According to preclinical studies using laboratory mice that model human infection with SARS-CoV-2, the virus that causes COVID-19, an inexpensive, readily available amino acid might limit the effects of the disease and provide a new therapeutic option for treating new SARS-CoV-2 variants and perhaps future novel coronaviruses.
A team led by researchers at the David Geffen School of Medicine at UCLA posted results of their preclinical work on BioRxiv, a preprint server that enables researchers to make manuscripts available to other scientists prior to peer review for journal publication.
They found that an amino acid called GABA, which is available over-the-counter in many countries, reduced disease severity, viral load in the lungs, and death rates in SARS-CoV-2-infected mice. Although the amino acid has a good safety track record in humans, the researchers cautioned that clinical trials are needed to determine if it works in humans with COVID-19, to ensure there are no adverse side effects, and to ascertain appropriate and effective timing intervals and dosing levels.
“SARS-CoV-2 variants and novel coronaviruses will continue to arise, and they may not be efficiently controlled by available vaccines and antiviral medications. Furthermore, the generation of new vaccines is likely to be much slower than the spread of new variants,” said senior author Daniel L. Kaufman, a researcher and professor in molecular and medical pharmacology at the David Geffen School of Medicine at UCLA. “If the results of our studies are confirmed in clinical trials, GABA could provide an off-the-shelf treatment to help ameliorate these conditions. GABA is inexpensive and stable at room temperature, which could make it widely and easily accessible, and especially beneficial in developing countries.”
The researchers said that GABA receptors are most often thought of as neurotransmitter receptors in the central nervous system. Years ago, they found that cells of the immune system also had GABA receptors and that the activation of these receptors inhibited the inflammatory actions of immune cells. Taking advantage of this property, they reported that GABA administration inhibited autoimmune diseases such as type 1 diabetes, multiple sclerosis, and rheumatoid arthritis in mouse models of these ailments.
Other researchers have found that lung epithelial cells also have GABA receptors and that drugs that activate these receptors could limit lung injuries and inflammation in the lung. The dual actions of GABA in inflammatory immune cells and lung epithelial cells, along with its safety for clinical use, made GABA a theoretically appealing candidate for limiting the overreactive immune responses and lung damage due to coronavirus infection.
Working with colleagues at the University of Southern California, the UCLA research team in this study administered GABA to the mice just after infection with SARS-CoV-2, or two days later when the virus levels are near their peak in the mouse lungs. While the vast majority of untreated mice did not survive this infection, those given GABA just after infection, or two days later, had less illness severity and a lower mortality rate over the course of the study. Treated mice also displayed reduced levels of virus in their lungs and changes in circulating immune signaling molecules, known as cytokines and chemokines, toward patterns that were associated with better outcomes in COVID-19 patients. Thus, GABA receptor activation had multiple beneficial effects in this mouse model that are also desirable for the treatment of COVID-19.
“In our mouse studies, GABA treatment reduced disease severity, viral load, inflammatory signaling molecules, and death rates in SARS-CoV-2 infected mice,” said first author Dr. Jide Tian in molecular and medical pharmacology at the David Geffen School of Medicine at UCLA. “The multiple actions of GABA-receptor modulators and their known safety profile appear to make them candidates for limiting dysregulated immune responses, severe pneumonia, and lung damage due to coronavirus infections.”
The researchers hope to follow up on their findings to better understand how GABA treatment modulates immune responses to the virus and whether GABA treatment is equally effective against other SARS-CoV-2 viral variants. Most importantly, they hope that their findings may provide a springboard for clinicians to test the safety and efficacy of GABA treatment in clinical trials with COVID-19 patients.
Since GABA has an excellent safety record, is inexpensive and available worldwide, clinical trials of GABA treatment for COVID-19 can be initiated rapidly. If successful in clinical trials, GABA could provide an off-the-shelf treatment to help reduce morbidity and mortality when SARS-CoV-2 variants and novel coronaviruses arise that may evade the immune responses induced by available vaccines, prior infections, and antiviral medications.
The researchers emphasize that until clinical trials are completed and GABA is approved for treating COVID-19 by relevant governing bodies, it should not be consumed for the treatment of COVID-19 since it could pose health risks, such as dampening beneficial immune or physiological responses.
Additional authors include Barbara Dillion, High Containment Program at UCLA, and Jill Henley and Lucio Comai, Keck School of Medicine at USC.
Funding: This work was supported by a grant to DLK from the UCLA DGSOM-Broad Stem Cell Research Center, the Department of Molecular and Medical Pharmacology, and the Immunotherapeutics Research Fund. Work at USC was supported by a grant from the COVID-19 Keck Research Fund to LC.
Conflicts of interests: DLK and JT are inventors of GABA-related patents. DLK serves on the Scientific Advisory Board of Diamyd Medical. BD, LC and JH have no financial conflicts of interest.
