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WO2022190064A1 - Procédés d'identification de sujets atteints d'infections à betacoronavirus qui présentent un risque de syndrome respiratoire aigu et leurs procédés de traitement - Google Patents

Procédés d'identification de sujets atteints d'infections à betacoronavirus qui présentent un risque de syndrome respiratoire aigu et leurs procédés de traitement Download PDF

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Publication number
WO2022190064A1
WO2022190064A1 PCT/IB2022/052222 IB2022052222W WO2022190064A1 WO 2022190064 A1 WO2022190064 A1 WO 2022190064A1 IB 2022052222 W IB2022052222 W IB 2022052222W WO 2022190064 A1 WO2022190064 A1 WO 2022190064A1
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Prior art keywords
ceramide
subject
risk
value
ethyl
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Mehran M. Khodadoust
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Vexo Pharmaceuticals Dmcc
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Vexo Pharmaceuticals Dmcc
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/08—RNA viruses
    • G01N2333/165—Coronaviridae, e.g. avian infectious bronchitis virus
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2405/00—Assays, e.g. immunoassays or enzyme assays, involving lipids
    • G01N2405/08—Sphingolipids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2560/00—Chemical aspects of mass spectrometric analysis of biological material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2570/00—Omics, e.g. proteomics, glycomics or lipidomics; Methods of analysis focusing on the entire complement of classes of biological molecules or subsets thereof, i.e. focusing on proteomes, glycomes or lipidomes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases
    • G01N2800/125—Adult respiratory distress syndrome
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/56—Staging of a disease; Further complications associated with the disease

Definitions

  • SARS-CoV-2 The 2019 novel Coronavirus (SARS-CoV-2) that is the cause of the highly infectious disease known as COVID-19, is a new member of a group, that includes previously recognized zoonotic pathogens, as is the case of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-1), that caused epidemics in China in 2002-2003, and the Middle East Respiratory Syndrome (MERS-CoV), affecting Saudi Arabia and neighbor countries in 2012-2013.
  • SARS-CoV-1 Severe Acute Respiratory Syndrome Coronavirus
  • MERS-CoV Middle East Respiratory Syndrome
  • the invention features methods for identifying patients at risk of acute respiratory distress syndrome or respiratory failure on the basis of certain biomarkers, and for intervening to reduce the risk or severity of the patient’s condition.
  • the invention features a method of reducing the risk of acute respiratory distress syndrome in a subject with a betacoronavirus infection, the method including administering to the subject a therapeutically effective amount of a ceramide modulating agent.
  • the invention features a method of reducing the risk of respiratory failure in a subject with a betacoronavirus infection, the method including administering to the subject a therapeutically effective amount of a ceramide modulating agent.
  • the invention further features a method of reducing the risk of acute respiratory distress syndrome in a subject with a betacoronavirus infection, the method including the steps of: (i) determining a value from one or more of a circulating concentration of ceramide (d18:0/24:1 ), ceramide (d18:1/24:1 ), ceramide (d18:1/24:0), ceramide (d18.0/20:0), ceramide (d18.1/20:0), ceramide (d18:1/22:0), and hexosylceramide (d18:1/22:0) in the subject; and (ii) on the basis of the value, administering to the subject a therapeutically effective amount of a ceramide modulating agent.
  • the invention also features a method of reducing the risk of respiratory failure in a subject with a betacoronavirus infection, the method including the steps of: (i) determining a value from one or more of a circulating concentration of ceramide (d18:0/24:1 ), ceramide (d18:1/24:1 ), ceramide (d18:1/24:0), ceramide (d18.0/20:0), ceramide (d18.1/20:0), ceramide (d18:1/22:0), and hexosylceramide (d18:1/22:0) in the subject; and (ii) on the basis of the value, administering to the subject a therapeutically effective amount of a ceramide modulating agent.
  • step (i) includes determining a value from the circulating concentration of ceramide (d18:0/24:1 ), wherein the circulating concentration is elevated in at risk subjects relative to an average observed for healthy control subjects and elevated in at risk subjects relative to an average observed for non-distressed covid control subjects, and based upon the value, administering to the subject a therapeutically effective amount of a ceramide modulating agent.
  • step (i) includes determining a value from the circulating concentration of ceramide (d18:1/24:1 ), wherein the circulating concentration is elevated in at risk subjects relative to an average observed for healthy control subjects and elevated in at risk subjects relative to an average observed for non-distressed covid control subjects, and based upon the value, administering to the subject a therapeutically effective amount of a ceramide modulating agent.
  • step (i) includes determining a value from the circulating concentration of ceramide (d18:1/24:0), wherein the circulating concentration is elevated in at risk subjects relative to an average observed for healthy control subjects and reduced in at risk subjects relative to an average observed for non-distressed covid control subjects, and based upon the value, administering to the subject a therapeutically effective amount of a ceramide modulating agent.
  • step (i) includes determining a value from the circulating concentration of ceramide (d18.0/20:0), wherein the circulating concentration is elevated in at risk subjects relative to an average observed for healthy control subjects and elevated in at risk subjects relative to an average observed for non-distressed covid control subjects, and based upon the value, administering to the subject a therapeutically effective amount of a ceramide modulating agent.
  • step (i) includes determining a value from the circulating concentration of ceramide (d18.1/20:0), wherein the circulating concentration is elevated in at risk subjects relative to an average observed for healthy control subjects and elevated in at risk subjects relative to an average observed for non-distressed covid control subjects, and based upon the value, administering to the subject a therapeutically effective amount of a ceramide modulating agent.
  • step (i) includes determining a value from the circulating concentration of ceramide (d18:1/22:0) and the circulating concentration of hexosylceramide (d18:1/22:0), wherein the ratio of the circulating concentration of ceramide (d18:1/22:0) to the circulating concentration of hexosylceramide (d18:1/22:0) is elevated in at risk subjects relative to an average observed for healthy control subjects and elevated in at risk subjects relative to an average observed for non-distressed covid control subjects, and based upon the value, administering to the subject a therapeutically effective amount of a ceramide modulating agent.
  • the ceramide modulating agent is administered once or twice per day.
  • the administering can occur over a treatment period (e.g., about 1 day to about 21 days, or about 1 week to about 6 weeks).
  • the circulating concentrations of one or more of a circulating concentration of ceramide (d18:0/24:1 ), ceramide (d18:1/24:1 ), ceramide (d18:1/24:0), ceramide (d18.0/20:0), ceramide (d18.1/20:0), ceramide (d18:1/22:0), and hexosylceramide (d18:1/22:0) in the subject are monitored at least once per day, twice a day, three times a day, or hourly; and (b) the treatment period continues until the circulating concentrations become comparable to an average observed for healthy control subjects or an average observed for non-distressed covid control subjects (e.g., altered to a level indicative of a reduced risk of acute respiratory distress syndrome or respiratory failure).
  • the ceramide modulating agent inhibits ceramide biosynthesis and targets at least one ceramide-biosynthetic enzyme selected from the group consisting of a sphingomyelinase, serine palmitoyltransferase, 3-ketosphinganine reductase, ceramide synthase, dihydroceramide desaturase, cerebrosidase, C1 P phosphatase, dihydroceramide synthase, and combinations thereof.
  • ceramide-biosynthetic enzyme selected from the group consisting of a sphingomyelinase, serine palmitoyltransferase, 3-ketosphinganine reductase, ceramide synthase, dihydroceramide desaturase, cerebrosidase, C1 P phosphatase, dihydroceramide synthase, and combinations thereof.
  • the ceramide modulating agent that inhibits ceramide biosynthesis can be a serine palmitoyltransferase inhibitor selected from the group consisting of sphingo-fungins, lipoxamycin, myriocin, L-cycloserine, beta-chloro-L-alanine, Viridiofungins, and combinations thereof.
  • the ceramide modulating agent that inhibits ceramide biosynthesis can be a dihydroceramide desaturase inhibitor selected from the group consisting of GT11 , GT85, GT98, GT99, GT55, GT77, and mixtures thereof.
  • the ceramide modulating agent that inhibits ceramide biosynthesis can be a sphingomyelinase inhibitor selected from the group consisting of L-alpha-phosphatidyl-D-myoinositol-3,5-bisphosphate, L- alpha-phosphatidyl-D-myo-inositol-3, 4, 5-triphosphate, ceramidel -phosphate, sphingosine-1 -phosphate, glutathione, desipramine, imipramine, SR33557, (3-carbazol-9-yl-propyl)-[2-(3,4dimethoxy-phenyl)-ethyl)- methyl-amine, hexanoic acid (2-cyclo-pent-1 -
  • the ceramide modulating agent inhibits ceramide biosynthesis is selected from fingolimod, (S)-2-amino-4-(4- (benzyloxy)phenyl)-2-methylbutan-1-ol, FB1 , D609, myriocin, and pharmaceutically acceptable salts thereof.
  • the ceramide modulating agent that inhibits ceramide biosynthesis is a ceramide synthase 1 (CerS1) inhibitor.
  • the CerS1 inhibitor can be (S)-2-amino-4-(4-((3, 4- dichlorobenzyl)oxy)phenyl)-2-methylbutan-1-ol (P053) or a pharmaceutically acceptable salt thereof.
  • the ceramide modulating agent is a TNF- alpha inhibitor, a TLFt-4 inhibitor, an FGF21 agonist, an adiponectin receptor agonist, an apoptosis inhibitor, or a mitophagy inhibitor (e.g., any TNF-alpha inhibitor, TLFt-4 inhibitor, adiponectin receptor agonist, apoptosis inhibitor, or mitophagy inhibitor described herein).
  • a mitophagy inhibitor e.g., any TNF-alpha inhibitor, TLFt-4 inhibitor, adiponectin receptor agonist, apoptosis inhibitor, or mitophagy inhibitor described herein.
  • the ceramide modulating agent or enzyme which causes reduction of concentration of circulating Ceramides in the plasma by causing chemical modifications and targets as agonist at least one ceramide-modifying enzymes selected from the group consisting of a Glucosylceramide synthase, Ceramidase, Ceramide kinase, and Sphingomyelin Synthase.
  • the invention features a method of treating a subject at risk of acute respiratory distress syndrome in a subject with a betacoronavirus infection, the method including the steps of: (i) determining a value from one or more of a circulating concentration of ceramide (d18:0/24:1 ), ceramide (d18:1/24:1), ceramide (d18:1/24:0), ceramide (d18.0/20:0), ceramide (d18.1/20:0), ceramide (d18:1/22:0), and hexosylceramide (d18:1/22:0) in the subject; and (ii) on the basis of the value, treating the subject to reduce the risk or severity of acute respiratory distress syndrome.
  • the invention further features a method of treating a subject at risk of respiratory failure in a subject with a betacoronavirus infection, the method including the steps of(i) determining a value from one or more of a circulating concentration of ceramide (d18:0/24:1), ceramide (d18:1/24:1), ceramide (d18:1/24:0), ceramide (d18.0/20:0), ceramide (d18.1/20:0), ceramide (d18:1/22:0), and hexosylceramide (d18:1/22:0) in the subject; and (ii) on the basis of the value, treating the subject to reduce the risk of respiratory failure.
  • step (i) includes determining a value from the circulating concentration of ceramide (d18:0/24:1), wherein the circulating concentration is elevated in at risk subjects relative to an average observed for healthy control subjects and elevated in at risk subjects relative to an average observed for non-distressed covid control subjects, and based upon the value, treating the subject to reduce the risk of respiratory failure.
  • step (i) includes determining a value from the circulating concentration of ceramide (d18:1/24:1), wherein the circulating concentration is elevated in at risk subjects relative to an average observed for healthy control subjects and elevated in at risk subjects relative to an average observed for non-distressed covid control subjects, and based upon the value, treating the subject to reduce the risk of respiratory failure.
  • step (i) includes determining a value from the circulating concentration of ceramide (d18:1/24:0), wherein the circulating concentration is elevated in at risk subjects relative to an average observed for healthy control subjects and reduced in at risk subjects relative to an average observed for non-distressed covid control subjects, and based upon the value, treating the subject to reduce the risk of respiratory failure.
  • step (i) includes determining a value from the circulating concentration of ceramide (d18.0/20:0), wherein the circulating concentration is elevated in at risk subjects relative to an average observed for healthy control subjects and elevated in at risk subjects relative to an average observed for non-distressed covid control subjects, and based upon the value, treating the subject to reduce the risk of respiratory failure.
  • step (i) includes determining a value from the circulating concentration of ceramide (d18.1/20:0), wherein the circulating concentration is elevated in at risk subjects relative to an average observed for healthy control subjects and elevated in at risk subjects relative to an average observed for non-distressed covid control subjects, and based upon the value, treating the subject to reduce the risk of respiratory failure.
  • step (i) includes determining a value from the circulating concentration of ceramide (d18:1/22:0) and the circulating concentration of hexosylceramide (d18:1/22:0), wherein the ratio of the circulating concentration of ceramide (d18:1/22:0) to the circulating concentration of hexosylceramide (d18:1/22:0) is elevated in at risk subjects relative to an average observed for healthy control subjects and elevated in at risk subjects relative to an average observed for non-distressed covid control subjects, and based upon the value, treating the subject to reduce the risk of respiratory failure.
  • the subject treated to reduce the risk of severity of acute respiratory distress syndrome or respiratory failure is treated with oxygen, a therapeutically effective amount of an antiviral agent (e.g., remdesivir, chloroquine, hydroxychloroquine, baricitinib, lopinavir/ritonavir, interferon beta, umifenovir, favipiravir, tocilizumab, or ribavirin), and/or a therapeutically effective amount of an anti inflammatory agent (e.g., celecoxib, diclofenac, difunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, prednisone, prednisolone, methylprednisolone, metformin, and dexamethasone).
  • an antiviral agent e.g., remdesivir, chloro
  • the circulating concentrations of one or more of a circulating concentration of ceramide (d18:0/24:1 ), ceramide (d18:1/24:1), ceramide (d18:1/24:0), ceramide (d18.0/20:0), ceramide (d18.1/20:0), ceramide (d18:1/22:0), and hexosylceramide (d18:1/22:0) in the subject are monitored at least once per day; and (b) the treatment period continues until the circulating concentrations become comparable to an average observed for healthy control subjects or an average observed for non-distressed covid control subjects (e.g., reduced or increased, as desired, to a level indicative of a reduced risk of acute respiratory distress syndrome or respiratory failure).
  • the subject is being hospitalized for the betacoronavirus infection.
  • the risk of death in the subject is reduced.
  • the subject can at least 40 years old, at least 50 years old, at least 60 years old, at least 70 years old, or at least 80 years old.
  • the betacoronavirus is SARS-CoV-2, SARS-CoV-1 , or MERS-CoV.
  • the invention features any of the above methods wherein the biomarker is replaced with one or more of the following: (i) a change in the circulating concentration (e.g., an increase or decrease with increasing risk in the subject) of a biomarker selected from ceramide (d18:0/16:0); ceramide (d18:0/18:0); ceramide (d18:0/20:0); ceramide (d18:0/22:0); ceramide (d18:0/24:0); ceramide (d18:0/24:1 ); ceramide (d18:1/16:0); ceramide (d18:1/18:0); ceramide (d18:1/20:0); ceramide (d18:1/22:0); ceramide (d18:1/24:0); ceramide (d18:1/24:1 ); hexosylceramide (d18:1/14:0); hexosylceramide (d18:1/16:0); hexo
  • the invention features a method of treating a subject at risk of acute respiratory distress syndrome in a subject with a betacoronavirus infection, the method including the steps of: (i) determining a value from one or more of a circulating concentration of ceramide (d18:0/16:0); ceramide (d18:0/18:0); ceramide (d18:0/20:0); ceramide (d18:0/22:0); ceramide (d18:0/24:0); ceramide (d18:0/24:1 ); ceramide (d18:1/16:0); ceramide (d18:1/18:0); ceramide (d18:1/20:0); ceramide (d18:1/22:0); ceramide (d18:1/24:0); ceramide (d18:1/24:1 ); hexosylceramide (d18:1 /14:0); hexosylceramide (d18:1 /16:0); hexosylcer
  • the invention further features a method of treating a subject at risk of respiratory failure in a subject with a betacoronavirus infection, the method including the steps of: (i) determining a value from one or more of a circulating concentration of ceramide (d18:0/16:0); ceramide (d18:0/18:0); ceramide (d18:0/20:0); ceramide (d18:0/22:0); ceramide (d18:0/24:0); ceramide (d18:0/24:1 ); ceramide (d18:1/16:0); ceramide (d18:1/18:0); ceramide (d18:1/20:0); ceramide (d18:1/22:0); ceramide (d18:1/24:0); ceramide (d18:1/24:1 ); hexosylceramide (d18:1 /14:0); hexosylceramide (d18:1 /16:0); hexosylceramide
  • step (ii) includes administering oxygen to the subject, administering to the subject a therapeutically effective amount of a ceramide modulating agent, administering a therapeutically effective amount of an antiviral agent to the subject, or administering a therapeutically effective amount of an anti-inflammatory agent to the subject (e.g., any treatment described herein).
  • administering is meant a method of giving a dosage of a cysteamine precursor compound to a subject.
  • the cysteamine precursor compounds utilized in the methods described herein can be administered, for example, orally, or by another other route described herein.
  • ceramide modulating agent refers to an agent that reduces the circulating concentration of ceramide either by inhibiting its biosynthesis or reducing its concentration in the plasma by chemical modifications.
  • ceramide modulating agents include, without limitation, sphingomyelinase inhibitors, serine palmitoyltransferase inhibitors, 3-ketosphinganine reductase inhibitors, ceramide synthase inhibitors, dihydroceramide desaturase inhibitors, cerebrosidase, C1 P phosphatase inhibitors, dihydroceramide synthase inhibitors, ceramide synthase 1 inhibitors, TNF-alpha inhibitors, TLR-4 inhibitors, FGF21 agonists, adiponectin receptor agonists, apoptosis inhibitors, and mitophagy inhibitors.
  • a “therapeutically effective amount” refers to that amount that must be administered to a patient (a human or non-human mammal) in order to ameliorate a symptom of risk of acute respiratory distress syndrome or respiratory failure in a subject.
  • a ceramide modulating agent e.g., a ceramide biosynthesis inhibitor, antiviral, anti-inflammatory, or oxygen
  • used to practice the invention for therapeutic or prophylactic treatment of conditions caused by or contributed to by a betacoronavirus infection varies depending upon the ceramide modulating agent being used, the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician will decide the appropriate amount and dosage regimen. Such amount is referred to as a "therapeutically effective amount.”
  • reducing the risk of acute respiratory distress syndrome in a subject refers to reducing the frequency of acute respiratory distress syndrome in subjects treated according to the methods of the invention. The reduction is in comparison to control subjects of the same age and condition (e.g., comorbidities) that are untreated.
  • the frequency of acute respiratory distress syndrome can be reduced by 10%, 20%, 30%, or 50% relative to the frequency of acute respiratory distress syndrome observed for the control subjects.
  • reducing the risk of respiratory failure in a subject refers to reducing the frequency of respiratory failure in subjects treated according to the methods of the invention. The reduction is in comparison to control subjects of the same age and condition (e.g., comorbidities) that are untreated.
  • the frequency of respiratory failure can be reduced by 10%, 20%, 30%, or 50% relative to the frequency of respiratory failure observed for the control subjects.
  • reducing the risk of death in a subject refers to reducing the frequency of death in subjects treated according to the methods of the invention. The reduction is in comparison to control subjects of the same age and condition (e.g., comorbidities) that are untreated. The frequency of death can be reduced by 10%, 20%, 30%, or 50% relative to the frequency of death observed for the control subjects.
  • reducing the duration of hospitalization in a subject refers to reducing the duration of hospitalization in subjects treated according to the methods of the invention. The reduction is in comparison to control subjects of the same age and condition (e.g., comorbidities) that are untreated. The duration of hospitalization can be reduced by 10%, 20%, 30%, or 50% relative to the duration of hospitalization observed for the control subjects.
  • composition any composition that contains therapeutic agent combined with a pharmaceutically acceptable carrier that together is suitable for administration to a subject and that treats or prevents a betacoronavirus infection or reduces the severity of, or ameliorates, one or more symptoms associated with a betacoronavirus infection
  • pharmaceutical compositions useful in the methods of the invention can take the form of tablets, gelcaps, capsules, pills, powders, granulates, suspensions, and/or emulsions.
  • a pharmaceutically acceptable carrier refers to an excipient or diluent in a pharmaceutical composition.
  • a pharmaceutically acceptable carrier may be a vehicle capable of suspending or dissolving the active ingredients (e.g., a cysteamine precursor compound).
  • the pharmaceutically acceptable carrier can be compatible with the other ingredients of the formulation and not deleterious to the recipient.
  • a solid carrier may be preferred.
  • the term “treat” or “treating” includes administration of a cysteamine precursor compound to a subject by any route, e.g., orally.
  • the subject e.g., a patient
  • Treatment is not limited to curing or complete healing, but can result in one or more of alleviating, relieving, altering, partially remedying, ameliorating, improving or affecting the betacoronavirus infection, reducing one or more symptoms of the betacoronavirus infection or the predisposition toward the betacoronavirus infection.
  • the treatment (at least partially) alleviates or relieves symptoms related to a betacoronavirus infection.
  • the treatment reduces at least one symptom of the betacoronavirus infection or delays onset of at least one symptom of the betacoronavirus infection. The effect is beyond what is seen in the absence of treatment.
  • pharmaceutically acceptable salt refers to salt forms (e.g., acid addition salts or metal salts) of the therapeutic agent suitable for therapeutic use according to the methods of the invention.
  • Figures 1 A-1 C are a series of bar graphs depicting the number of subclasses identified per lipid class in plasma of COVID-19 infected individuals (as described in Example 1 ), and fold sum of MEDM changes in peak areas of identified lipid classes between the non-infected and with (Fig. 1 A) mild (Fig 1 C) with respiratory distress symptoms.
  • Figure 1 C depicts comparative differences analysis of lipids with in the lipidome of plasma, in individuals with COVID-19 infection with mild vs respiratory distress symptoms. Data was collected as described in Example 1 . These figures show that COVID-19 causes profound changes in the levels of lipid’s in the plasma of infected individuals.
  • Plasma concentration of Lipids such as: Cer, Hex2Cer, Hex3Cer, PE, PG, PI and PS are shown to be increased on average more than 40 fold in this study, in both mild and sever cases of COVID-19 infection.
  • PS Phosphatidylserine
  • SM Sphingomyelin
  • Cer Ceramides
  • LPC Lysophosphatidylcholine
  • LPE Lysophosphatidyl-ethanolamine
  • PC Phosphatidylcholine
  • PE Phosphatidylethanolamine
  • PI Phosphatidylinositol
  • HexCer Hexosylceramide
  • Hex2Cer DiHexosylceramide
  • DAG Diacylglycerol
  • PG Prostaglandin
  • SE Steriol
  • TAG Triacylglycerol
  • LPI LysoPhosphatidylinosito
  • Figures 2A and 2B are bar graphs depicting that a 200 nmoles/ml increase in plasma Ceramide levels to be correlated with transition from mild symptoms to the observed respiratory distress symptoms in COVID-19 infected individuals.
  • Figures 2A and 2B are graphs depicting the fold sum of MEDM changes of peak area times number of subclasses identified per lipid class.
  • Figure 2A depicts an overall estimation of relative changes in concentration of various lipid classes.
  • Figure 2B depicts the relative Concentration of Lipid’s per class in nmoles/ml of plasma as determined via SRM 1950 consensus LIPID MAPS consortium.
  • Figure 3 is a bar graphs depicting the observed increases in plasma Ceramide concentration back into it’s subclass levels. This figure shows the relative contribution of each of the subclasses, in terms of fold increases in plasma compared to the uninfected and in the mild vs the respiratory distress patients. These figures show 20 to 160 fold increase, relative to the uninfected plasma, of Cer(d18:0/24:1), Cer(d18:1/24:1), Cer(d18.0/20:0), and Cer(d18:1/20:0) in plasma of mild vs the respiratory distress patients.
  • Figure 4 is a bar graph depicting relative ratios of Ceramide/HexCer for each of the observed subclass in the plasma of Covid-19 infected individuals with mild and sever symptoms. This figure shows that the Cer(d18:1 /22:0)/HexCer(d18:1/22:0) ratio is significantly higher in the plasma of Covid-19 infected individuals with respiratory distress. This demonstrates a change that can act as the predictor of the severe respiratory distress symptom.
  • Figure 5 is a schematic illustration of models for both ceramide synthesis and clearing.
  • Ceramides are synthesized de novo by reaction between Palmitate-CoA and serine mediated by SPT enzyme.
  • the activity of this enzyme can be modified by activation of the TLR4 receptor and the fungal toxin, Myriocin.
  • Salvage pathways are also mechanisms for synthesis and clearing of Ceramide’s include pathway’s involved in synthesis of Sphingosine, Sphingomyelin and Hex Ceramides. Each of which are mediated by specific enzymes and factors including adiponectin, FGF-21 and TNF-alpha that have been shown to be involved in its regulation.
  • the invention features methods for identifying patients at risk of acute respiratory distress syndrome or respiratory failure on the basis of certain biomarkers, and for intervening to reduce the risk or severity of the patient’s condition.
  • the methods can include administering a ceramide modulating agent (e.g., a ceramide biosynthesis inhibitor, antiviral, anti-inflammatory, anti-apoptotic, anti-mitophagy, ceramide modifying enzymes or agents, FGF-21 , adiponectin or oxygen) to reduce the risk or severity of the acute respiratory distress syndrome or respiratory failure.
  • a ceramide modulating agent e.g., a ceramide biosynthesis inhibitor, antiviral, anti-inflammatory, anti-apoptotic, anti-mitophagy, ceramide modifying enzymes or agents, FGF-21 , adiponectin or oxygen
  • circulating concentrations of one or more of ceramide (d18:0/24:1), ceramide (d18:1/24:1), ceramide (d18:1/24:0), ceramide (d18.0/20:0), ceramide (d18.1/20:0), ceramide (d18:1/22:0), and hexosylceramide (d18:1/22:0) in a subject can be used to assess the subject’s risk of acute respiratory distress syndrome or respiratory failure.
  • These circulating concentrations can also be used to guide therapeutic interventions to treat the subjects and reduce the risk of hospitalization and death.
  • Ceramides are a family of lipids composed of sphingosine and a fatty acid. Ceramide synthesis in the body occurs via one of three major pathways: the de novo pathway, the sphingomyelin pathway, and the salvage pathway.
  • the de novo pathway results in ceramide synthesis from less complex molecules in the body.
  • the sphingomyelin pathway produces ceramide through the breakdown of sphingomyelin mediated by the enzyme sphingomyelinase. Ceramide is produced via the salvage pathway by the breakdown of complex sphingolipids into sphingosine, which is then used to form ceramide.
  • ceramides Up-regulation of ceramides can mediate both extrinsic and intrinsic pathways of apoptosis in various cell types. In addition to apoptosis, ceramides are involved in endothelial oxidative stress, growth arrest, cytoskeletal changes, and senescence . Through these effects, ceramides regulate major aspects of lung endothelial cell function and are involved in the pathogenesis of several conditions associated with pulmonary vascular dysfunction.
  • Biomarkers including of ceramide (d18:0/24:1), ceramide (d18:1/24:1), ceramide (d18:1/24:0), ceramide (d18.0/20:0), ceramide (d18.1/20:0), ceramide (d18:1/22:0), and hexosylceramide (d18:1/22:0) have been identified as useful diagnostics in the pathogenesis of acute respiratory distress syndrome and respiratory failure of subjects suffering from a betacoronavirus infection.
  • the invention features methods for treating subjects at risk of acute respiratory distress syndrome and respiratory failure by administering to the subjects factors which can reduce circulating levels of ceramide including inhibitors of ceramide biosynthesis, or reducing its concentration in the plasma by chemical modifications.
  • the ceramide de novo pathway includes a series of enzymes that produce ceramide from the starting components serine and palmitoyl CoA.
  • Serine palmitoyltransferase catalyzes the first step in the synthesis of ceramide in the de novo pathway, which is the production of 3-ketodihydrosphingosine from serine and palmitoyl CoA.
  • inhibitors of SPT include the sphingo-fungins, lipoxamycin, myriocin, L-cycloserine and beta-chloro-L-alanine, as well as the class of Viridiofungins.
  • Ceramide synthase catalyzes the acylation of the amino group of sphingosine, sphinganine, and other sphingoid bases using acyl CoA esters.
  • inhibitors of this enzyme include the Fumonisins, the related AAL-toxin, and australifungins.
  • the Fumonisins family of inhibitors are produced by Fusarium verticillioides and includes Fumonisin B1 (FB1).
  • N-acylated forms of FB1 are known to be potent CerS inhibitors while the O-deacylated form is less potent (structures shown below; see Delgado et al ., BBA-Biomembranes 1758(12):1957-1977 (2006)).
  • Dihydroceramide desaturase is the last enzyme in the de novo biosynthesis pathway of ceramide synthesis. At least two different forms, DES1 and DES2, are known.
  • inhibitors of these enzymes include the cyclopropene-containing sphingolipid GT11 , GT54, GT45, as well as a-ketoamide (GT85, GT98, GT99), urea (GT55), and thiourea (GT77) analogs of this molecule (structures shown below; see Delgado et al ., BBA-Biomembranes 1758(12):1957-1977 (2006)).
  • Sphingomyelin hydrolysis by sphingomyelinases produces phosphorylcholine and ceramide.
  • SMases sphingomyelinases
  • At least five isotypes of SMase are known, including acid and neutral forms.
  • Several physiological inhibitors of acid SMase have been described including L-alpha-phosphatidyl-D-myo- inositol-3,5-bisphosphate, a specific acid SMase inhibitor, and L-alpha-phosphatidyl-D-myo-inositol-3, 4,5- triphosphate, a non-competitive inhibitor of acid SMase.
  • Ceramide-1 -phosphate and sphingosine-1 - phosphate have also been described as physiological inhibitors.
  • Glutathione is an inhibitor of neutral SMase at physiological concentrations with a greater than 95% inhibition observed at 5 mM GSH.
  • Compounds that are structurally unrelated to sphingomyelin but function as SMase inhibitors included desipramine, imipramine, SR33557, (3-carbazol-9-yl-propyl)-[2-(3,4-dimethoxy-phenyl)-ethyl)-methyl- amine (NB6), hexanoic acid (2-cyclo-pent-1 -enyl-2-hydroxy-1 -hydroxy-methyl-ethyl)-amide (NB12)
  • Compound SR33557 is a specific acid SMase inhibitor (72% inhibition at 30 .mu.M).
  • the compound NB6 has been reported as an inhibitor of the SMase gene transcription.
  • Inhibitors derived from natural sources include Scyphostatin, Macquarimicin A, and Alutenusin, which are non-competitive inhibitors of neutral SMase, and Chlorogentisylquinone, and Manumycin A, which are irreversible specific inhibitors of neutral SMase. Also described is alpha-mangostin, an inhibitor of acid SMase.
  • Scyphostatin analogs with inhibitory proprieties include spiroepoxide 1 , Scyphostatin, and Manumycin A sphingolactones.
  • Sphingomyelin analogs with inhibitory proprieties include 3-0- methylsphingomyelin, and 3-O-ethylsphingomyelin.
  • Table 1 provides a non-exhaustive list of exemplary sphingomyelinase inhibitors known in the art. TABLE T Exemplary Sphingomyelinase Inhibitors
  • L-carnitine 200 mcg/ml
  • siylmarin 1-phenyl-2-decanoylaminon-3-morpholine-1 -propanol
  • 1-phenyl-2- hexdecanoylaminon-3-pyrrolidino-1 -propanol Scyphostatin
  • L-carnitine glutathione
  • human milk bile salt- stimulated lipase myriocin
  • cycloserine Fumonisin 9, PPMP
  • D609 MS209
  • methylthiodihydroceramide propanolol
  • resveratrol resveratrol
  • agents comprised of polypeptide sequences have also been shown to reduce ceramide levels, as describe in U.S. Pat. No. 7,037,700, incorporated herein by reference.
  • the agent that inhibits ceramide biosynthesis is a ceramide synthase 1
  • the selective CerS1 inhibitor can be (S)-2-amino-4-(4-((3,4- dichlorobenzyl)oxy)phenyl)-2-methylbutan-1-ol (P053, structure below) or a pharmaceutically acceptable salt thereof (see Turner et al., Nat Commun . 9(1 ):3165 (2016)).
  • Glucosylceramide synthase catalyzes the transfer of glucose to Ceramide it is the first committed step in glycolipid biosynthesis.
  • Ceramidase is an enzyme which cleaves fatty acids from Ceramide, producing sphingosine which is then phosphorelated by sphngosine kinase to form sphingosine-1 - phosphate (S1 P).
  • Ceramide kinase(CERK) is the enzyme that catalyzes the formation of Ceramide-1 - Phosphate. Ceramide-1 -phosphate and sphingosine-1 -phosphate have also been described as physiological inhibitors.
  • Sphingomyelin Synthase SMS is the enzyme which causes the synthesis of SM by transfer of phosphorylcholine to ceramide. Tight association between circulating cytokines such as TNF-alpha, interleukins and TLR4 agonists and ceramide levels have been reported. TLR4 induced ceramide synthesis has also been reported to be an essential component of fat induced insulin resistance.
  • Agents that can block activity of the TLR4 and TNF-alpha pathways can be utilize to reduce circulating ceramide concentration adiponectin secretion is stimulated by FGF21and adiponectin signaling through their receptors AdipoRI and R2 stimulate deacylation of ceramide yielding sphingosine that can be converted into sphingosine 1 - phosphate.
  • FGF21 , adiponectin or Agents / antibodies that can activate the AdipoRI and R2 receptors can act to reduce circulating ceramide concentrations.
  • the methods of the invention can include reducing ceramide levels by administering a TNF-alpha inhibitor.
  • TNF-alpha inhibitors include, but not limited to, Adalimumab (Flumira), biosimilars to Flumira (Adalimumab-adbm (Cyltezo), Adalimumab-adaz (Flyrimoz), and Adalimumab-atto (Amjevita)), Certolizumab pegol (Cimzia), Etanercept (Enbrel), and Etanercept-szzs (Ereizi), a biosimilar to Enbrel.
  • TLR-4 inhibitory compounds include, but are not limited to, (i) TLR4-IN-C34, which is an aminomonosaccharide that inhibits TLR4 signaling by docking with the hydrophobic pocket of the MD2 (Matthew D et al., PLoS One (2013) 8:e65779), (ii) NBP2-26244, which is a peptide that inhibits TLR4 signaling by blocking interactions between TLR4 and its intracellular adaptor protein (Mal/TIRAP and TRAM) (Lysakova-Devine T et al., J Immunol.
  • CLI-095 which is a cyclohexene derivative that inhibits TLR4 signaling by blocking the intracellular domain of TLR4, but not the extracellular domain
  • Fibroblast Growth Factor 21 is a secreted polypeptide that belongs to a subfamily of Fibroblast Growth Factors (FGFs) that includes FGF19, FGF21 , and FGF23 (Itoh et al., (2004) Trend Genet. 20:563-69).
  • the methods of the invention can include reducing ceramide levels by administering an FGF21 agonist.
  • Exemplary FGF21 agonists include, but are not limited to, human FGF21 and analogues of FGF21 , such LY2405319 (a glycosylated FGF21 variant) PF-05231023 (molecule consisting of human FGF21 covalently linked to each Fab region of a humanized lgG1 k mAb scaffold), pegbelfermin (PEGylated FGF21 , formerly BMS-986036), efruxifermin (a 92 kDa Fc-FGF21 fusion protein, formerly AKR-001 , AMG 876), BI089-100 (a PEGylated FGF21 ), BFKB8488A (a humanized bispecific antibody that specifically activates the FGFR1/p-Klotho complex), and MK-3655 (a monoclonal antibody targeted to b-Klotho and FGFRIc, formerly NGM313), among others.
  • LY2405319 a glycosy
  • the methods of the invention can include reducing ceramide levels by administering an adiponectin receptor agonist.
  • adiponectin receptor agonists include, but are not limited to, ADP355 (dAsn-lle-Pro-Nva-Leu-Tyr-dSer-Phe-Ala-dSer), ADP399 (dAsn-lle-Pro-Nva-Leu-Tyr-dSer-Phe- Ala-dSer-His-Pro-Dab-d/Asn-lle-Pro-Nva-Leu-Tyr-dSer-Phe-Ala-dSer-His-Pro), Pep70 (Pro-Gly-Leu-Tyr- Tyr-Phe-Asp), BHD1028 (Tyr-Tyr-Phe-Ala-Tyr-His-Pro-Asn-lle-Pro-Gly- Leu-Tyr-Tyr-Phe), A
  • the methods of the invention can include reducing ceramide levels by administering an apoptosis inhibitor.
  • Any apoptosis inhibitor may be employed, wherein the apoptosis inhibitor may exhibit inhibitory activity on an extrinsic apoptotic pathway, an intrinsic apoptotic pathway, or a general apoptotic pathway.
  • Extrinsic apoptotic pathway factors that may be targeted by the apoptotic inhibitor include, but are not limited to: A20, CYLD, AP02L, Bid, Caspase-3, Caspase-7, Caspase-8, CD95L, C-IAP1 , C-IAP2, DDR4/5, DR/CD95, FADD, FLIP, ITCH, RIP2, TNF-alpha, TNFR1 , TRADD, TRAF2, TRAIL and the like.
  • Intrinsic apoptotic pathway factors that may be targeted by the apoptotic inhibitor include, but are not limited to: Apaf-1 , BAD, BAK, BAX, BCL-2, BCL-XL, BIM, Caspase-9, Cytochrome C, FBW7, MCL1 , ML-IAP,
  • apoptotic pathway factors that may be targeted by the apoptotic inhibitor include, but are not limited to: AIF, AKT/PKT, ANT, APAF1 , AP03L, ARTS, ASK1 , ATM, BAGs, BCL-X, BI-1 , BIT1 , CAD, Calpains, Caspase-10, Caspase- 12, CHK2 CYPD, DAXX, DNA-PK (Ku70), EndoG, FAS, FASL, HSP70, HSP90, HTRA2/OMI, Humanin, ICAD, IKK, IRE-alpha, MDM2, MMP, NUR77/TR3, p19ARF, p53AIP1 , PAR4, PARP, PBR, PI3K, PIDD, PKC, PML, PTEN, R
  • the agent is an inhibitor of Caspase activity, i.e. a Caspase inhibitor.
  • Caspase inhibitors that may be employed include, but are not limited to: AQZs, nicotinyl aspartyl ketones, M826, M867, IDN-6556, Ac-AAVALLPAVLLALLAPDEVD-CHO (Ac-Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu- Leu-Ala-Leu-Leu-Ala-Pro-Asp-Glu-Val-Asp-cho), Ac-AAVALLPAVLLALLAPLEHD-CHO (Ac-Ala-Ala-Val- Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Leu-Leu-Ala-Pro-Leu-G- lu-His-Asp-CHO), Ac- AAVALLPAVLLALLAPLEVD-CHO (Ac-Ala-
  • the agent is a modulator of a non-caspase member of the apoptotic pathway.
  • Modulators including e.g, antibodies, peptides, small molecules, and the like.
  • Modulators that may be employed include, but are not limited to: modulators of death receptors or death receptor complex components (e.g., TRAIL, HGS-ETR1 , HGS-TR2J, C75, EGCG, cerulenin, and the like), modulators of FLIP (e.g., CDDO, and the like), modulators of IKK (e.g., SPC-839, SC-514, a pyridooxazinone derivative, BMS-345541 , beta-carboline, a 2-amino-6-[2-cyclopropyl-methoxy)-6-hydrophenyl]-4-piperidin-4- ylnicotino- nitrile, an ureido-thiophene carboxamide derivative, an ind
  • MDM2 modulators of MDM2 (e.g., chlorofusin, sulfonamide compound 1 , 2-phenoxybenzoyl-tryptophan derivatives, nutlins, and the like) and the like.
  • the agent is an inhibitor of the general apoptotic pathway, i.e. an apoptosis inhibitor.
  • Apoptosis inhibitors that may be employed include, but are not limited to: 10058-F4 (5-[(4- Ethylphenyl)methylene]-2-thioxo-4-thiazolidinone), 4'-Methoxyflavone (2-(4-Methoxyphenyl)-4H-chromen- 4-one), BAX Inhibiting Peptide V5 (Val-Pro-Met-Leu-Lys), BEPP monohydrochloride (1 H-Benzimidazole- 1 -ethanol, 2,3-dihydro-2-imino-alpha-(phenoxymethyl)-3-(phenylmethyl)-monohydrochlor- ide), BI-6C9 (N- [4-[(4-Aminophenyl)thio]phenyl]-4-[(4-methoxyphenyl)sulfonyl]amino
  • the methods of the invention can include reducing ceramide levels by administering an mitophagy inhibitor.
  • mitophagy inhibitors include bafilomycin A1 and chloroquine, which could disturb lysosomal acidification and fusion of lysosomes with autophagosomal membranes (Georgakopoulos et al..Chemistry and Biology 21 (11 ):1585—1596 (2017)).
  • general autophagy inhibitors such as 3-methyladenine, are successfully used to suppress mitophagy.
  • An alternative indirect method to prevent mitochondrial removal is through the modulation of mitochondrial fission machinery.
  • Mitochondrial division inhibitor 1 is a quinazolinone derivative found to perturb mitochondrial morphology by inhibiting organelles division in yeast and mammalian cells (Cassidy-Stone et al. , Developmental CelM 4(2):193—204 (2008)).
  • the mitophagy inhibitor is selected from SP600125, U0126, mdivi-1 , 3- methyladenine, bafilomycin A1 , chloroquine, LY294002, SB202190, SB203580, SC79, wortmannin, and salts thereof.
  • the methods of the invention can utilize pharmaceutical compositions of an agent in combination with a pharmaceutically acceptable excipient for treating patients at risk of acute respiratory distress syndrome or respiratory failure.
  • the pharmaceutical compositions can be prepared in a variety of ways well known in the pharmaceutical art.
  • the pharmaceutical composition can contain one or more pharmaceutically acceptable carriers.
  • the cysteamine precursor, pharmaceutically acceptable salt, solvate, or prodrug thereof is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, tablet, sachet, paper, vial or other container.
  • the excipient or carrier is selected on the basis of the mode and route of administration. As is known in the art, the type and amount of excipients vary depending upon the intended drug release characteristics.
  • Suitable pharmaceutical carriers as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro,
  • excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium carbonate, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, cellulose derivatives, polyvinylpyrrolidone, poly(lactic-co-glycolic acid) (PLGA), cellulose, water, syrup, methyl cellulose, vegetable oils, polyethylene glycol, hydrophobic inert matrix, carbomer, hypromellose, gelucire 43/01 , docusate sodium, and white wax.
  • suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium carbonate, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, cellulose derivatives, polyvinylpyrrolidone, poly(lactic-co-glycoli
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending agents such as methyl- and propylhydroxy-benzoates
  • preserving agents such as methyl- and propylhydroxy-benzoates
  • sweetening agents and flavoring agents.
  • oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals or granules, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • Excipients are selected to provide acceptable organoleptic properties, to control drug release properties, to facilitate efficient manufacturing and to ensure long term stability of pharmaceutical compositions, among other considerations known to those skilled in the arts of pharmacology, pharmaceutics and drug manufacturing.
  • the excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antia
  • excipients can be colorants, flavoring agents, plasticizers, humectants, preservatives, buffering agents, stabilizing agents and the like. Many of these excipients are sold by multiple excipient manufacturers in a variety of chemical forms, and/or can be used at different concentrations, and/or in different combinations with other excipients, with ensuing differences in performance characteristics. Specific excipients may accomplish more than one purpose in a formulation.
  • the biomarkers e.g., of ceramide (d18:0/24:1), ceramide (d18:1/24:1), ceramide (d18:1/24:0), ceramide (d18.0/20:0), ceramide (d18.1/20:0), ceramide (d18:1/22:0), and hexosylceramide (d18:1/22:0)
  • ceramide d18:0/24:1
  • ceramide ceramide (d18:1/24:1)
  • ceramide d18.0/20:0
  • ceramide d18.1/20:0
  • the methods of the invention can include treating a subject at risk with inhibitors of ceramide biosynthesis, oxygen, antiviral agents, and/or anti-inflammatory agents.
  • the subject can be treated one or more times per day (e.g., once, twice, or thrice) or every so- many hours (e.g., about every 8, 12, or 24 hours).
  • the pharmaceutical composition is administered 1 or 2 times per 24 hours.
  • the time course of treatment may be of varying duration, e.g., for two, three, four, five, six, seven, eight, nine, ten, or more days, two weeks, or 1 month.
  • the treatment can be twice a day for three days, twice a day for seven days, twice a day for ten days. ⁇
  • one or more biomarkers e.g., of ceramide (d18:0/24:1 ), ceramide (d18:1/24:1), ceramide (d18:1/24:0), ceramide (d18.0/20:0), ceramide (d18.1/20:0), ceramide (d18:1/22:0), and hexosylceramide (d18:1/22:0)
  • ceramide d18:0/24:1
  • ceramide d18:1/24:1
  • ceramide d18.0/20:0
  • ceramide ceramide
  • ceramide d18.1/20:0
  • hexosylceramide e.g., of ceramide (d18:1/22:0)
  • MS/MS data was collected for structural deduction and data base searches.
  • the combined monitored ion profile confirmed the PCA-directed selection process. Structural deduction and data base searches demonstrated that >300 of the metabolites identified belong to the Lipid family.
  • a biological process associated with generation of such a profile would be apoptosis with two signatures, PS and Cer enriched.
  • Cer with C16:0 and C18:0 fatty acids have been reported to be elevated in apoptosis.
  • Mitophagy a tightly regulated process for mitochondria degradation, can activate a type of programmed cell death independent of apoptosis, also named lethal mitophagy, dependent on C18- ceramide generated by CerS1 should also be considered.
  • Figures 1 A-1C are a series of bar graphs depicting the fold sum of MEDM changes in peak areas of identified lipid classes between the non-infected and with (Fig. 1A) mild (Fig 1C) with respiratory distress symptoms.
  • Figure 1C depicts comparative differences analysis of lipids with in the lipidome of plasma, in individuals with COVID-19 infection with mild vs respiratory distress symptoms. These figures show that COVID-19 causes profound changes in the levels of lipid’s in the plasma of infected individuals.
  • Figures 2A and 2B show that a 200 nmoles/mL increase in plasma Ceramide levels to be correlated with transition from mild symptoms to the observed respiratory distress symptoms in COVID-19 infected individuals.
  • the fold sum of MEDM changes of peak area times number of subclasses identified per lipid class are shown.
  • Figure 2A depicts an overall estimation of relative changes in concentration of various lipid classes.
  • Figure 2B depicts the relative Concentration of Lipid’s per class in nmoles/ml of plasma as determined via SRM 1950 consensus LIPID MAPS consortium.
  • Figure 3 shows the observed increases in plasma Ceramide concentration back into it’s subclass levels. This figure shows the relative contribution of each of the subclasses, in terms of fold increases in plasma compared to the uninfected and in the mild vs the respiratory distress patients. These figures show 20 to 160 fold increase, relative to the uninfected plasma, of Cer(d18:0/24:1), Cer(d18:1/24:1), Cer(d18.0/20:0), and Cer(d18:1/20:0) in plasma of mild vs the respiratory distress patients.
  • Figure 4 shows the relative ratios of Ceramide/HexCer for each of the observed subclass in the plasma of Covid-19 infected individuals with mild and sever symptoms. This figure shows that the Cer(d18:1/22 :0)/HexCer(d18:1/22:0) ratio is significantly higher in the plasma of Covid-19 infected individuals with respiratory distress. This demonstrates a change that can act as the predictor of the severe respiratory distress symptom.
  • Ammonium Formate and Formic acid were purchased from SigmaAldrich Chemicals Co., (St. Louis, Mo, USA), LC-MS Grade Methanol, and Optima-grad acetonitrile (ACN) from Fisher Scientific (Pittsburg, PA, USA).
  • a Millipore Mili-Q purification system (Bedford, MA, USA) was used to prepare deionized water.
  • a total of 50 Human Plasma samples (K3EDTA) from active COVID-19 infected participants (positive via PCR), including 18 with Severe Respiratory Distress and 32 with mild symptoms were purchased from PRECISION FOR MEDICINE (Norton, MA, USA). All biospecimens have been certified to have been collected under a clinical study that has been reviewed by an institutional/independent Review Board (IRB) in accordance with the requirements of local governing regulatory agencies, including the DHHS and FDA Codes of Federal Regulations, on the Protection of Human Subjects (45 CFR Part 46 and 21 CFR Part 56, respectively). The participants age range was 19 - 83 with 37 of them being female and 13 males.
  • the NIST Standard Reference Material for Human Plasma was purchased from SigmaAldrich Chemicals Co., (St. Louis, Mo, USA).
  • the ISP contains for internal standards six steroids in its panel included d7- Androstenedione, d4- Cortisol, d5- DHEAS, d5-11-Deoxycortisol, d8-17-hydroxyprogesterone, and d3- Testosterone.
  • the ion source temperature was set to 500 S C and the ion source voltage was set to 5500 V.
  • An information dependent acquisition (IDA) method consisting of a TOF-MS survey (250-1100 Da for 350 msec).
  • the declustering potential (DP) was set to 80V.
  • the collision energy (CE) was set to 10 eV with a collision energy spread (CES) of ⁇ 0 eV.
  • DBS dynamic background subtraction
  • MarkerViewTM Software 1 .3 (SCIEX) was used to process, aligned, deconvoluted, and normalized (sum of total area) the obtained raw data in which the retention time (RT) was from 0.5 min to 26 min. Mass and RT tolerance values were set to 10 ppm and 0.15 minutes. Mass and RT of internal standards used for analysis include: d7-Androstenedione, d4- Cortisol, d5- DHEAS, d5-11-Deoxycortisol, d8-17-hydroxyprogesterone, and d3-Testosterone introduced via the ISP mixture during sample preparation. Principal component analysis (PCA) was used to visualize system stability of the system and sample distribution.
  • PCA Principal component analysis
  • the orthogonal partial least squares discriminant analysis was used to identify the variables responsible for the discrimination.
  • a list of the intensities for each detected peak was generated, using retention time and the mass- to-charge (m/z) ratio data pairs as the parameters for each ion.
  • Manual scanning of the 10,000 spectral features represented by a unique m/z, retention time, and peak area allowed for generation of a list of 670 peaks of interest used for further evaluation.
  • the Formula Finder algorithm was used to identify potential differential metabolites and generate a group of probable formulas on an unknown ion based on the secondary fragment information, mass error, and isotope distribution patterns.

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  • Food Science & Technology (AREA)
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Abstract

L'invention concerne l'analyse diagnostique de concentrations circulantes de céramide (dl 8:0/24 : 1), de céramide (dl 8: 1/24: 1), de céramide (dl 8: 1/24:0), de céramide (dl 8,0/20:0), de céramide (dl 8,1/20:0), de céramide (dl 8: 1/22:0), et d'hexosylcéramide (dl 8: 1/22:0) chez un patient atteint d'une infection par le bétacoronavirus et présentant un risque de syndrome de détresse respiratoire aiguë (SDRA) ou d'insuffisance respiratoire. L'invention concerne également l'utilisation d'agents de modulation de céramides pour le traitement et la prophylaxie du SDRA et d'une insuffisance respiratoire chez des patients atteints d'infections par le bétacoronavirus, telles que des infections par le SARS-CoV-2, le SARS-CoV-1 ou le MERS-CoV.
PCT/IB2022/052222 2021-03-12 2022-03-11 Procédés d'identification de sujets atteints d'infections à betacoronavirus qui présentent un risque de syndrome respiratoire aigu et leurs procédés de traitement Ceased WO2022190064A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011137427A2 (fr) * 2010-04-30 2011-11-03 The Johns Hopkins University Compositions et procédés pour traiter des maladies pulmonaires
WO2013181530A1 (fr) * 2012-06-01 2013-12-05 Icahn School Of Medicine At Mount Sinai Niveaux de céramide dans le traitement et la prévention d'infections
WO2020185675A1 (fr) * 2019-03-08 2020-09-17 University Of Virginia Patent Foundation Compositions et méthodes de modulation d'infections virales par régulation de glucosylcéramides

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011137427A2 (fr) * 2010-04-30 2011-11-03 The Johns Hopkins University Compositions et procédés pour traiter des maladies pulmonaires
WO2013181530A1 (fr) * 2012-06-01 2013-12-05 Icahn School Of Medicine At Mount Sinai Niveaux de céramide dans le traitement et la prévention d'infections
WO2020185675A1 (fr) * 2019-03-08 2020-09-17 University Of Virginia Patent Foundation Compositions et méthodes de modulation d'infections virales par régulation de glucosylcéramides

Non-Patent Citations (8)

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Title
CATERINO MARIANNA, GELZO MONICA, SOL STEFANO, FEDELE ROBERTA, ANNUNZIATA ANNA, CALABRESE CECILIA, FIORENTINO GIUSEPPE, D’ABBRACCIO: "Dysregulation of lipid metabolism and pathological inflammation in patients with COVID-19", SCIENTIFIC REPORTS, vol. 11, no. 1, 1 December 2021 (2021-12-01), XP055887862, DOI: 10.1038/s41598-021-82426-7 *
DEI CAS MICHELE, OTTOLENGHI SARA, MORANO CAMILLO, RINALDO ROCCO, RODA GABRIELLA, CHIUMELLO DAVIDE, CENTANNI STEFANO, SAMAJA MICHEL: "Link between serum lipid signature and prognostic factors in COVID-19 patients", SCIENTIFIC REPORTS, vol. 11, no. 1, 1 December 2021 (2021-12-01), XP055968679, DOI: 10.1038/s41598-021-00755-z *
GHIDONI RICCARDO, CARETTI ANNA, SIGNORELLI PAOLA: "Role of Sphingolipids in the Pathobiology of Lung Inflammation", MEDIATORS OF INFLAMMATION., RAPID COMMUNICATION OF OXFORD LTD., OXFORD., GB, vol. 2015, 1 January 2015 (2015-01-01), GB , pages 1 - 19, XP055968674, ISSN: 0962-9351, DOI: 10.1155/2015/487508 *
GRAY NICOLA, LAWLER NATHAN, ZENG ANNIE, RYAN MONIQUE, BONG SZE, BOUGHTON BERIN, BIZKARGUENAGA MAIDER, BRUZZONE CHIARA, EMBADE NIEV: "Diagnostic Potential of the Plasma Lipidome in Infectious Disease: Application to Acute SARS-CoV-2 Infection", METABOLITES, vol. 11, no. 7, 20 July 2021 (2021-07-20), pages 467, XP055968675, DOI: 10.3390/metabo11070467 *
HOROWITZ R.I. ET AL.: "Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases", RESPIRATORY MEDICINE CASE REPORTS, vol. 30, no. 101063, 2020, XP086239681, DOI: 10.1016/j.rmcr.2020.101063 *
KHODADOUST MEHRAN M.: "Inferring a causal relationship between ceramide levels and COVID-19 respiratory distress", SCIENTIFIC REPORTS, vol. 11, no. 1, 1 December 2021 (2021-12-01), XP055887739, DOI: 10.1038/s41598-021-00286-7 *
TORRETTA ENRICA, GARZIANO MICAELA, POLISENO MARIACRISTINA, CAPITANIO DANIELE, BIASIN MARA, SANTANTONIO TERESA ANTONIA, CLERICI MAR: "Severity of COVID-19 Patients Predicted by Serum Sphingolipids Signature", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 22, no. 19, pages 10198, XP055968677, DOI: 10.3390/ijms221910198 *
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