Patent Application
20230381125
Infections, be they bacterial, fungal, and/or viral, can result in harmful medical conditions. For example, severe acute respiratory syndrome coronavirus 2 (“SARS-CoV-2”) is a virus responsible for the coronavirus disease (“COVID-19”). As of Sep. 14, 2020, there have been over 200,000,000 confirmed cases of COVID-19 reported to the World Health Organization, and nearly 5,000,000 deaths.
There is an urgent need for compositions and methods that: ameliorate infection-related medical conditions; ameliorate and/or prevent coronavirus-related medical conditions; inhibit viral replication; inhibit coronavirus replication; ameliorate and/or treat coronavirus-induced medical conditions; ameliorate and/or prevent respiratory virus-related medical conditions; and ameliorate and/or modulate dysregulated immune responses in patients suffering from an infection.
The claimed invention uses gamma-aminobutyric acid (“GABA”)-receptor agonists to ameliorate, treat, and/or prevent illness arising from infections, including bacterial, fungal, and/or viral infections. The claimed invention includes methods that: ameliorate infection-related medical conditions; ameliorate and/or prevent coronavirus-related medical conditions; inhibit viral replication; inhibit coronavirus replication; ameliorate and/or treat coronavirus-induced medical conditions; ameliorate and/or prevent respiratory virus-related medical conditions; and ameliorate and/or modulate dysregulated immune responses in patients suffering from an infection by administering a GABA-receptor agonist, either alone or with one or more positive allosteric modulators (“PAMs”), anti-inflammatory compounds, and/or antiviral treatments, e.g., one that limits viral replication or impacts other viral functions.
While GABA is well-known as a commonly used neurotransmitter in the central nervous system (“CNS”), it is becoming increasingly appreciated that many immune cells express GABA receptors (“GABA-Rs”). The biological roles of GABA-Rs on immune cells is not yet well understood, but there is a growing body of evidence that the activation of these receptors generally has immunoregulatory actions. In the innate immune system, antigen presenting cells (“APCs”) express GABA-A-type receptors (“GABAA-Rs,” which form a chloride channel) and their activation reduces APC reactivity [1, 2]. Neutrophils express GABA-B-type receptors (“GABAB-Rs,” which are G-protein coupled receptors), which modulate their function [3]. In the CNS, microglia express both GABAA-Rs and GABAB-Rs and their activation reduces microglia responsiveness to inflammatory stimuli [4]. Alveolar macrophages express GABAA-Rs and application of a GABA-R-specific agonist decreases the expression of many pro-inflammatory molecules in cultures of LPS-stimulated lung macrophages [5]. In the adaptive immune system, it has been shown that GABA-R activation promotes effector T-cell cycle arrest without inducing apoptosis [6]. In vivo, administration of GABA, or the GABAA-R-specific agonist homotaurine, inhibits autoreactive Th1 and Th17 cells while promoting CD4+ and CD8+ Treg responses [7-9]. Taking advantage of these properties, it has been demonstrated the that administration of GABA or homotaurine inhibits disease progression in mouse models of type 1 diabetes (“T1D”), multiple sclerosis, and rheumatoid arthritis, and limits inflammation in a mouse model of type 2 diabetes [1, 6, 8-10]. There are currently several ongoing clinical trials that are testing GABA treatment in individuals newly diagnosed with T1D (NCT02002130, NCT03635437, NCT03721991, NCT04375020).
Patients who develop severe COVID-19 appear to mount weaker or delayed innate immune responses to SARS-CoV-2, which leads to excessive adaptive immune responses later that do not taper off appropriately [11-13]. This can lead to “cytokine storms,” disseminated intravascular coagulation, multiple organ dysfunction syndrome (“MODS”), and death. Studies of anti-CD3-activated human PBMC have shown that GABA inhibits IL-6, CXCL10/IP-10, CCL4, CCL20, and MCP-3 production [14]. Longitudinal studies of COVID-19 patients reveal that high levels of serum IL-6 and Th1, Th17, and Th2-secreted proteins are associated with progression to severe illness [11, 15]. Many of these biomarkers of severe illness have been shown to be reduced by GABA-R agonists in the aforementioned in vitro studies of human PBMC and/or mouse models of autoimmune diseases.
Prior to Applicants' invention, there was no information on whether GABA treatment would modulate the outcome of viral infections. Moreover, an NIH drug screening program found that GABA and GABA agonists had no effect on SARS infection or replication.
Applicants' claimed invention uses GABA-receptor agonists to impact medical conditions in a positive way for the patient, thereby providing a surprising, new, and useful approach to limiting, e.g., excessive immune responses in COVID-19 patients.
In an embodiment, provided is a method for ameliorating an infection-related medical condition, comprising administering to a patient in need thereof an effective amount of a GABA-receptor agonist.
In another embodiment, provided is a method for ameliorating and/or preventing a coronavirus-related medical condition, comprising administering to a patient in need thereof an effective amount of a GABA-receptor agonist.
In yet another embodiment, provided is a method for inhibiting coronavirus replication in a patient, comprising administering to a patient in need thereof an effective amount of a GABA-receptor agonist.
In another embodiment, provided is a method for ameliorating and/or treating a coronavirus-induced medical condition, comprising administering to a patient in need thereof an effective amount of a GABA-receptor agonist.
In yet another embodiment, provided is a method for inhibit viral replication in a patient, comprising administering to a patient in need thereof an effective amount of a GABA-receptor agonist.
In yet another embodiment, provided is a method for ameliorating and/or preventing a respiratory virus-related medical condition, comprising administering to a patient in need thereof an effective amount of a GABA-receptor agonist.
In another embodiment, provided is a method for ameliorating and/or modulating dysregulated immune response in a patient suffering from an infection, comprising administering to said patient an effective amount of a GABA-receptor agonist.
Infections ameliorated by the claimed invention include bacterial, fungal, and viral infections.
Viral infections ameliorated by the claimed invention include those caused by coronaviruses, such as those caused by any strain of viruses such as human coronavirus OC43 (“HCoV-0043”) (β-CoV), human coronavirus HKU1 (“HCoV-HKU1”) (β-CoV), human coronavirus 229E (“HCoV-229E”) (α-CoV), human coronavirus NL63 (“HCoV-NL63”) (α-CoV), Middle East respiratory syndrome-related coronavirus (“MERS-CoV”) (β-CoV), severe acute respiratory syndrome coronavirus (“SARS-CoV”) (β-CoV), and SARS-CoV-2 (β-CoV).
By GABA-receptor agonist is meant an agonist of GABAA-receptors, GABAB-receptors, and/or GABAA-rho receptors (formerly known as GABAc-receptors).
GABAA-receptor agonists include: α5IA, adipiplon, beta-alanine, bretazenil, CL-218,872, (−)-epigallocatechin-3-gallate, GABA, gaboxadol, homotaurine, imidazenil, isoguvacine, L-838,417, muscimol, piperidine-4-sulfonic acid, progabide, QH-ii-066, SL-651,498, taurine, zolpidem, and 3-acyl-4-quinolones.
GABAB-receptor agonists include: baclofen, CGP-44532, GABA, gamma-hydroxybutyrate, isovaline, lesogaberan, phenibut, 3-aminopropylphosphinic acid, and 3-aminopropyl(methyl)phosphinic acid (SKF-97541).
GABAA-rho receptor agonists include: CACA, CAMP, and GABOB.
Positive allosteric modulators (“PAMs”) include: alcohol (ethanol), barbiturates, benzodiazepines (such as alprazolam, diazepam, chlordiazepoxide), BHFF, BHF-177, BSPP, certain carbamates (such as carisoprodol, lorbamate, meprobamate), CGP-7930, cinacalcet, etomidate, fendiline, glutethimide, GS-39783, kavalactones, lanthanum, meprobamate, neuroactive steroids, neurosteroids, niacin/niacinamide, nonbenzodiazepines (such as eszopiclone, zolpidem), propofol, quinazolinones (such as diproqualone, etaqualone, methaqualone), riluzole, stiripentol, theanine, thienodiazepines, valerenic acid, volatile/inhaled anesthetics. GABAB-receptor agonists are listed in italics.
Anti-inflammatory compounds include corticosteroids, such as dexamethasone.
The GABA-receptor agonist, PAM, and/or anti-inflammatory compound can be administered intradermally, intramuscularly, intraperitoneally, intravenously, orally, subcutaneously, sublingually, via aerosol delivery, or via a combination of delivery routes. Preferred routes include orally, sublingually, and/or via aerosol delivery. Administration of the GABA-receptor agonist and PAM and/or an anti-inflammatory compound can occur concurrently or in a staggered format.
In some embodiments, the GABA-receptor agonist is GABA administered in an amount of 1 ng/kg/day to 500 mg/kg/day. In particular examples, the GABA is administered in an amount of about 1 ng/kg/day-500 mg/kg/day, 10 ng/kg/day-500 mg/kg/day, 50 ng/kg/day-500 mg/kg/day, 100 ng/kg/day-500 mg/kg/day, 200 ng/kg/day-500 mg/kg/day, 400 ng/kg/day-250 mg/kg/day, 750 ng/kg/day-100 mg/kg/day, 1-1000 μg/kg/day 50-1500 μg/kg/day, 100-1000 μg/kg/day, 150-500 μg/kg/day, or 200-400 μg/kg/day.
Infection that is ameliorated by the claimed invention can result in one or more of: death, edema, excess immune response, fever, illness, increased secretion of inflammatory factors, increased viral replication, inflammation, lethargy, pneumonia, pneumonitis, and tussis.
Viral replication that is prevented and/or ameliorated by the claimed invention can result in one or more of: death, edema, excess immune response, fever, illness, increased secretion of inflammatory factors, increased viral replication, inflammation, lethargy, pneumonia, pneumonitis, and tussis.
Respiratory virus-related medical conditions that are prevented and/or ameliorated by the claimed invention can comprise one or more of: death, excess immune response, fever, illness, inflammation, lethargy, pneumonia, pneumonitis, and tussis.
Excessive immune responses that are prevented and/or ameliorated by the claimed invention can manifest as one or more of: increased alveolar fluid, inflammation of the lungs, and impaired lung function.
Applicants' invention is especially surprising because previous studies of GABA treatment were focused on autoimmune diseases. Autoimmune diseases progress slowly and the immune responses against the body's own tissue is very low. Moreover, during the development of T cells, T cells that strongly recognize self-proteins are eliminated in a process termed “central tolerance induction.” After this elimination, only T cells that very weakly recognize self-proteins are allowed to persist. T cells that do not recognize self-proteins are allowed to survive, and because there is no selection against them, T cells that strongly recognize foreign antigens persist and form the basis of our immunity against pathogens, such as coronaviruses. Therefore, when GABA is administered in autoimmune conditions it acts on low frequency T cells that weakly interact with self-proteins.
In contrast, after a viral infection, it is the innate immune system that first responds and adaptive immune responses do not arise until approximately a week later. The T cells that recognize foreign pathogens have “high affinity” to the antigens and these responses expand until they become a sizable fraction of the total T cell population. Prior to Applicants' invention there simply were no data on whether GABA treatment can assuage the strong innate and adaptive immune responses against a virus. Moreover, the activation of GABA-receptors on immune cells has only a weak effect on the immune cells—it is not like the immunodepletive therapies (anti-CD3) that lead to the death of T cells, or the anti-cytokine (anti-TNF) therapies that have robust effects on the immune cells and are in used in the clinic.
Autoimmune diseases studied prior to Applicants' invention are mediated by autoreactive T cells of the adaptive immune system. After a viral infection, however, it is the innate immune system that responds first, and adaptive immune responses arise approximately a week later. In mice, coronavirus infection causes illness almost the next day, and illness peaks about 5-7 days later, well before adaptive immune responses arise.
Because GABA has an immunosuppressive effect on autoimmune responses, those of skill in the art thought it was likely that GABA-receptor agonist treatment would suppress innate immune responses to the virus, allowing the virus to replicate to a greater extent and exacerbating disease, the opposite of what is desired. Moreover, in an effort to find new drugs to treat COVID-19, an NIH core screening facility screened thousands of compounds, including GABA and many GABA-receptor agonists and antagonists, for their ability to interfere with SARS-CoV-2 binding to its cellular receptor and to inhibit SARS-CoV-2 replication (https://opendata.ncats.nih.gov/covid19/databrowser). It was determined that GABA and other GABA-receptor agonists or antagonists did not interfere with SARS-CoV-2 interaction with its cellular receptor, nor its replication. These data argue against the hypothesis that GABA-receptor agonists may modulate coronavirus replication.
Thus, it was especially surprising that GABA-receptor agonists impact medical conditions in a beneficial way for the patient, thereby providing a new and useful approach to limiting excessive immune responses in COVID-19 patients.
There is an urgent need for new treatments to prevent and ameliorate serious illness arising from excessive immune responses to SARS-CoV-2 in COVID-19 patients.
Many immune cells express GABA-Rs and their activation generally has immunoregulatory actions. In particular, treatment with GABA has been shown to inhibit Th1 and Th17 responses in mouse models of autoimmune disease, and to reduce human PBMC production of many of the inflammatory mediators that are associated with disease severity in COVID-19 patients. Because GABA-R agonists like GABA and homotaurine are safe for human consumption, stable, inexpensive, and available worldwide, they show promise as an effective treatment for COVID-19 patients.
This study evaluated a new therapeutic approach based on targeting gamma-aminobutyric acid (GABA) receptors (GABA-Rs). Specifically, this example studied whether oral GABA, a GABA-receptor agonist, treatment beginning at the time of murine hepatitis virus-1 (“MHV-1,” a pneumotropic coronavirus that has been widely used to model SARS-CoV infection in mice) inoculation, or starting three days post-inoculation (by which time signs of illness are apparent), could modulate the seriousness of the ensuing illness and the rate of mortality. This example shows that oral GABA treatment greatly reduced illness, lung inflammation, and death when administered at the time of MHV-1 inoculation or after the appearance of illness.
Mice. Female A/J mice (7 weeks in age) were purchased from The Jackson Laboratory and maintained in microisolator cages and fed a standard diet and water ad libitum. One week after arrival they were inoculated with MHV-1. The mice were immediately randomized and treated (or not treated) with GABA, as described below. This study was carried out in accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocols for all experiments using vertebrate animals were approved by the Animal Research Committee at UCLA.
Reagents: GABA was purchased from Millipore-Sigma (stock #A2129, St. Louis, MO, USA).
Virus: Like SARS-CoV and SARS-CoV-2, MHV-1 is a pneumotropic beta-coronavirus of the group 2 lineage and is widely used as a safe model of SARS-CoV infection [16-19]. MHV-1 was used because unlike the MHV-JHM and MHV-A59 strains, which primarily infect the brain or liver, MHV-1 is pneumotropic. MHV-1 infection creates a lethal pneumonitis, similar to SARS-CoV-induced disease, in A/J mice. Intranasal inoculation with 5000 plaque-forming units (“PFU”) of MHV-1 in A/J mice induces an acute respiratory distress syndrome with a lethality rate of about 50%. The infected mice develop pathological features of SARS-CoV-2, including high levels of pulmonary cytokines/chemokines, pneumonitis, dense macrophage infiltrates, hyaline membranes, fibrin deposits, accompanied by loss of body weights and respiratory distress [16-19]. MHV-1, DBT cells, and HeLa-CECAM1 cells to grow and titer the virus were generously provided by Dr. Stanley Pearlman. MHV-I was prepared and titered as previously described [16-19].
Viral infection and GABA treatment: At 8 weeks in age, female A/J mice were anesthetized and inoculated intranasally with 5000 PFU MHV-1 in 50 μl cold Dulbecco's modified Eagle's medium (“DMEM”). The mice were immediately randomized and provided with plain water (controls) or water that contained GABA (20 mg/ml) for the entirety of the observation period. Another group of MHV-1 inoculated mice received plain water for three days, by which time they displayed signs of illness, and then were placed on GABA-containing water for the rest of the observation period. Body weights were monitored daily beginning on the infection day and up to 14 days post-infection.
Illness scoring. Individual mice were monitored for illness development and progression, which were scored on the following scale: 0) no symptoms, 1) slightly ruffled fur and altered hind limb posture; 2 ruffled fur and mildly labored breathing; 3) ruffled fur, inactive, moderately labored breathing; 4) ruffled fur, obviously labored breathing and lethargy; 5) moribund and death. The percent survival of each group of mice was determined longitudinally for each group. Mice with a disease score of 5 were weighed, euthanized, and their lungs removed and weighed for calculation of lung coefficient index (the ratio of lung weight to total body weight, which reflects the extent of edema and inflammation in the lungs). On day 14 post-infection, the surviving animals were weighed, euthanized, and their lungs were removed and weighed for determination of the lung coefficient index.
Following MHV-1 inoculation, mice receiving plain water began to progressively lose body weight each day. By day 6, the control group had lost an average of 23% of their weight, as expected [16-19]. At this time point, the mice that had been given GABA immediately after MHV-1 infection had lost an average of 11% of their body weight, and those given GABA three days after infection had lost an average of 17% of their body weight (
In terms of illness, MHV-1 infected control mice began to display signs of illness two days post-infection and rapidly became severely ill thereafter, with their illness peaking around day 7 post-infection. While most control mice died between days 6-11 post-infection, those that survived displayed only partial recovery from illness. In contrast, the mice receiving GABA immediately after inoculation developed only mild illness, with a highest average illness score of 1.6 on day 7 post-infection. Notably, illness in the mice given GABA at 3 days post-infection was also significantly reduced compared to that in the control group, and their maximum mean illness score was 2.5. Thus, GABA treatment immediately or 3 days after MHV-1 infection when the clinical signs of the disease appear, reduced the severity of coronavirus-induced illness and death.
The lung coefficient index reflects the edema and inflammation of the lung. The lung coefficient index of mice that were given GABA immediately after MHV-1 infection was 49% of that of control mice (p<0.001). The mice receiving GABA treatment beginning 3 days post-infection had a lung coefficient index that was 62% of that in the control mice (p<0.01). This provides an independent measure indicating that GABA treatment limited the MHV-1 induced pulmonary edema and inflammation in AM mice.
Together, the reduction in body weight loss, illness scores, death rate, and lung coefficient index indicate that GABA treatment can reduce illness severity and death rate following coronavirus infection, even when the treatment is initiated after symptoms appear.
Given that weaker and delayed interferon responses to the virus are associated with severe illness in COVID-19 patients [11] and GABA has anti-inflammatory effects, prior to Applicants' invention one would have anticipated that treatment with GABA immediately after MHV-1 infection might be deleterious by limiting or delaying innate immune responses. Applicants' invention is surprising in that early GABA treatment immediately after MHV-1 infection was very effective in preventing illness progression and death, suggesting a rapid effect of GABA on inflate immune responses or the lung airway cells. The lung epithelial cells of mice and humans also express GABAA-Rs [20, 21]. Activation of these GABAA-Rs may lead to Cl− efflux, which would act to limit Ca2+ influx in these epithelial cells. Because many viruses, including coronaviruses, elevate intracellular Ca2+ concentrations in order to enhance viral replication [22, 23], the activation of GABAA-Rs can limit MHV-1 replication.
Additionally, it has been shown that treatment with GABA, a GABAB-agonist, or GABA-R positive allosteric modulators can reduce inflammation and improve alveolar fluid clearance and lung functional recovery in rodent models of acute lung injury [24-28].
Added benefits to Applicants' claimed invention include that GABA treatment was tested in hundreds of epilepsy patients for its ability to reduce seizures [29-31]. While it had no clinical benefit (probably because it cannot cross the blood brain barrier), it had no adverse effects in these long-term studies. A more recent phase 1b GABA oral dosing study also indicated that GABA is safe [32] and there are currently several ongoing clinical trials which are administering oral GABA to individuals with Type 1 Diabetes (“T1D”) (ClinicalTrials.gov Identifiers: NCT02002130, NCT03635437, NCT03721991, NCT04375020). In addition, the GABAA-R specific agonist homotaurine was tested in a large long-term phase III clinical trial for Alzheimer's disease and while it was not effective it had an excellent safety record (see [8, 9] for a discussion of homotaurine's safety). Both GABA and homotaurine are inexpensive, stable at room temperature, and available world-wide making them excellent candidates for clinical testing as adjunctive treatments for, inter alia, COVID-19.
We assessed whether GABA's therapeutic effects were mediated through GABAA-Rs, GABAB-Rs, or both GABA-R subtypes. A/J mice were inoculated MHV-1 and given plain water or water containing GABA (2 mg/mL), a clinically applicable GABA-R-specific agonist (homotaurine, 0.25 mg/mL), or a GABAB-R-specific agonist (baclofen, 0.25 mg/mL). We found that treatment with GABA or homotaurine significantly reduced the body weight loss (
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We performed a study in which K18-hACE2 mice (N=5 mice/group) were inoculated with SARS-CoV-2 (1×103 PFU) and placed on plain water or water with 0.2 or 20 mg/ml GABA. The mice were monitored for their disease progression and survival up to 7 days post-inoculation. The surviving mice were euthanized at day 7 post-infection.
GABA treatment reduced the death rates in SARS-CoV-2 infected mice compared to that of mice given plain water (p=0.049 and p=0.174 for 0.2 and 20 mg/mL GABA vs. control, respectively by log-rank test). While 3/5 of the control mice died during the 7-day observation period, none of the mice treated with GABA 0.2 mg/mL died (p<0.05), and 1/5 of those given GABA 20 mg/ml died (
Treatment with 0.2 mg/ml GABA also reduced the lung coefficient index (the ratio of lung weight to total body weight, which reflects the extent of edema and inflammation in the lungs) (p<0.01, data not shown). Additionally, RT-qPCR analysis found viral N1 and N2 transcripts tended to be lower in the lungs from GABA-treated vs. control mice harvested on days 6-7 (data not shown).
Collectively, these findings demonstrate that administration of a GABA-R agonist, such as GABA, can reduce death rates and pneumonia severity and improve outcomes in SARS-CoV-2 infected K18-hACE2 mice.
The study of Example 3 will be repeated in a modified procedure aimed at evaluating the efficacy of GABA-R agonist treatment (such as GABA at 0.2, 2.0, and 20 mg/mL doses) when the treatment is initiated 2-3 days post-infection (PI) as to opposed to at the time of infection. Mice will be euthanized when the reach euthanasia criteria (>25% weight loss or behaviors indicative of imminent demise) and all surviving mice will be euthanized on day 7 PI. Their lungs will be weighed to determine the lung coefficient index. The right lung and brains of individual mice will be placed into Trizol and saved for analysis of cytokine/chemokine gene expression, and the left lung will be formalin-fixed for histological analysis of lung pathology in Aim 2. The inventors expect to find that GABAA-R agonist treatment initiated 2-3 days PI will reduce the severity of pneumonia and death rate.
In order to study the effects of GABAA-R agonists on virial load in the lungs, we will test groups of GABAA-R agonist-treated mice two days after SARS-CoV-2 inoculation using methods based on the examples set forth above. At time points of interest following SARS-CoV-2 inoculation and GABAA-R agonist treatment, the right lung and brain of some mice will be weighed, homogenized into PBS, centrifuged, and the supernatants will be stored at −80° C. Viral loads in the lung and brain from each mouse will be determined by plaque assay using Vero E6 cells. As a complementary measure, we will also quantify the amount of SARS-CoV-2 genomic RNA in the lungs and brain using the CDC-developed RT-qPCR 2019-nCoV_N1 assay and a secondary qPCR assay to measure a subgenomic RNA of region E, normalized to GADPH. N=8-10 mice per group at each time point.
This study is expected to provide evidence that activation of GABA-Rs modulates SARS-CoV-2 replication. Activation of ATII cell GABAA-Rs leads to CI-efflux, which we hypothesize will limit SARS-CoV-2 induced influx of extracellular Ca2+ making the cellular environment less conducive to viral replication. If viral loads are reduced, it will represent a new pathway to limit coronavirus replication in the lungs.
An effective amount of one or more GABA-receptor agonists, either alone or in combination with: one or more PAMs, anti-inflammatory compounds, and/or antiviral treatments, e.g., one that limits viral replication or impacts other viral functions, administered concurrently or in a staggered format to a patient in need thereof at the first signs of illness, improves outcome for the patient.
An effective amount of one or more GABA-receptor agonists, either alone or in combination with: one or more PAMs, anti-inflammatory compounds, and/or antiviral treatments, e.g., one that limits viral replication or impacts other viral functions, administered concurrently or in a staggered format to a patient in need thereof after serious illness develops, improves outcome for the patient.
An effective amount of one or more GABA-receptor agonists, either alone or in combination with: one or more PAMs, anti-inflammatory compounds, and/or antiviral treatments, e.g., one that limits viral replication or impacts other viral functions, administered concurrently or in a staggered format to a patient in need thereof at a time optimized for the stage of disease process, improves outcome for the patient.
An effective amount of one or more GABA-receptor agonists, either alone or in combination with: one or more PAMs, anti-inflammatory compounds, and/or antiviral treatments, e.g., one that limits viral replication or impacts other viral functions, administered concurrently or in a staggered format to a patient in need thereof at a time optimized for the stage of disease process, improves outcome for the patient.
An effective amount of one or more GABA-receptor agonists, either alone or in combination with: one or more PAMs, anti-inflammatory compounds, and/or antiviral treatments, e.g., one that limits viral replication or impacts other viral functions, administered concurrently or in a staggered format to a patient in need thereof as precision medication based upon the patient's genotype and/or biomarkers, improves outcome for the patient.
This invention was made with government support under Grant Number DE029020, awarded by the National Institutes of Health, and Grant Number W81XWH-20-1-0097, awarded by U.S. Army, Medical Research and Materiel Command. The government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US21/51965 | 9/24/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63083277 | Sep 2020 | US |
