UT Health San Antonio urologist demonstrates potential of valproic acid-DHA in lessening risk of contracting COVID-19
When the world locked down due to the COVID-19 pandemic in 2020, rather than slowing down, this distinguished urologist and medical educator merely switched gears.
Ronald Rodriguez, MD, PhD, is a professor of medical education and urology at Joe R. and Teresa Lozano Long School of Medicine, The University of Texas Health Science Center at San Antonio (UT Health San Antonio) specializing in the treatment of prostate, kidney and bladder cancers.
His study, published Aug. 2 in PLOS ONE, demonstrates how the combination of a common anti-seizure medication and simple dietary supplement could be a powerful tool in lowering the risk of contracting COVID-19 or lessening the virus’s severity.
In the 1990s, Rodriguez developed a recombinant adenoviral system targeted for prostate cancer.
“That forced me to learn some virology and in order to do recombinant adenoviral work, I actually had to understand how viruses replicated and how they worked in general,” Rodriguez said.
He came to The University of Texas Health Science Center at San Antonio in 2013, to serve as chairman of the urology department. In 2017, he was named the interim dean for the Joe R. and Teresa Lozano Long School of Medicine. Newly mantled with administrative duties, Rodriguez’s research was largely put aside.
A rapid series of events changed all of that.
Just weeks into his term as interim dean, Rodriguez developed acute kidney failure and was hospitalized. Within a year, he lost nearly all kidney function and was placed on a transplant list.
Shortly after his kidney transplant, the COVID-19 pandemic hit in 2020.
“The whole world was locked down and as a transplant recipient, I was particularly concerned that I would be a high risk for death or complications if I were to get COVID,” Rodriguez said.
Instead of dwelling on what he could not do, Rodriguez instead turned his eye to learning everything he could about COVID-19 and what could be done about it.
“It became a world problem and even though it was not my area of expertise, I had much to gain from it, as well as everyone else in the world,” he said.
Rodriguez aimed to find a potential treatment that was both effective and affordable on a large scale.
Antiviral potential of valproic acid
Some of his previous studies in prostate cancer gene therapy demonstrated certain pathways that could inhibit the replication of viruses. There are many different viruses that work on various pathways, so Rodriguez focused his efforts on the pathways that had similar patterns to coronaviruses.
Valproic acid is a Food and Drug Administration-approved drug commonly prescribed for treatment of seizures or bipolar disorder. For years, it was thought to be inert and was used as a carrier for other medications until its anti-convulsant properties were discovered in the 1960s.
Rodriguez did some initial tests with valproic acid, a drug he previously studied for prostate cancer gene therapy. He found the drug could effectively inhibit coronavirus replication, but it took a massive dose that would potentially be toxic and not feasible for widespread use.
He applied for a grant to further the investigation but was turned down.
“Nobody believed it was going to work,” he said.
Dismayed, but not dissuaded
In a unique twist of fate, a grateful former patient of Rodriguez’s, Abe Littenberg, through the Abe Littenberg Foundation, provided financial support for this research. In 2020, the Foundation formed a committee of three people – Jeff Bodycomb, Mark Litwack and Littenberg who ultimately decided to fund the study. Littenberg said the choice was made because the Foundation could act quickly to help initiate this time-sensitive research; private funding was better suited for this risky but potentially high-reward pilot study; and the idea was something that could potentially be an inexpensive solution that could benefit the whole world.
“Dr. Rodriguez was transparent with us concerning the hurdles that would be encountered due to working beyond the traditional line of a urologic scientist. Nevertheless, we had faith and trust in the team and the potential was so important. We are humbled and grateful to be associated with Dr. Rodriguez’s research and we are so proud of him and the team that accomplished this study and a paper that was accepted for publication,” Littenberg said.
Could it work on COVID?
Rodriguez began with testing viral replication of a less severe form of coronavirus. In the lab, he successfully demonstrated molecular pathways that the virus was sensitive to, but if the drug could not work in a human at a reasonable dose, the drug was not going to be useful.
He then contacted Pankil Shah, MD, PhD, MSPH, assistant professor in the Department of Urology, Division of Research, co-first author for this study, data scientist and informatician, to explore a national patient database of medical records for people that tested positive for COVID-19. Shah said he leveraged the OptumInsight Life Sciences, Inc. electronic medical records (EMR) data of more than 3 million patients.
“We looked for epidemiological evidence of a protective association between valproic acid therapy and the development of COVID-19 infection,” Shah said.
The study team also investigated if people taking valproic acid who tested positive for COVID-19 were less likely to be admitted to the emergency room, inpatient hospital and intensive care unit (ICU).
There was a statistically significant difference in these factors for patients who listed valproic acid as a current medication.
Rodriguez then requested several months of valproic acid levels pulled for anyone testing for it at a large clinical laboratory network. He was surprised to find that only about a quarter of the individuals had valproic acid levels within the dosage range he predicted would have an impact on viral replication.
“Our findings spurred further basic science research in Dr. Rodriguez’s lab to understand the biological mechanism at the molecular level that would explain the effects observed in the real-world evidence. The epidemiological real-world evidence and the basic science mechanistic findings are presented in this manuscript together. Such a synergistic approach is quite unique and it makes a stronger argument to support causality,” Shah said.
Nutritional supplement could be key
Back at the lab, Rodriguez wondered if adding another substance could decrease the toxicity of valproic acid or improve its effects well enough to allow for a lower dosage.
Through his previous work in prostate cancer, Rodriguez found that omega-3 fatty acids seemed to have some activity in augmenting valproic acid histone deacetylase activity. Testing shows that a combination treatment of valproic acid plus docosahexaenoic acid (DHA) provided a stronger antiviral effect than either substance individually.
“We could show that the combination was more potent, and we could show the shifts. It was not just one gene, there were a couple thousand so it really was a whole genome response that was more profound than what any one drug would typically do,” Rodriguez said.
They then tested the treatment with COVID-19 on a specialized cell line. One problem was that this cell line had deletions and mutations in pathways that they needed turned on for the treatment to work.
“But we realized if we can only get 1% of the cells infected with COVID-19 through a secondary receptor, we can still measure that with our molecular mechanisms or PCR-based techniques that are highly sensitive,” Rodriguez said.
Their measurements found the same antiviral effect of valproic acid/DHA on the COVID-19-infected cell line.
“Valproic acid in combination with DHA is strongly activating ancient antiviral pathways against large classes of viruses in the cells that are repressed by viruses, like coronaviruses. When they get in, the first thing they do is repress many of these antiviral pathways. This combination drug overcomes that and then turns it on to a strong extent and those ancient pathways are able to rid themselves of the virus,” Rodriguez said.
What’s next?
Shortly before publication of this study, Rodriguez applied for a patent for this drug combination.
With this strong body of evidence supporting the potential for a valproic acid/DHA drug, Rodriguez said he will try again to secure funding for a national trial and continue this investigation.
“A combination of a nutritional supplement and an anti-seizure drug in the right ratios with the right timing could be very profound in inhibiting the development of and replication of COVID and more importantly, because of the way it works, there are a couple of thousand genes that are affected,” Rodriguez said.
He envisions usage of the valproic acid combo as a short-term, preventive treatment to avoid contracting COVID-19 or to lessen its severity, like how a Z-Pak, a short course of azithromycin, diminishes the chance of developing a bacterial infection.
For people who are older, have health issues or are immunocompromised like Rodriguez himself, this treatment could allow them to go back out into the world and experience things they have not been able to since COVID began.
“I haven’t gone on an airplane, gone in a restaurant or done anything in a large public area since COVID hit because of my kidney transplant. I’d love to be able to do more,” he said.
Rodriguez would also like to see this as a potentially low-cost alternative for treatment in third-world countries where other medications are not available or are cost-prohibitive.
UT Health San Antonio departments contributing to this study include the Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, Department of Urology, Department of Microbiology, Immunology and Molecular Genetics and Department of Medical Education.
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Valproic acid use is associated with diminished risk of contracting COVID-19, and diminished disease severity: Epidemiologic and in vitro analysis reveal mechanistic insights
Published Aug. 2, 2024. PLOS ONE. Amanda Watson, Pankil Shah, Doug Lee, Sitai Liang, Geeta Joshi, Ediri Metitiri, Wasim H. Chowdhury, Dean Bacich, Peter Dube, Yan Xiang, Daniel Hanley, Luis Martinez-Sobrido, Ronald Rodriguez.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0307154