WO2023172441A2 - Inhibiteurs de trpv4 pour le traitement d'infections virales respiratoires - Google Patents

Inhibiteurs de trpv4 pour le traitement d'infections virales respiratoires Download PDF

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WO2023172441A2
WO2023172441A2 PCT/US2023/014445 US2023014445W WO2023172441A2 WO 2023172441 A2 WO2023172441 A2 WO 2023172441A2 US 2023014445 W US2023014445 W US 2023014445W WO 2023172441 A2 WO2023172441 A2 WO 2023172441A2
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respiratory
trpv4
virus
trpv4 inhibitor
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WO2023172441A3 (fr
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Haiqing BAI
Donald E. Ingber
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President And Fellows Of Harvard College
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides

Definitions

  • Respiratory viruses are the most frequent causative agents of disease in humans, impacting morbidity and mortality worldwide, and many of their injurious effects are due to stimulation of inflammatory responses in host tissues and organs.
  • Common respiratory agents from several virus families are well adapted to efficient person-to-person transmission and circulate globally. Community-based studies have confirmed that these viruses are the predominant etiological agents of acute respiratory infections.
  • the respiratory viruses that most commonly circulate as endemic or epidemic agents are influenza virus, respiratory syncytial virus, parainfluenza viruses, metapneumovirus, rhinovirus, coronaviruses, adenoviruses, and bocaviruses. Vaccines and effective antiviral drugs are not yet available for most of these viruses.
  • compositions and methods for treating respiratory virus infections by inhibiting respiratory virus replication and/or inhibiting an inflammatory response to infection with a respiratory virus, for example, an influenza virus or a coronavirus.
  • Respiratory viruses including influenza virus and coronavirus, pose a great challenge for public health. While many antiviral agents and vaccines directly target viruses, their development usually lags behand the progression of pandemics and their effects are compromised by rapid viral evolution. Regardless of the nature of the viruses, they can cause severe symptoms when the initial infection spreads from the upper airway to the distal lung, causing viral pneumonia, lung edema, and acute respiratory distress syndrome (ARDS).
  • ARDS acute respiratory distress syndrome
  • TRPV4 transient receptor potential vanilloid-type 4
  • Some aspects of the present disclosure provide methods of treating a respiratory virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a transient receptor potential vanilloid-type 4 (TRPV4) inhibitor.
  • the subject is infected with a respiratory virus (e.g., has tested positive for a respiratory virus).
  • the subject is at risk of a respiratory virus infection.
  • the present disclosure also provides the use of TRPV4 inhibitors (alone or in combination with one or more antiviral agents) to treat an inflammatory response in a subject caused by a disease state, including infections caused by viruses, e.g., respiratory viruses.
  • These methods can treat one or more symptoms of respiratory virus infections, including symptoms related to aberrant inflammation (e.g., viral pneumonia, lung edema, and acute respiratory distress syndrome (ARDS)), thereby decreasing the likelihood of serious illness and death.
  • ARDS acute respiratory distress syndrome
  • the therapeutically effective amount reduces an inflammatory immune response induced by the respiratory virus infection in the subject, relative to a control. In some embodiments, the therapeutically effective amount reduces an inflammatory immune response by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, relative to a control. In some embodiments, the therapeutically effective amount reduces inflammatory cytokine production in the subject, relative to a control.
  • the inflammatory cytokines are selected from interferon lambda 1 (IFNkl), interferon gamma- induced protein 10 (IP- 10), interleukin-6 (IL- 6), interleukin-8 (IL-8), granulocyte-macrophage colony-stimulating factor (GM-CSF), and Monocyte chemoattractant protein- 1 (MCP-1).
  • IFNkl interferon lambda 1
  • IP- 10 interferon gamma- induced protein 10
  • IL-6 interleukin-6
  • IL-8 interleukin-8
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • MCP-1 Monocyte chemoattractant protein- 1
  • the therapeutically effective amount reduces viral replication in the subject, relative to a control. In some embodiments, the therapeutically effective amount reduces viral replication by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, relative to a control. In some embodiments, the therapeutically effective reduces viral load in the subject, relative to a control. In some embodiments, the therapeutically effective reduces viral load by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, relative to a control.
  • Also provided herein are methods comprising administering a TRPV4 inhibitor to a subject, wherein the subject has or is at risk of a respiratory virus infection.
  • the TRPV4 inhibitor is administered in an amount effective to treat a respiratory virus infection in the subject.
  • the TRPV4 inhibitor is administered in an amount effective to reduce an inflammatory immune response induced by the respiratory virus infection in the subject, relative to a control. In some embodiments, the TRPV4 inhibitor is administered in an amount effective to reduce an inflammatory immune response induced by the respiratory virus infection by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, relative to a control. In some embodiments, the amount is effective to reduce inflammatory cytokine production by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, relative to a control.
  • the amount is effective to reduce inflammatory cytokine production in the subject, relative to a control.
  • the inflammatory cytokines are selected from IFNL1, IP-10, IL-6, IL-8, and GM-CSF. Other inflammatory cytokines are contemplated herein.
  • the TRPV4 inhibitor is administered in an amount effective to reduce viral replication in the subject, relative to a control. In some embodiments, the TRPV4 inhibitor is administered in an amount effective to reduce viral replication by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, relative to a control.
  • the TRPV4 inhibitor is administered in an amount effective to reduce viral mRNA in the subject, relative to a control. In some embodiments, the TRPV4 inhibitor is administered in an amount effective to reduce viral mRNA by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, relative to a control.
  • the subject has one or more symptom(s) of a respiratory virus infection. In some embodiments, one or more of the symptom(s) is related to aberrant inflammation. In some embodiments, the aberrant inflammation is aberrant pulmonary inflammation. In some embodiments, the subject has an inflammatory disease. In some embodiments, the subject has acute respiratory distress syndrome (ARDS). In some embodiments, the subject requires use of a respiratory ventilator.
  • ARDS acute respiratory distress syndrome
  • the respiratory virus is selected from the group consisting of influenza viruses, coronaviruses, rhinoviruses, enteroviruses, parainfluenza viruses, metapneumoviruses, respiratory syncytial viruses, adenoviruses, and bocaviruses.
  • the respiratory virus is a common cold virus.
  • the respiratory virus is an influenza virus.
  • the respiratory virus is a betacoronavirus.
  • the betacoronavirus is SARS-CoV-2.
  • the TRPV4 inhibitor is a small molecule. In some embodiments, the TRPV4 inhibitor is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the TRPV4 inhibitor comprises a compound of Formula (I), or a pharmaceutically acceptable sat thereof. In some embodiments, the TRPV4 inhibitor comprises Compound 1:
  • the TRPV4 inhibitor comprises Compound 1. In some embodiments, the TRPV4 inhibitor is Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the TRPV4 inhibitor is Compound 1.
  • the TRPV4 inhibitor is an antibody or antigen-binding fragment thereof.
  • the TRPV4 inhibitor is a nucleic acid.
  • the nucleic acid is selected from the group consisting of micro RNAs (miRNAs), short interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs).
  • the TRPV4 inhibitor is a programmable nuclease.
  • the programmable nuclease is selected from the group consisting of RNA- guided CRISPR nucleases (in combination with a guide RNA (gRNA)), zinc finger nucleases, transcription activator-like effector nucleases, and meganucleases.
  • a method provided herein further comprises administering to the subject an antiviral agent. In some embodiments, a method provided herein further comprises administering to the subject an inducer of host protective response. In some embodiments, the inducer of host protective response is a type I interferon. In some embodiments of the methods provided herein, the subject is a human.
  • FIGs 1A-1B Mechanical strain reversibly regulates innate immune response in Alveolus Chip in uninfected chips.
  • FIG. 1A shows a volcano plot of differentially expressed genes (DEGs) comparing epithelial cells from Alveolus Chips under static or 5% strain culture condition for 4 days. DEGs (P a dj ⁇ 0.05) with a fold change >1.5 (or ⁇ — 1.5) are provided above the dotted line within the graph. The names of DEGs belonging to the innate immune pathway are labeled.
  • FIG. IB shows a dot plot of the biological processes activated or suppressed by 5% strain vs. static culture condition in Alveolus Chips from FIG. 1A.
  • FIG. 2 shows the relative abundance of mechanosensitive ion channels expressed in the human Alveolus Chip.
  • Graph shows the expression of these mechanosensors in the epithelial and endothelial cells on-chip, as determined from RNA-seq. TPM, transcript per million.
  • FIGs. 3A-3C TRPV4 inhibitor Compound 1 decreases overstretch-induced lung inflammatory responses.
  • FIGs. 4A-4D Inhibition of TRPV4 decreases viral load and host inflammatory responses.
  • FIG. 4A shows an illustration of the experimental protocol involving prophylactic treatment with signaling inhibitors for 48 hours prior to viral infection of the human Alveolus Chip.
  • FIG. 4B shows the cytotoxicity of TRPV4 inhibitor on human Alveolus Chip measured using an EDH assay.
  • FIG. 4C shows graphs of cytokine levels on chips.
  • FIG. 4D shows graph of mRNA levels of H3N2 NP in epithelial cells treated with azeliragon or Compound 1 at indicated doses on-chip.
  • TRPV4 inhibitors such as TRPV4 inhibiting small molecules, for inhibiting respiratory virus replication and/or suppressing inflammation associated with respiratory virus infection.
  • TRPV4 inhibitors can be used treat infection with various respiratory viruses including infections with various influenza and coronavirus strains (e.g., SARS-CoV-2).
  • TRPV4 inhibitors can be used to reduce severe inflammation associated with respiratory virus infections, e.g., in the case of viral pneumonia and ARDS. As inflammation and ARDS are observed in patients on respiratory ventilators that exert cyclic mechanical strain on lung, TRPV4 inhibitors may also be useful, in some embodiments, to suppress inflammation in these conditions.
  • TRPV4 Transient receptor potential vanilloid-type 4
  • TRPV4 is an ion channel protein that in humans is encoded by the TRPV4 gene.
  • TRPV4 is a member of the vanilloid subfamily in the transient receptor potential (TRP) superfamily of ion channels.
  • TRPV4 protein is a Ca 2+ - permeable, nonselective cation channel that has been found involved in multiple physiologic functions, dysfunctions and disease.
  • the TRPV4 channel is activated by osmotic, mechanical and chemical cues. It also responds to thermal changes (e.g., warmth). Channel activation can also be sensitized by inflammation and injury.
  • TRPV4 transient receptor potential vanilloid-type 4
  • a respiratory virus infection in a subject e.g., by treating one or more symptoms of a respiratory virus infection such as pulmonary inflammation
  • administering comprising administering to the subject a TRPV4 inhibitor, wherein the subject is infected with or at risk of viral infection.
  • a “TRPV4 inhibitor” is an agent that reduces a measurable level of or eliminates TRPV4 activity, for example, by inhibiting TRPV4 gene expression, mRNA expression, protein expression, and/or protein activity e.g., signaling).
  • the TRPV4 inhibitor is an inhibitor of TRPV4 gene expression.
  • the TRPV4 inhibitor is an inhibitor of TRPV4 mRNA expression.
  • the TRPV4 inhibitor is an inhibitor of TRPV4 protein expression.
  • the TRPV4 inhibitor is an inhibitor of TRPV4 protein activity (e.g., signaling).
  • the TRPV4 inhibitor is an inhibitor of any combination of TRPV4 gene expression, mRNA expression, protein expression, and protein activity.
  • a TRPV4 inhibitor inhibits TRPV4 protein activity (e.g., signaling).
  • a TRPV4 inhibitor may reduce TRPV4 protein activity (e.g., signaling) by at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%, relative to a control.
  • a control may be, for example, a measurable level of TRPV4 protein activity (e.g., signaling) in the absence of the TRPV4 inhibitor.
  • the TRPV4 inhibitor is a modality selected from the group consisting of small molecules, antibodies and antigen-binding fragments thereof, nucleic acids (e.g., micro RNAs (miRNAs), short interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs)), and programmable nucleases (e.g., RNA-guided CRISPR nucleases, zinc finger nucleases, transcription activator-like effector nucleases, and meganucleases).
  • nucleic acids e.g., micro RNAs (miRNAs), short interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs)
  • programmable nucleases e.g., RNA-guided CRISPR nucleases, zinc finger nucleases, transcription activator-like effector nucleases, and meganucleases.
  • the TRPV4 inhibitor is a small molecule.
  • “Small molecule(s)” include organic and inorganic compounds (including heterorganic and organometallic compounds) generally having a molecular weight less than about 5,000 grams per mole, e.g., organic or inorganic compounds having a molecular weight less than about 2,000 grams per mole, e.g., organic or inorganic compounds having a molecular weight less than about 1,000 grams per mole, e.g., organic or inorganic compounds having a molecular weight less than about 500 grams per mole, and salts, esters, and other pharmaceutically acceptable forms of such compounds.
  • Non-limiting examples of small molecule TRPV4 inhibitors are provided in Table 1.
  • the TRPV4 inhibitor comprises a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • Ri is independently Ci-6 alkyl or C3-6 cycloalkyl
  • R2 is independently -OH, -OC1-4 alkyl, C1-4 alkyl, -CH2OH, -F, -CH2OC1-4 alkyl, -CF3, or -CF 2 H;
  • R3 is morpholinyl, piperidinyl, pyrrolidinyl, or hexahydroazepinyl, all of which may be unsubstituted or substituted by one or two R2; or R3 is -N(CI-6 alkyl)2, wherein C1-6 alkyl may be unsubstituted or substituted by -OH or -OCH3;
  • R4 is independently -CF3, halogen, C1-3 alkyl, or -OC1-3 alkyl;
  • R 5 is independently ’ , -SO2R1, -NH 2 , -NHSO2R1, -NR1SO2R1,
  • Re is independently halogen, methyl, or -OMe
  • R7 is pyrrolidinyl, morpholinyl, or piperidinyl; n is independently 0, 1, or 2;
  • X is N or C; and y is independently 0, 1, or 2.
  • Alkyl refers to a monovalent saturated hydrocarbon chain having the specified number of member atoms.
  • C1-4 alkyl refers to an alkyl group having from 1 to 4 member atoms, inclusive.
  • Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches.
  • Alkyl includes methyl, ethyl, propyl, (i.e., n- propyl and iso-propyl), and butyl (e.g., n-butyl, iso-butyl, sec-butyl, and t-butyl).
  • Alkenyl refers to a monovalent unsaturated hydrocarbon chain having the specified number of member atoms and comprising a carbon-carbon double bond.
  • C2-4 alkenyl refers to an alkenyl group having from 2 to 4 member atoms, inclusive.
  • the alkene i.e., carbon-carbon double bond
  • the alkene may be internal or terminal.
  • Vinyl (C2 alkenyl) is an example of an alkenyl group.
  • Cycloalkyl refers to a monovalent saturated or unsaturated hydrocarbon ring having the specified number of member atoms.
  • C3-6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms, inclusive.
  • Unsaturated cycloalkyl groups have one or more carbon-carbon double bonds within the ring.
  • Cycloalkyl groups are not aromatic. Cycloalkyl includes cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.
  • Halo or “halogen” refers to fluorine, chlorine, bromine, or iodine.
  • “Substituted” in reference to a group indicates that one or more hydrogen atom attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e., one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituents, one or more (as appropriate) member atoms within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.
  • “Pharmaceutically acceptable salts” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the peptides of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (CI-4 alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • the TRPV4 inhibitor comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the TRPV4 inhibitor comprises a compound of Formula (I). In some embodiments, the TRPV4 inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the TRPV4 inhibitor is a compound of Formula (I).
  • the TRPV4 inhibitor comprises Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the TRPV4 inhibitor comprises Compound 1. In some embodiments, the TRPV4 inhibitor is Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the TRPV4 inhibitor is Compound 1.
  • the TRPV4 inhibitor comprises Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the TRPV4 inhibitor comprises Compound 2. In some embodiments, the TRPV4 inhibitor is Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the TRPV4 inhibitor is Compound 2.
  • the TRPV4 inhibitor is an antibody or antigen-binding fragment thereof.
  • Antibody refers to a molecule that specifically binds to, or is immunologically reactive with, a particular antigen and includes at least the variable domain of a heavy chain, and normally includes at least the variable domains of a heavy chain and of a light chain of an immunoglobulin. Unless otherwise indicated, the term “antibody” (Ab) is meant to include both intact (whole) molecules as well as antibody fragments (such as, for example, Fab and F(ab')2 fragments) that are capable of specifically binding to a target protein.
  • Antibodies include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized, primatized, or chimeric antibodies, heteroconjugate antibodies (e.g., bi- tri- and quad-specific antibodies, diabodies, triabodies, and tetrabodies), single-domain antibodies (sdAb), epitope-binding fragments, e.g., Fab, Fab' and F(ab')2, Fd, Fvs, singlechain Fvs (scFv), rlgG, single-chain antibodies, disulfide-linked Fvs (sdFv), fragments containing either a VL or VH domain, fragments produced by an Fab expression library, and anti-idiotypic (anti-Id) antibodies.
  • heteroconjugate antibodies e.g., bi- tri- and quad-specific antibodies, diabodies, triabodies, and tetrabodies
  • single-domain antibodies sdAb
  • epitope-binding fragments
  • Antibody molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass of immunoglobulin molecule.
  • Antigen-binding fragment refers to one or more fragments of an immunoglobulin that retain the ability to specifically bind to a target antigen.
  • the antigen- binding function of an immunoglobulin can be performed by fragments of a full-length antibody.
  • the antibody fragments can be a Fab, F(ab’)2, scFv, SMIP, diabody, a triabody, an affibody, a nanobody, an aptamer, or a domain antibody.
  • binding fragments encompassed by the term “antigen-binding fragment” of an antibody include, but are not limited to: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb (Ward et al., Nature 341:544-546, 1989) including VH and VL domains; (vi) a dAb fragment that consists of a VH domain; (vii) a dAb that consists of a VH or a VL domain; (viii) an isolated complementarity determining region (CDR); and (ix) a combination
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv)).
  • scFv single chain Fv
  • Other antibody fragments are described above. These antibody fragments can be obtained using conventional techniques known to those of skill in the art, and the fragments can be screened for utility in the same manner as intact antibodies.
  • Antigen-binding fragments can be produced by recombinant DNA techniques, enzymatic or chemical cleavage of intact immunoglobulins, or, in certain cases, by chemical peptide synthesis procedures known in the art.
  • the TRPV4 inhibitor is a nucleic acid. In some embodiments, the TRPV4 inhibitor is an antisense oligonucleotide. Antisense oligonucleotide (ASOs) are small-sized single- stranded nucleic acids that bind to their target RNA or DNA sequence inside cells to cause gene silencing. In some embodiments, a TRPV4 inhibitor is an ASO that binds to a nucleic acid encoding TRPV4.
  • ASOs Antisense oligonucleotide
  • the TRPV4 inhibitor is an RNA interference molecule.
  • RNA interference molecules include micro RNAs, short interfering RNAs, and short hairpin RNAs.
  • Small RNA molecules regulate eukaryotic gene expression during development and in response to stresses including viral infection. Specialized ribonucleases and RNA binding proteins govern the production and action of small regulatory RNAs. After initial processing in the nucleus by Drosha, pre-miRNAs are transported to the cytoplasm, where Dicer cleavage generates mature microRNAs (miRNAs) and short interfering RNAs (siRNAs).
  • miRNAs microRNAs
  • siRNAs short interfering RNAs
  • a TRPV4 inhibitor is an RNA interference molecule that binds to a nucleic acid encoding TRPV4 .
  • the TRPV4 inhibitor is a programmable nuclease, for example, an RNA-guided nuclease.
  • programmable nucleases include CRISPR nucleases, zinc finger nucleases, transcription activator-like effector nucleases, and meganucleases.
  • Transcription activator- like effector nucleases are restriction enzymes that can be engineered to cut specific sequences of DNA. They are made by fusing a TAL effector DNA-binding domain to a DNA cleavage domain (a nuclease which cuts DNA strands). Transcription activator-like effectors (TALEs) can be engineered to bind to practically any desired DNA sequence, so when combined with a nuclease, DNA can be cut at specific locations.
  • TALEs Transcription activator-like effectors
  • the restriction enzymes can be introduced into cells, for use in gene editing or for genome editing in situ, a technique known as genome editing with engineered nucleases.
  • Zinc-finger nucleases are artificial restriction enzymes generated by fusing a zinc finger DNA-binding domain to a DNA-cleavage domain. Zinc finger domains can be engineered to target specific desired DNA sequences, and this enables zinc-finger nucleases to target unique sequences within complex genomes. By taking advantage of endogenous DNA repair machinery, these reagents can be used to precisely alter the genomes of higher organisms.
  • the CRISPR-Cas system is a prokaryotic immune system that confers resistance to foreign genetic elements such as those present within plasmids and phages and provides a form of acquired immunity.
  • RNA harboring the spacer sequence helps Cas (CRISPR- associated) proteins recognize and cut foreign pathogenic DNA.
  • Other RNA-guided Cas proteins cut foreign RNA.
  • CRISPR are found in approximately 50% of sequenced bacterial genomes and nearly 90% of sequenced archaea. These systems have created CRISPR gene editing that commonly utilizes the cas9 gene.
  • Meganucleases are endodeoxyribonucleases characterized by a large recognition site (double- stranded DNA sequences of 12 to 40 base pairs); as a result, this site generally occurs only once in any given genome. For example, the 18-base pair sequence recognized by the I- Scel meganuclease would on average require a genome twenty times the size of the human genome to be found once by chance (although sequences with a single mismatch occur about three times per human-sized genome). Meganucleases are therefore considered to be the most specific naturally occurring restriction enzymes.
  • a TRPV4 inhibitor is a programmable nuclease system designed to target a nucleic acid encoding TRPV4.
  • any combination of two or more of the agents provided herein may be administered to a subject to treat a viral infection, such as a respiratory virus infection.
  • a viral infection such as a respiratory virus infection.
  • any therapeutically effective amount of an agent as disclosed herein can be administered to a subject in need thereof.
  • compositions comprising any of the agents as disclosed herein (e.g., TRPV4 inhibitors).
  • the compositions further comprise a pharmaceutically acceptable excipient (e.g., carrier, buffer, and/or salt, etc.).
  • a pharmaceutically acceptable excipient e.g., carrier, buffer, and/or salt, etc.
  • a molecule or other substance/agent is considered “pharmaceutically acceptable” if it is approved or approvable by a regulatory agency of the Federal government or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans.
  • An excipient may be any inert (inactive), non-toxic agent, administered in combination with an agent provided herein.
  • Non-limiting examples of pharmaceutically acceptable excipients include water, saline, dextrose, glycerol, ethanol and combinations thereof. The excipient may be selected on the basis of the mode and route of administration, and standard pharmaceutical practice.
  • Agents as disclosed herein, in some embodiments, may be formulated in a delivery vehicle.
  • Non-limiting examples of delivery vehicles include nanoparticles, such as nanocapsules and nanospheres. See, e.g., Sing, R et al. Exp Mol Pathol. 2009;86(3):215-223.
  • nanoparticles are less than 1 pm in diameter. In some embodiments, nanoparticles are between about 1 and 100 nm in diameter.
  • Nanoparticles include organic nanoparticles, such as dendrimers, liposomes, or polymeric nanoparticles. Nanoparticles also include inorganic nanoparticles, such as fullerenes, quantum dots, and gold nanoparticles. Compositions may comprise an aggregate of nanoparticles. In some embodiments, the aggregate of nanoparticles is homogeneous, while in other embodiments the aggregate of nanoparticles is heterogeneous.
  • a nanocapsule is often comprised of a polymeric shell encapsulating a drug e.g., agents of the present disclosure). Nanospheres are often comprised of a solid polymeric matrix throughout which the drug (e.g., agent) is dispersed.
  • the nanoparticle is a lipid particle, such as a liposome. See, e.g., Puri, A et al. Crit Rev Ther Drug Carrier Syst. 2009;26(6):523-80.
  • the term ‘nanoparticle’ also encompasses microparticles, such as microcapsules and microspheres.
  • compositions comprising any of the agents disclosed herein may be found, for example, in Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Co., Easton, Pa (1990) (incorporated herein by reference in its entirety).
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation .
  • Administration and Treatment Methods are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation .
  • any of the agents or compositions disclosed herein may be administered to a subject (e.g., mammalian subject, such as a human, mouse, rabbit, goat, sheep or pig) to treat a viral infection, such as a respiratory virus infection.
  • a subject e.g., mammalian subject, such as a human, mouse, rabbit, goat, sheep or pig
  • Treatment refers to the treatment of a disease e.g., a disease caused by a viral infection), including the alleviation of one or more symptoms associated with the disease.
  • treating a viral infection e.g., a respiratory virus infection
  • treating a viral infection in a subject involves preventing the onset or worsening of the viral infection.
  • “treating a viral infection,” including “treating a respiratory virus infection” encompasses treating a disease caused by a viral infection, such as a respiratory virus infection.
  • Suitable routes of administration include, without limitation, intravenous, intranasal, intramuscular, subcutaneous, and inhalation.
  • an agent of the disclosure is administered intravenously, subcutaneous, intramuscularly or intranasally.
  • an agent of the disclosure is delivered to the lung, for example, via aerosol, nebulizer, or tracheal wash.
  • Other routes of administration are contemplated herein.
  • the administration route of an agent of the disclosure can be changed depending on a number of factors, including the pathogen and/or mechanism of pathogenesis.
  • the route of administration of the compositions provided herein may vary depending on the specific agents (e.g., chemical compound, a programmable nuclease, or a small molecule).
  • an effective amount (or therapeutically effective amount) of a transient receptor potential vanilloid-type 4 (TRPV4) inhibitor of the present disclosure is administered to a subject to inhibit pathogenesis of a virus (e.g., respiratory virus).
  • a virus e.g., respiratory virus
  • an effective amount of a TRPV4 inhibitor of the present disclosure is administered to a subject to suppress inflammation associated with viral infection, such as respiratory viral infection (e.g., inflammation in the lung and/or other organ).
  • an effective amount of a TRPV4 inhibitor is administered to a subject to alleviate one or more symptoms associated with a disease caused by a viral infection.
  • a therapeutically effective amount in some embodiments, is an amount of a TRPV4 inhibitor required to prevent viral infection or a disease caused by viral infection in a subject. In some embodiments, an effective amount is an amount of a TRPV4 inhibitor required to prevent or reduce viral propagation in a subject. In some embodiments, an effective amount is an amount of a TRPV4 inhibitor required to prevent or reduce viral survival (e.g., length of time that a virus survives in a subject). In some embodiments, an effective amount is an amount of a TRPV4 inhibitor required to reduce viral titer in a subject. In some embodiments, an effective amount is an amount of a TRPV4 inhibitor required to reduce an inflammatory immune response induced by the respiratory virus infection in a subject.
  • an effective amount is an amount of a TRPV4 inhibitor required to reduce inflammatory cytokine production in a subject. In some embodiments, an effective amount is an amount of a TRPV4 inhibitor required to reduce viral replication in a subject. In some embodiments, an effective amount is an amount of a TRPV4 inhibitor required to reduce viral mRNA in a subject.
  • Effective amounts vary, as recognized by those skilled in the art, depending on the route of administration, excipient usage, and co-usage with other active agents. Effective amounts depend on the subject, including, for example, the weight, sex and age of the subject as well as the strength of the subject’s immune system and/or genetic predisposition. Suitable dosage ranges are readily determinable by one skilled in the art.
  • compositions herein may be administered as a single dose or as multiple doses.
  • any two doses of the multiple doses include different or substantially the same amounts of a dosage described in this application.
  • Dosage forms may be administered at a variety of frequencies.
  • the frequency of administering the multiple doses to the subject is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks, or less frequent than every four weeks.
  • the frequency of administering the multiple doses to the subject is one dose per day.
  • the frequency of administering the multiple doses to the subject is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject is three doses per day. In certain embodiments, when multiple doses are administered to a subject, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
  • the duration between the first dose and last dose of the multiple doses is the lifetime of the subject.
  • dose ranging studies can be conducted to establish optimal therapeutic or effective amounts of the component(s) (e.g., proteins or peptides) to be present in dosage forms.
  • the component(s) are present in dosage forms in an amount effective as a therapeutic intervention after diagnosis of viral infection, ARDS, or an inflammatory lung disease.
  • a composition is administered as a prophylactic treatment before diagnosis of viral infection, ARDS, or an inflammatory lung disease.
  • more than one agents associated with the disclosure is administered to a subject.
  • the agents are administered concomitantly.
  • the agents are not administered concomitantly.
  • the first agent is not administered within 1 month, 1 week, 6 days, 5, days, 4 days, 3 days, 2 days, 1 day, 12 hour, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour of the second agent.
  • concomitantly refers to administering two or more agents to a subject in a manner that is correlated in time, preferably sufficiently correlated in time such that a first agent has an effect on a second agent, such as increasing the efficacy of the second agent, preferably the two or more agents are administered in combination.
  • a second agent has an effect on a first agent, such as regulating the efficacy of the first composition.
  • concomitant administration may encompass administration of two or more agents within a specified period of time.
  • the two or more agents are administered within 1 month, within 1 week, within 1 day, or within 1 hour.
  • concomitant administration encompasses simultaneous administration of two or more agents. In some embodiments, when two or more agents are not administered concomitantly, there is little to no effect of the first agent on the second agent.
  • the TRPV4 inhibitors provided herein may include, or may be administered in combination with, other agents, such as antiviral agents, to the subject.
  • the TRPV4 inhibitors provided herein may include, or may be administered in combination with, other agents, such as an inducer of host protective response, to the subject.
  • an inducer of host protective response can be a type I interferon, for example.
  • an inducer of host protective response can be any compound, agent, or substance that is capable of inducing host protective immune response. Such compound, agent, or substance can include but are not limited to chemokines.
  • compositions provided herein are administered concomitantly with other agents such as antiviral agents or inducers of host protective response.
  • the compositions provided herein e.g., a TRPV4 inhibitor are not administered concomitantly with other agents such as antiviral agents or inducers of host protective response.
  • an agent, or a combination of agents, as disclosed herein is administered in an amount effective for decreasing viral infectivity, such as respiratory virus infectivity.
  • viral infectivity such as respiratory virus infectivity, is decreased by at least 20%, relative to a control.
  • viral infectivity such as respiratory virus infectivity
  • viral infectivity such as respiratory virus infectivity
  • an agent, or a combination of agents, as disclosed herein is administered in an amount effective for decreasing viral replication, such as respiratory virus replication, in the subject.
  • viral replication such as respiratory virus replication
  • viral replication such as respiratory virus replication
  • viral replication such as respiratory virus replication
  • an agent, or a combination of agents, as disclosed herein is administered in an amount effective for decreasing viral load in the subject.
  • viral load is decreased by at least 5%, relative to a control.
  • viral load may be decreased by least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, relative to a control.
  • viral load is decreased by 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 20%-50%, 20%-40%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, or 50%-60%, relative to a control.
  • an agent, or a combination of agents is administered in an amount effective for increasing viral inhibition rate.
  • viral inhibition rate is increased by at least 20%, relative to a control.
  • viral infectivity such as respiratory virus infectivity
  • viral inhibition rate is increased by 20%-100%, 20%-90%, 20%-80%, 20%- 70%, 20%-60%, 20%-50%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%- 50%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%- 90%, 50%-80%, 50%-70%, or 50%-60%, relative to a control.
  • an agent, or a combination of agents is administered in an amount effective for reducing an inflammatory immune response induced by the respiratory virus infection in the subject.
  • an inflammatory immune response induced by the respiratory virus infection is reduced by at least 5%, relative to a control.
  • an inflammatory immune response induced by the respiratory virus infection may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, relative to a control.
  • an inflammatory immune response induced by the respiratory virus infection is reduced by 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 20%-100%, 20%-90%, 20%- 80%, 20%-70%, 20%-60%, 20%-50%, 20%-40%, 30%-100%, 30%-90%, 30%-80%, 30%- 70%, 30%-60%, 30%-50%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%- 50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, or 50%-60%, relative to a control.
  • a control is a control subject who has not been administered the agent or combination of agents of the disclosure (e.g., Compound 1). In some embodiments, the control subject has been administered a different anti-viral therapeutic. In some embodiments, a control is the subject prior to administration of the agent or combination of agents of the disclosure e.g., Compound 1). For example, in some embodiments, the agent, or a combination of agents, as disclosed herein, is administered in an amount effective for decreasing viral replication in a subject, wherein the control is the level of viral replication in the subject prior to administration of the agent or combination of agents.
  • an agent, or a combination of agents is administered in an amount effective for reducing inflammatory cytokine production in the subject.
  • inflammatory cytokines include interferon lambda 1 (IFNkl), interferon gamma-induced protein 10 (IP- 10), interleukin-6 (IL-6), interleukin-8 (IL-8), granulocyte-macrophage colony-stimulating factor (GM-CSF), and Monocyte chemoattractant protein- 1 (MCP-1).
  • IFNkl interferon lambda 1
  • IP- 10 interferon gamma-induced protein 10
  • IL-6 interleukin-6
  • IL-8 interleukin-8
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • MCP-1 Monocyte chemoattractant protein- 1
  • inflammatory cytokine production is reduced by at least 5%, relative to a control.
  • inflammatory cytokine production may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, relative to a control.
  • inflammatory cytokine production is reduced by 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 20%-100%, 20%- 90%, 20%-80%, 20%-70%, 20%-60%, 20%-50%, 20%-40%, 30%-100%, 30%-90%, 30%- 80%, 30%-70%, 30%-60%, 30%-50%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%- 60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, or 50%-60%, relative to a control.
  • an agent, or a combination of agents is administered in an amount effective for reducing the amount of viral RNA (e.g., viral mRNA) in the subject.
  • the amount of viral RNA e.g., viral mRNA
  • the amount of viral RNA is reduced by at least 5%, relative to a control.
  • the amount of viral RNA may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, relative to a control.
  • the amount of viral RNA is reduced by 5%-100%, 5%-90%, 5%-80%, 5%- 70%, 5%-60%, 5%-50%, 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 20%-50%, 20%-40%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, or 50%-60%, relative to a control.
  • an agent, or a combination of agents is administered in an amount effective for reducing the severity, duration or occurrence of one or more symptoms of a viral infection, e.g., a respiratory virus infection.
  • the severity, duration or occurrence of one or more symptoms of a viral infection is reduced by at least 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 20%-50%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, or 50%-60%, or by at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, or at least 1000-fold compared to a control.
  • one or more of the symptom(s) is related to aberrant inflammation (e.g., aberrant pulmonary inflammation).
  • an agent, or a combination of agents is administered in an amount effective for treating, e.g., improving the symptoms of acute respiratory distress syndrome (ARDS) by at least 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 20%- 50%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 40%-100%, 40%- 90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%- 70%, or 50%-60%, or by at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, or at least 1000-fold compared to a control.
  • ARDS acute respiratory distress syndrome
  • an agent, or a combination of agents is administered in an amount effective for treating, e.g., improving the symptoms of an inflammatory lung disease such as COPD by at least 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 20%- 50%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 40%-100%, 40%- 90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%- 70%, or 50%-60%, or by at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, or at least 1000-fold compared to a control.
  • a subject may be, for example, a human subject.
  • Other non-human subjects are also contemplated herein, for example, a livestock animal such as a cow, a sheep, a goat, a poultry, or a pig.
  • Other non-human mammals subject to viral infection, such as respiratory virus infection, are also contemplated herein.
  • a subject in some embodiments, is infected with a virus e.g., a respiratory virus) or at risk of viral infection (e.g., a respiratory virus infection).
  • a subject is considered “at risk of viral infection” if the subject is, for example, immunocompromised, a child (e.g., under the age of 18 years), an elderly person (e.g., over the age of 65 years), or has been in contact with or plans to be in contact with another person who is infected with a virus.
  • the subject is immunocompromised.
  • the subject is a child.
  • the subject is an elderly person.
  • a subject has been exposed to a virus, such as a respiratory virus. Exposure to a virus includes indirect or direct contact with the virus. For example, a subject may be considered exposed to a virus if the subject was in the presence of another subject who has been infected with the virus. A subject “exposed to” a virus may also be “suspected of having” a viral infection. In some embodiments, a subject is infected with (and diagnosed with) a virus.
  • Non-limiting examples of respiratory viruses include influenza viruses (e.g., influenza A/Hong Kong/8/68 (H3N2), A/WSN/33 (H1N1), or influenza A/ Avian Influenza (H5N1)), coronaviruses (e.g., betacoronavirus, e.g., MERS-CoV, SARS-CoV, or SARS-CoV-2), rhinoviruses, enteroviruses, parainfluenza viruses, metapneumoviruses, respiratory syncytial viruses, adenoviruses, and bocaviruses. Other virus and thus other viral infections are contemplated herein.
  • influenza viruses e.g., influenza A/Hong Kong/8/68 (H3N2), A/WSN/33 (H1N1), or influenza A/ Avian Influenza (H5N1)
  • coronaviruses e.g., betacoronavirus, e.g., MERS-CoV, SARS-CoV,
  • a virus is an influenza virus.
  • Influenza virus infects hosts such as humans and livestock animals (e.g., cattle, sheep, goat, poultry, or pig). Infection can result in global pandemics as the virus spreads among hosts who are contagious but have not yet developed symptoms of infection.
  • Influenza virus primarily infects cells of the airway e.g., lung epithelial, airway epithelial, and/or alveoli) before spreading throughout the body.
  • the symptoms of influenza virus infection include, for example, congestion, cough, sore throat, fever, chills, aches, and fatigue, and typically appear two days after exposure to the virus and last less than a week.
  • influenza virus infection can lead to pneumonia, secondary bacterial pneumonia, sinus infection, and worsening of previous health problems including asthma or heart failure.
  • influenza virus infection can lead to death, particularly in young children, the elderly, and immunosuppressed subjects.
  • the methods and composition provided herein are used to inhibit infection of, pathogenesis of, or symptoms associated with, an influenza virus.
  • influenza viruses There are four types of influenza viruses: A, B, C and D. Human influenza A and B viruses cause seasonal epidemics of disease almost every winter in the United States. The emergence of a new and very different influenza A virus to infect people can cause an influenza pandemic. Influenza type C infections generally cause a mild respiratory illness and are not thought to cause epidemics. Influenza D viruses primarily affect cattle and are not known to infect or cause illness in people. Influenza A viruses are divided into subtypes based on two proteins on the surface of the virus: the hemagglutinin (H) and the neuraminidase (N). There are 18 different hemagglutinin subtypes and 11 different neuraminidase subtypes (Hl through Hl 8 and N1 through Ni l respectively).
  • H hemagglutinin
  • N neuraminidase
  • Influenza A viruses can be further broken down into different strains.
  • Current subtypes of influenza A viruses found in people are influenza A (H1N1) and influenza A (H3N2) viruses.
  • H1N1 influenza A
  • H3N2 influenza A
  • a new influenza A (H1N1) virus (CDC 2009 H1N1 Flu website) emerged to cause illness in people.
  • This virus was very different from the human influenza A (H1N1) viruses circulating at that time.
  • the new virus caused the first influenza pandemic in more than 40 years. That virus (often called “2009 H1N1”) has now replaced the H1N1 virus that was previously circulating in humans.
  • H1N1 refers to any H1N1 virus circulating in humans.
  • Influenza A viruses can be influenza A/Hong Kong/8/68 (H3N2), A/WSN/33 (H1N1), or influenza A/ Avian Influenza (H5N1), for example.
  • Influenza B viruses are not divided into subtypes but can be further broken down into lineages and strains. Currently circulating influenza B viruses belong to one of two lineages: B/Yamagata and B/Victoria. See, e.g., cdc.gov/flu/about/viruses/types.htm (Centers for Disease Control and Prevention website).
  • influenza virus infection as provided herein may be caused by any strain of influenza virus.
  • the influenza virus is an influenza type A virus, an influenza type B virus, or an influenza type C virus.
  • an influenza A strain is selected from the following subtypes: H1N1, H1N2, H1N3, H1N8, H1N9, H2N2, H2N3, H2N8, H3N1, H3N2, H3N8, H4N2, H4N4, H4N6, H4N8, H5N1, H5N2, H5N3, H5N6, H5N8, H5N9, H6N1, H6N2, H6N4, H6N5, H6N6, H6N8, H7N1, H7N2, H7N3, H7N7, H7N8, H7N9, H8N4, H9N1, H9N2, H9N5, H9N8, H10N3, H10N4, H10N7, H10N8, H10N9, H11N2, H11N6, H11N9,
  • the strain of influenza virus is an influenza A (H1N1) strain. In some embodiments, the strain of influenza virus is an influenza A (H3N2) strain. In some embodiments, the strain of influenza virus is an influenza A (H5N1) strain.
  • Non-limiting examples of particular strains of influenza virus include influenza A/WSN/33 (H1N1), influenza A/Hong Kong/8/68 (H3N2), and influenza A/ Avian Influenza (H5N1), influenza A/Netherlands/602/2009 (H1N1), and influenza A/Panama/2007/99 (H3N2).
  • a virus is a coronavirus.
  • Coronaviruses are a large family of zoonotic viruses that are transmitted between animals and people, causing illness ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV).
  • MERS-CoV Middle East Respiratory Syndrome
  • SARS-CoV Severe Acute Respiratory Syndrome
  • Other nonlimiting examples of coronaviruses include coronavirus 229E and NL63, which are common human alpha coronaviruses, and OC43 and HKU1, which are common human beta coronaviruses.
  • the methods and composition provided herein are used to inhibit infection of, pathogenesis of, or symptoms associated with, an alpha coronavirus.
  • the methods and composition provided herein are used to inhibit infection of, pathogenesis of, or symptoms associated with, a beta coronavirus.
  • Several known coronaviruses are circulating in animals
  • coronavirus infection includes respiratory symptoms, fever, cough, shortness of breath, and breathing difficulties. In more severe cases, infection can cause pneumonia, severe acute respiratory syndrome, kidney failure, and even death.
  • WHO World Health Organization
  • COVID-19 the 2019 novel coronavirus outbreak
  • ‘CO’ stands for ‘corona,’ ‘VI’ for ‘virus,’ and ‘D’ for disease.
  • this disease was referred to as “2019 novel coronavirus” or “2019-nCoV.”
  • the coronavirus infection being inhibited is COVID- 19, also referred to as SARS-CoV2.
  • a virus is a rhinovirus.
  • Rhinovirus which belongs to the genus Enterovirus in the family Picornaviridae, is the most common viral infectious agent in humans and is the predominant cause of the common cold.
  • the three species of rhinovirus include around 160 recognized types of human rhinovirus that differ according to their surface proteins (serotypes). Common signs of rhinovirus include runny nose, sneezing, sore throat, headache, cough, body aches, mild fever, ear infections, sinus infections, and lung problems such as bronchiolitis and pneumonia.
  • the methods and composition provided herein are used to inhibit infection of, pathogenesis of, or symptoms associated with, a rhinovirus.
  • rhinovirus A and rhinovirus B use "major” ICAM-1 (Inter-Cellular Adhesion Molecule 1), also known as CD54 (Cluster of Differentiation 54), as receptors on respiratory epithelial cells. Some subgroups under rhinovirus A and rhinovirus B uses the “minor” LDL receptor.
  • Rhinovirus C uses cadherin- related family member 3 (CDHR3) to mediate cellular entry. As the virus replicates and spreads, infected cells release distress signals known as chemokines and cytokines (which in turn activate inflammatory mediators). Cell lysis occurs at the upper respiratory epithelium.
  • a virus is an enterovirus.
  • Enterovirus is a genus of positivesense single-stranded RNA viruses associated with several human and mammalian diseases. Enteroviruses can be classified based on the genotyping of VP1 capsid region such as EV- D68, EV-B69, EV-D70, EV-A71. Without wishing to be bound by any theory, EV-D68 can cause mild to severe respiratory illness. For more severe cases, difficulty breathing, wheezing or problems catching one’s breath may occur. In some embodiments, the methods and composition provided herein are used to inhibit infection of, pathogenesis of, or symptoms associated with, an enterovirus.
  • Poliovirus affects millions of people worldwide each year and is often found in the respiratory secretions such as saliva, sputum, or nasal mucus and stool of an infected person. Poliovirus, including PV-1, PV-2, and PV-3, can cause poliomyelitis, which is the most significant disease that can be caused by enterovirus. Common signs of poliovirus include mild respiratory illness (the common cold), hand, foot and mouth disease, acute hemorrhagic conjunctivitis, aseptic meningitis, myocarditis, severe neonatal sepsis-like disease, acute flaccid paralysis, and the related acute flaccid myelitis.
  • enterovirus includes non-polio enteroviruses such as Coxsackie A viruses, Coxsackie B viruses, echoviruses, and other enteroviruses. In some embodiments, enterovirus includes any serotypes that contribute to respiratory infections.
  • a virus is a parainfluenza virus.
  • Parainfluenza virus or human parainfluenza virus, causes human parainfluenza.
  • Parainfluenza virus comprises four distinct single- stranded RNA viruses belonging to the Paramyxoviridae family. HPIVs remain the second main cause of hospitalization in children under 5 years of age suffering from a respiratory illness.
  • Parainfluenza virus can be classified as human parainfluenza virus type 1 (HPIV-1), human parainfluenza virus type 2 (HPIV-2), human parainfluenza virus type 3 (HPIV-3), and human parainfluenza virus type 4 (HPIV-4).
  • HPIVs can be further categorized as respirovirus (HPIV-1 and HPIV-3) and rubulavirus (HPIV-2 and HPIV-4).
  • the methods and composition provided herein are used to inhibit infection of, pathogenesis of, or symptoms associated with, a parainfluenza virus.
  • parainfluenza virus Common signs include upper respiratory illness such as fever, runny nose, or cough, lower respiratory illness such as croup (infection of the vocal cords (larynx), windpipe (trachea) and bronchial tubes (bronchi)), bronchitis (infection of the main air passages that connect the windpipe to the lungs), bronchiolitis (infection in the smallest air passages in the lungs), or pneumonia (an infection of the lungs), and other illness such as sore throat, sneezing, wheezing, ear pain, irritability, or decreased appetite.
  • different types of parainfluenza virus may cause different symptoms.
  • HPIV-1 and HPIV-2 can cause croup, with HPIV-1 most often identified as the cause in children. Both can also cause upper and lower respiratory illness, and cold-like symptoms.
  • HPIV-3 can cause bronchiolitis, bronchitis, and pneumonia.
  • HPIV-4 may be associated with mild to severe respiratory illnesses.
  • a virus is a metapneumo virus.
  • Metapneumovirus also called human metapneumovirus (HMPV)
  • HMPV human metapneumovirus
  • AMPV Avian metapneumovirus
  • HMPV infects airway epithelial cells in the nose and lung.
  • AMPV Avian metapneumovirus
  • the HMPV fusion (F) protein encodes an RGD (Arg-Gly-Asp) motif that engages RGD-binding integrins as cellular receptors, and then mediates fusion of the cell membrane and viral envelope in a pH- independent fashion.
  • HMPV can cause upper and lower respiratory disease in people of all ages, especially among young children, older adults, and people with weakened immune systems.
  • HMPV is associated with 5% to 40% of respiratory tract infections in hospitalized and outpatient children. Signs of HMPV infection includes cough, fever, nasal congestion, and shortness of breath. Clinical symptoms of HMPV infection may progress to bronchitis or pneumonia and are similar to other viruses that cause upper and lower respiratory infections.
  • the methods and composition provided herein are used to inhibit infection of, pathogenesis of, or symptoms associated with, a metapneumo virus.
  • a virus is a respiratory syncytial virus.
  • Respiratory syncytial virus or human respiratory syncytial virus and human orthopneumovirus, is a common, contagious virus that causes infections of the respiratory tract.
  • RSV is a negativesense, single- stranded RNA virus.
  • RSV is divided into two antigenic subtypes, subtype A and subtype B, based on the reactivity of the F and G surface proteins to monoclonal antibodies. The subtypes tend to circulate simultaneously within local epidemics, although subtype A tends to be more prevalent.
  • RSV subtype A (RSVA) is thought to be more virulent than RSV subtype B (RSVB), with higher viral loads and faster transmission time.
  • the methods and composition provided herein are used to inhibit infection of, pathogenesis of, or symptoms associated with, a respiratory syncytial virus.
  • RSV was discovered in 1956 and has since been recognized as one of the most common causes of childhood illness. It causes annual outbreaks of respiratory illnesses in all age groups. RSV infection can present with a wide variety of signs and symptoms that range from mild upper respiratory tract infections (URTI) to severe and potentially life-threatening lower respiratory tract infections (LRTI) requiring hospitalization and mechanical ventilation. While RSV can cause respiratory tract infections in people of all ages and is among the most common childhood infections, its presentation often varies between age groups and immune status. Reinfection is common throughout life, but infants and the elderly remain at highest risk for symptomatic infection. Signs of RSV infection can include runny nose, decrease in appetite, coughing, sneezing, fever, and wheezing. Severe infections can lead to bronchiolitis and pneumonia. RSV can also make chronic health problems worse such as people with asthma and people with congestive heart failure.
  • a virus is an adenovirus.
  • Adenovirus belongs to the family of Adenoviridae, which is a medium-sized (90-100 nm), nonenveloped (without an outer lipid bilayer) virus with an icosahedral nucleocapsid containing a double stranded DNA genome.
  • Adenovirus can be classified as 57 human adenovirus types (HAdV-1 to 57) in seven species (Human adenovirus A to G).
  • HdV-1 to 57 human adenovirus types
  • Human adenovirus A to G Human adenovirus A to G
  • different types or serotypes of adenovirus are associated with different conditions. For example, HAdV-B and C can be associated with respiratory disease.
  • HAdV-B and D can be associated with conjunctivitis.
  • adenovirus types 3, 4 and 7 are most commonly associated with acute respiratory illness.
  • adenovirus type 7 has been associated with more severe outcomes than other adenovirus types, particularly in people with weakened immune systems.
  • adenovirus types 8, 19, 37, 53, and 54 can cause epidemic keratoconjunctivitis.
  • the methods and composition provided herein are used to inhibit infection of, pathogenesis of, or symptoms associated with, an adenovirus.
  • Signs of adenovirus infection include common cold or flu-like symptoms such as fever, sore throat, acute bronchitis, pneumonia, pink eye (conjunctivitis), acute gastroenteritis (inflammation of the stomach or intestines causing diarrhea, vomiting, nausea and stomach pain), bladder inflammation or infection, and neurologic disease.
  • a virus is a bocavirus.
  • Bocavirus also called human bocavirus, which belongs to the genus Bocaparvovirus of virus family Parvoviridae and is a small (20 nm), non-enveloped virus. It is a new viral genus that was discovered in 2005 in upper respiratory secretions from acutely ill children.
  • there are four human genotypes of BoV which include type 1 to 4.
  • HBoVl and HBoV3 are members of species Primate bocaparvovirus 1 whereas viruses HBoV2 and HBoV4 belong to species Primate bocaparvovirus 2.
  • HBoVl is strongly implicated in causing some cases of lower respiratory tract infection, especially in young children, and several of the viruses have been linked to gastroenteritis. Signs of bocavirus infection include acute respiratory tract infections, cough, wheezing, fever, cyanosis, runny nose, and diarrhea. In some embodiments, the methods and composition provided herein are used to inhibit infection of, pathogenesis of, or symptoms associated with, a bocavirus.
  • a subject is diagnosed with acute respiratory distress syndrome (ARDS).
  • ARDS causes fluid to leak into the lungs, making it difficult to get oxygen into the bloodstream.
  • ARDS acute respiratory distress syndrome
  • fluid from the smallest blood vessels in the lungs starts to leak into the alveoli, which are the tiny air sacs where oxygen exchange takes place.
  • the lungs become smaller and stiffer which leads to having difficulty of breathing and the amount of oxygen in the blood falls (“hypoxemia”).
  • hypoxemia hypoxemia
  • the brain and other tissues can be harmed and leads to organ failure.
  • a subject has been exposed to harmful conditions that result in ARDS.
  • a subject may have sepsis or inhale high concentrations of smoke or chemical fumes.
  • a subject may infections or trauma.
  • a subject may have pneumonia.
  • a subject may have trauma to the head.
  • a subject may undergo blood transfusions.
  • a subject may have been infected with any of the respiratory viruses as disclosed herein.
  • a subject is diagnosed with an inflammatory lung disease.
  • inflammatory lung disease include asthma, pulmonary fibrosis, and interstitial lung disease.
  • the inflammatory lung disease may be, for example, a chronic inflammatory lung disease, such as Chronic Obstructive Pulmonary Disease (COPD).
  • COPD Chronic Obstructive Pulmonary Disease
  • an inflammatory lung disease is any lung disease that is contributed by either acute or chronic inflammations.
  • COPD chronic obstructive pulmonary disease
  • Symptoms include shortness of breath, cough, excess phlegm, mucus, or sputum production, chest tightness, lack of energy, swelling in ankles, feet or legs, and wheezing.
  • COPD can be caused by long-term exposure to irritating gases or particulate matter, most often from cigarette smoke. Other factor such as air pollutants, genetic factors, and respiratory infections may contribute to the onset of COPD.
  • Emphysema and chronic bronchitis are the two most common conditions that contribute to COPD.
  • Chronic bronchitis is characterized by daily cough and mucus (sputum) production.
  • Emphysema is a condition in which the alveoli at the end of bronchioles of the lungs are destroyed as a result of damaging exposure to cigarette smoke and other irritating gases and particulate matter.
  • a subject requires use of a respiratory ventilator, which can exert cyclic mechanical strain on the lungs.
  • a respiratory ventilator which can exert cyclic mechanical strain on the lungs.
  • compositions and methods of the disclosure may be used to suppress inflammation due to this cyclic mechanical strain on the lungs.
  • Example 1 Treatment of respiratory viral infection and associated inflammation by inhibition of TRPV4
  • TRPV4 is a major mechanoreceptor expressed in the human lung
  • TRPV4 Transient Receptor Potential Cation Channel Subfamily V Member 4
  • Physiological lung breathing is associated with 0-5% changes in alveolar cell surface area while higher percentage of strains can lead to damage, such as ventilator- induced lung injury.
  • both low-tidal volume (6 ml/kg) and high-tidal volume ventilation (12 ml/kg) can lead to -10% mechanical strain in the alveolus, which is often seen in patients with emphysema or lung edema due to increased lung compliance or surface tension.
  • TRPV4 inhibitor Compound 1
  • S100A7 a protein known to be associated with promotion of inflammation
  • CXCL10 an inflammatory cytokine
  • TRPV4 inhibitor can decrease influenza viral load and inflammatory responses
  • FIG. 4A The TRPV4 inhibitor Compound 1 was perfused at non-toxic doses (FIG. 4B) through the vascular channel of the Alveolus Chip for 48 hours before infection with H3N2 while 5% mechanical strain was applied. This resulted in significantly decreased viral mRNA levels (FIG. 4C) as well as reduced concentrations of cytokines, including IFNL1, IP-10, IL-6, IL-8, and GM-CSF (FIG. 4D).
  • cytokines including IFNL1, IP-10, IL-6, IL-8, and GM-CSF
  • TRPV4 was one of the factors that mediated the mechanotransduction process by which mechanical strain applied to the lung alveolar epithelium and endothelium resulted in activation of an innate immune response.
  • TRPV4 inhibitors such as Compound 1, may both limit inflammation and viral burden, representing a promising therapy against lung viral infections.

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Abstract

La présente divulgation concerne des compositions et des méthodes comprenant des inhibiteurs de TRPV4 pour le traitement d'infections virales respiratoires, de maladies inflammatoires et/ou d'inflammations respiratoires.
PCT/US2023/014445 2022-03-07 2023-03-03 Inhibiteurs de trpv4 pour le traitement d'infections virales respiratoires WO2023172441A2 (fr)

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