceptible to the disease, providing information regarding the protective impact of the immune response in susceptible individuals. Prior studies of the Zika virus have tested vaccines in animal models that are naturally resistant to Zika. This study extends these prior research studies in an important manner.

In this latest study, Weiner and colleagues demonstrated how a synthetic DNA vaccine expressed specific antigens for Zika in vivo. They observed that this novel vaccine generated robust antigen-specific antibody and T cell responses that neutralized the virus in preclinical animal models. Moreover, they found that the vaccine provided protection against the disease and death in animal models while also being neuroprotective, meaning that the disease was unable to spread to the brain. This is especially important given the risk that infants born with the disease have of developing microcephaly, a birth defect resulting in an abnormally small head and that may prevent the brain from developing properly.

Ken Ugen, PhD

One important aspect of Zika and many other mosquito-borne diseases is that not everyone infected with the virus will actually become ill as a result. With Zika, only about 20 to 25 percent of individuals with the virus are actually impacted by the disease, according to previous studies from the U.S. Centers for Disease Control (CDC). However, there is no way to know for certain who will be at risk for illness due to the virus, which is why it was crucial for this study to examine how a vaccine would operate in an infected, symptomatic host.

This Zika vaccine was developed by investigators at the Wistar Institute and Inovio Pharmaceuticals, with contributions from other investigators at multiple institutions. The vaccine has been approved by the FDA for clinical evaluation in Phase I clinical trials now being conducted in several U.S. and Canadian cities as well as in Puerto Rico.

Nearly 4,000 cases of Zika infection have been reported in the United States alone, according to the CDC. While most of these are travel-associated cases, more than 100 cases of Zika infection originating within the United States have been reported. Globally, more than 60 countries have reported mosquito-borne transmission of the disease.

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This work was supported by the National Institutes of Health and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases grant NIH R01 AI092843. Weiner received funding from Inovio Pharmaceuticals Inc. and Gene One Life Science Inc.

Lithium salicylate produced steady blood and brain lithium levels up to 48 hours following oral dose, the recent preclinical study showed

Tampa, FL (March 11, 2014) – Lithium, one of the oldest and most widely used drugs to treat neuropsychiatric illnesses, such as bipolar disorder, has a serious drawback – toxicity. In a continued effort to find a safer form of lithium, researchers at the University of South Florida (USF) have discovered that lithium salicylate, an alternative salt form, might be the answer.

The researchers found that oral lithium salicylate produced steady lithium levels up to 48 hours in rats without the toxic spike associated with the rapid absorption of current FDA-approved lithium carbonate.  They concluded that lithium salicylate could be more effective than lithium carbonate, yet without accompanying risks of toxicity, a potentially important development in the next generation of lithium therapeutics.

Their study results appeared in a recent issue of RSC Advances, the journal of the Royal Society of Chemistry.

Douglas Shytle. left, and Adam J. Smith, of the Center of Excellence for Aging and Brain Repair at USF Health, are working on reducing the toxicity of lithium, a drug used to treat bipolar disorder, while enhancing its therapeutic window.

While lithium carbonate has been very effective for the treatment of mania in bipolar disorder, and credited for reducing suicides in depressive phases of the disease, patients who take lithium carbonate are often noncompliant because of adverse effects, including hand tremor, diarrhea, vomiting, weight gain and decreased thyroid function. New drugs that are as effective as lithium carbonate, but without toxicity, have not been forthcoming.

“Despite its narrow therapeutic window and the emergence of proprietary alternatives, U.S. FDA-approved lithium therapeutics are still regarded as the ‘gold standard’ for the treatment of the manic phase of bipolar disorder,” said study lead author Adam J. Smith, PhD, a neuroscientist at the Center of Excellence for Aging and Brain Repair, Department of Neurosurgery, at USF Health.

“Our previous research suggested that re-engineering lithium therapeutics by crystal engineering might produce better performance with reduced toxicities.”

Crystal engineering is the design and synthesis of molecular solid crystal structures with desired properties using intermolecular interactions, Smith said.

The monitor behind Smith in the microscopy lab shows the image of a crystal.

For their latest study published in RSC Advances, the  researchers tested two previously untested salts of lithium — salicylate and lactate — both of which are structurally different from lithium carbonate. In laboratory rats, they found that lithium salicylate and lithium lactate exhibited “profoundly different pharmacokinetics” when compared to the FDA-approved and widely used lithium carbonate. Pharmacokinetics is the way the body absorbs, distributes and gets rid of a drug.

“To our knowledge, this is the first pharmacokinetic study of lithium salicylate and lithium lactate in laboratory animals,” Smith said.

The findings support earlier suggestions that an ideal lithium preparation would be one that would both “flatten” high blood level peaks and also slow declining blood concentrations, the researchers report.

“This is exactly the pharmacokinetic profile produced by lithium salicylate in our study,” said senior author Doug Shytle, PhD, also of the Center of Excellence for Aging and Brain Repair at USF Health. “Remarkably, lithium salicylate produced elevated levels of lithium in the blood and brain 48 hours after the dose, but without the sharp peaks that contribute to the toxicity problems of lithium in the currently used form.”

That 48-hour window, the researchers said, represents a critical difference between lithium salicylate and current FDA-approved lithium therapeutics. If these preclinical results hold true in humans, this would allow for a less frequent dosing regimen and possibly fewer troublesome side effects that plague conventional lithium therapy.

“Psychiatry has long struggled with the fact that, while lithium is highly effective for treating bipolar disorder, the narrow therapeutic window and side effect profile often makes lithium both difficult and sometimes dangerous to work with clinically,” said Todd Gould, MD, of the Department of Psychiatry at the University of Maryland, an expert in the mechanisms of lithium and the neurobiology of bipolar disorder.

“The pharmacokinetic data by Dr. Smith and colleagues suggests that lithium salts other than the commonly used lithium carbonate may have a broader therapeutic window and potentially fewer side effects. Studies in humans will be needed to confirm safety and demonstrate that the pharmacokinetic profile observed in rats is similarly observed in humans.”

USF researchers continue to pursue a safer, more effective lithium therapy, and expect to soon conduct the experiments required to support early clinical trials.

A link to their full study in RSC Advances can be found here: http://pubs.rsc.org/en/content/articlelanding/2014/ra/c3ra46962j#!divAbstract

Smith, A. J., S. Kim, J. Tan, K. B. Sneed, P. R. Sanberg, C. V. Borlongan and R. D. Shytle (2014). “Plasma and brain pharmacokinetics of previously unexplored lithium salts.” RSC Advances 2014, 12362–12365. 

-USF Health-

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Media contact:
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(813) 974-3303 or abaier@health.usf.edu