WO2023107977A1 - Procédés et compositions pour traiter l'inflammation des voies respiratoires - Google Patents
Procédés et compositions pour traiter l'inflammation des voies respiratoires Download PDFInfo
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- WO2023107977A1 WO2023107977A1 PCT/US2022/081056 US2022081056W WO2023107977A1 WO 2023107977 A1 WO2023107977 A1 WO 2023107977A1 US 2022081056 W US2022081056 W US 2022081056W WO 2023107977 A1 WO2023107977 A1 WO 2023107977A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
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- 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
- A61K31/4704—2-Quinolinones, e.g. carbostyril
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- 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
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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- 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
- A61K31/69—Boron compounds
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- 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
Definitions
- This invention relates to the field of medicine and treatment of disease.
- TR- AMs Tissue-resident alveolar macrophages
- the alveolus maintains the highest oxygen concentration of any tissue compartment within the human body (7). Moreover, under steady-state conditions, glucose concentrations within airway lumen are less than one-tenth of blood glucose concentrations (8). These environmental conditions alone suggest a cellular preference for oxidative metabolism for cells that reside within the alveoli.
- TR-AMs rely predominantly on oxidative phosphorylation under steady-state conditions and that glycolysis is dispensable for proinflammatory effector function (12). Together, these findings highlight the lung microenvironment’s central role in dictating TR-AM responses.
- the disclosure relates to a method of treating lung disease in a subject, the method comprising administering an effective amount of a Hypoxia-inducible factor la (HIF-la) inducer to the subject. Also described is a method of treating airway inflammation in a subject, the method comprising administering an effective amount of a Hypoxia-inducible factor la (HIF-la) inducer to the subject. Also described are compositions comprising i) a Hypoxia-inducible factor la (HIF- la) inducer and ii) an anti-viral therapy, an anti-inflammatory agent, or combinations thereof. Also described is nebulizer or inhalation device comprising a Hypoxia-inducible factor la (HIF-la) inducer.
- the virus may exclude influenza, paramyxovirus, coronavirus, respiratory syncytial virus, bocavirus, metapneumovirus, rhinovirus, parainfluenza, severe acute respiratory syndrome coronavirus 1 (SARS-Covl), severe acute respiratory syndrome coronavirus 1 (SARS-Cov2), a respiratory adenovirus, Middle eastern respiratory syndrome coronavirus (MERS-COV), yellow fever virus, H5N1, Margurg, or Ebola.
- the respiratory virus may comprise SARS-Covl or SARS-Cov2.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including, for example, aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
- compositions will typically be via any common route. This includes, but is not limited to oral, or intravenous administration. Alternatively, administration may be by orthotopic, intradermal, subcutaneous, intratracheal, intramuscular, intraperitoneal, or intranasal administration. Such compositions would normally be administered as pharmaceutically acceptable compositions that include physiologically acceptable carriers, buffers or other excipients.
- the pharmaceutical compositions may include classic pharmaceutical preparations. Administration of pharmaceutical compositions may be via any common route so long as the target tissue is available via that route. This may include oral, nasal, buccal, rectal, vaginal or topical. Alternatively, administration may be by orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal or intravenous injection. Such compositions would normally be administered as pharmaceutically acceptable compositions that include physiologically acceptable carriers, buffers or other excipients. For treatment of conditions of the lungs, aerosol delivery can be used. Volume of the aerosol may be between about 0.01 ml and 0.5 ml, for example.
- At least one pharmaceutical composition is delivered in a particle size effective for reaching the lower airways of the lung or sinuses.
- Some specific examples of commercially available inhalation devices suitable for the practice of this invention are TurbohalerTM (Astra), Rotahaler®) (Glaxo), Diskus® (Glaxo), SpirosTM inhaler (Dura), devices marketed by Inhale Therapeutics, AERxTM (Aradigm), the Ultravent® nebulizer (Mallinckrodt), the Acorn II® nebulizer (Marquest Medical Products), the Ventolin® metered dose inhaler (Glaxo), the Spinhaler® powder inhaler (Fisons), Aerotech II® or the like.
- All such inhalation devices can be used for the administration of a pharmaceutical composition in an aerosol.
- aerosols may comprise either solutions (both aqueous and nonaqueous) or solid particles.
- Metered dose inhalers typically use a propellant gas and require actuation during inspiration. See, e.g., WO 98/35888 and WO 94/16970.
- Dry powder inhalers use breath-actuation of a mixed powder. See U.S. Patents 5,458,135 and 4,668,218; PCT publications WO 97/25086, WO 94/08552 and WO 94/06498; and European application EP 0237507, each of which is incorporated herein by reference in their entirety.
- Nebulizers produce aerosols from solutions, while metered dose inhalers, dry powder inhalers, and the like generate small particle aerosols.
- Suitable formulations for administration include, but are not limited to nasal spray or nasal drops, and may include aqueous or oily solutions of a composition described herein.
- the propellant can be any conventional material employed for this purpose such as chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon including trichlorofluoromethane, dichlorodifluoromethane, di chlorotetrafluoroethanol and 1, 1,1,2- tetrafluoroethane, HFA-134a (hydrofluroalkane-134a), HFA-227 (hydrofluroalkane-227), or the like.
- chlorofluorocarbon a hydrochlorofluorocarbon
- a hydrofluorocarbon or a hydrocarbon including trichlorofluoromethane, dichlorodifluoromethane, di chlorotetrafluoroethanol and 1, 1,1,2- tetrafluoroethane, HFA-134a (hydrofluroalkane-134a), HFA-227 (hydrofluroalkane-227), or the like.
- the anti-viral drug is one that inhibits the virus directly, instead of destroying or killing the virus.
- an anti-viral drug is not an immunoglobulin or agent that involves the immune system.
- One anti-viral strategy is to interfere with the ability of a virus to infiltrate a target cell.
- This stage of viral replication can be inhibited by using agents that mimic the virus associated protein (VAP) and bind to the cellular receptors; or by using agents which mimic the cellular receptor and bind to the VAP.
- VAP virus associated protein
- Two such “entryblockers” or “viral mimetics” are amantadine and rimantadine. Amantadine, rimantadine, or compounds with similar mechanisms of action can be used in composition described herein. It is contemplated that amantadine and rimantadine can be formulated as a treatment for influenza.
- a second approach to anti-viral therapy is to target the processes that synthesize virus components after a virus invades a cell.
- One way of doing this is to develop nucleotide or nucleoside analogues that look like the building blocks of RNA or DNA, but deactivate the enzymes that synthesize the RNA or DNA once the analog is incorporated.
- Nucleotide analogs include, but are not limited to ribivirin, vidarabine, acyclovir, gangcyclovir, zidovudine, didanosine, zalcitabine, stavudine, and lamivudine.
- sialidases also referred to as neuraminidases.
- Sialidases hydrolyse alpha-(2/3)-, alpha-(2/6)-, alpha-(2/8)-glycosidic linkages of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid, and synthetic substrates.
- Sialidases act as pathogenic factors in virus infections.
- sialidase inhibitors can be used to attenuate the ability of a virus to infect a subject.
- the final stage in the life cycle of a virus is the release of mature viruses from the host cell.
- Two drugs nerveaminidase inhibitors, also referred to as sialidase inhibitors
- zanamivir RELENZA TM
- TAMIFLUTM oseltamivir
- An anti-inflammatory agent may be used in combination with a composition described herein.
- Steroidal anti-inflammatories for use herein include, but are not limited to fluticasone, beclomethasone, any pharmaceutically acceptable derivative thereof, and any combination thereof.
- a pharmaceutically acceptable derivative includes any salt, ester, enol ether, enol ester, acid, base, solvate or hydrate thereof. Such derivatives may be prepared by those of skill in the art using known methods for such derivatization.
- Providing steroidal anti-inflammatories according to the present invention may enhance the compositions and methods of the invention by, for example, attenuating any unwanted inflammation.
- examples of other steroidal anti-inflammatories for use herein include, but are not limited to, betamethasone, triamcinolone, dexamethasone, prednisone, mometasone, flunisolide and budesonide.
- kits may be packaged either in an aqueous, powdered, or lyophilized form.
- the container means of the kits will generally include at least one inhaler, canister, vial, test tube, flask, bottle, syringe or other container means, into which a component(s) may be placed, and preferably, suitably aliquoted. Where there is more than one component in the kit (second agent, etc.), the kit also will generally contain a second, third or other additional container into which the additional components may be separately placed.
- various combinations of components may be comprised in a vial, canister, or inhaler.
- TR-AMs Tissue-resident alveolar macrophages exhibit HIF-la stabilization and develop a glycolytic phenotype after exposure to hypoxia
- TR-AMs treated with dimethyloxalylglycine a prolyl hydroxylase inhibitor
- HIF-la stabilization and enhanced glycolytic function (12).
- DMOG broadly inhibits a-ketoglutarate-dependent hydroxylases and is thus an imperfect tool for studying HIF-la stabilization, necessitating further study to determine the role hypoxia, a physiological relevant stimulus, in shaping TR-AM metabolism (22).
- Glycolysis stress tests were performed following overnight (16 hours) exposure to decreasing levels of ambient oxygen.
- BMDMs have limited metabolic adaptation to hypoxia
- TR-AM HIF-la responsiveness to hypoxia correlated with increased glycolytic (HK2 and LDHA) and prolyl hydroxylase (EGLN1 and EGLN3) protein expression in TR-AMs (FIG. 3F).
- hypoxic TR-AMs In contrast, IL-6 and CCL2 secretion was decreased in hypoxic TR-AMs (FIG. 4A-B).
- the cytokine gene expression pattern in hypoxic TR-AMs treated with LPS mirrored the secreted cytokine profile (FIG. 4C).
- enhanced proIL-ip protein production was observed in hypoxic TR-AMs treated with LPS (FIG. 4D).
- BMDMs experienced limited metabolic alterations in response to hypoxia, treatment with LPS revealed that hypoxia induced similar alterations in their cytokine profile.
- Hypoxic BMDMs had increased TNF-a, KC, and IL-ip, and decreased IL-6 secretion.
- the only discordance in the hypoxic cytokine response profile between TR-AMs and BMDMs was CCL2, which remained unchanged in hypoxic BMDMs in response to LPS compared to normoxic controls (FIG. 10A-B).
- TR-AMs do not respond to LPS metabolically the same way as BMDMs and do not exhibit a change in glycolytic function following LPS.
- macrophage activation in BMDMs is characterized by immediate enhancement in glycolytic output in response to LPS (FIG. 10C), but the inventors have previously shown that this is not the case in TR-AMs.
- hypoxic TR-AMs experienced further increases in glycolytic intermediates in the presence of LPS (6h) compared to normoxic cells, suggesting an increased reliance on glycolysis following treatment with inflammatory stimuli (FIG. 5F).
- hypoxia leads to significant alterations in TR-AM cytokine production and increased glycolytic metabolites in response to prolonged LPS treatment.
- hypoxic TR-AMs do not robustly increase their extracellular acidification in response to LPS.
- TR-AM cytokine production in response to LPS was highly susceptible to inhibition by low doses of ETC inhibitors, rotenone and antimycin A, under normoxic conditions. This effect was greatly attenuated and almost completely reversed after exposure to hypoxia (FIG. 5D-E). Additionally, high doses of ETC inhibitors induce cytotoxicity in normoxic TR-AMs, but hypoxic preconditioning protected TR-AMs from cell death (FIG. 5F). In contrast, BMDM cytokine production was unaffected by high dose ETC inhibitor treatment with the exception of observed decreases in IL-ip. Unlike TR-AMs, hypoxia did not alter BMDM cytokine production in the presence of ETC inhibitors (FIG. 11D-E). Similarly, ETC inhibition failed to induce cytotoxicity in BMDMs under normoxia or hypoxia.
- TR-AM survival correlates with a shift to glycolytic metabolism during influenza-induced acute lung injury
- TR-AMs undergo cell death in response to influenza infection and that depletion of TR-AMs is associated with worse outcomes in models of influenza-induced acute lung injury (ALI) (27-31).
- ALI influenza-induced acute lung injury
- the inventors utilized PKH26 Red Fluorescent Linker dye to specifically label, track, and collect TR-AMs over the time course of infection (32, 33).
- PKH26+ PKH26+
- dpi 3 and 6 post days post infection
- Mo- AMs monocyte-derived alveolar macrophages
- RNAseq on TR-AMs (PKH26+) and Mo-AMs (PKH26-) at DO, D3, and D6 (note: Mo- AMs are not present in an uninfected (0 dpi) mouse) to identify changes in the metabolic gene signature of these two macrophage populations during influenza infection.
- TR-AMs experienced decreased expression in genes related to oxidative phosphorylation with simultaneous increased expression of genes related to glycolytic metabolism.
- the metabolic gene signature of 6 dpi TR-AMs was most similar to that of Mo-AMs at 3 and 6 dpi (FIG. 6B-C).
- TR-AMs adapted to hypoxia, a common occurrence in alveoli during ARDS, through HIF-1 induction.
- TR- AMs suffered from a glycolytic deficiency and HIF-1 a protein was undetectable.
- Hypoxia could stabilize TR-AM HIF-1 a in a dose-dependent manner resulting in robust increases in glycolytic protein expression and function.
- hypoxia could stabilize TR-AM HIF-1 a in a dose-dependent manner resulting in robust increases in glycolytic protein expression and function.
- hypoxic TR-AMs treated with echinomycin an inhibitor of HIF-1 a DNA binding activity, lost glycolytic capabilities.
- BMDM HIF-1 a expression and glycolytic output remained unchanged in response to hypoxia.
- TR-AMs are unique in their adaptation to hypoxia compared to macrophages of monocytic origin. The environmental shift from high oxygen and low glucose under steady-conditions to low oxygen and increased glucose during lung injury necessitates cellular adaptation to the microenvironment to ensure survival.
- TR-AMs The functional consequences of hypoxia on effector function have been well documented in macrophages of monocytic origin, but no studies, until ours, have conducted a thorough investigation in TR-AMs (38). Using standard ELISA, the inventors found that TR-AMs experience marked changes in their secreted cytokine profile under hypoxia in response to LPS. Hypoxic TR-AMs secreted more TNF-a, KC, and IL-ip and less IL-6 and CCL2 compared to normoxic controls. Similar alterations occurred at the gene expression level. BMDMs exposed to hypoxia and treated with LPS responded similarly to TR-AMs with the exception to CCL2, which remained unchanged in response to hypoxia in BMDMs.
- BMDMs experience enhanced glycolytic output in response to LPS.
- TR-AMs do not experience this phenomenon (12).
- hypoxia granted TR-AMs the functional capacity for glycolysis the inventors were interested to see if hypoxic TR-AMs adopted glycolytic responsiveness to LPS.
- acute glycolytic responsiveness to LPS remained the same in TR-AMs under normoxia and hypoxia based on extracellular acidification data.
- metabolomic analysis suggested that hypoxic TR- AMs treated with LPS had increased levels of glycolytic intermediates compared to TR-AMs exposed to hypoxia alone. The discordance in these two readouts could simply be related to sensitivity. Metabolomics can measure relatively small changes in metabolic function.
- TR-AMs Loss of TR-AMs during influenza infection enhances mortality, and several studies have shown that there is a progressive loss of TR-AMs over the infection time course (27, 29, 31, 34, 44).
- the inventors performed RNAseq on TR-AMs and infiltrating, Mo-AMs isolated from influenza-infected mice to assess metabolic gene expression in response to progressive lung injury. Like previous studies, the inventors found that TR-AM numbers drastically decreased by 6 dpi. The inventors also found that the metabolic gene profile of TR-AMs underwent marked decreases in genes involved in oxidative phosphorylation with simultaneous increases in glycolytic genes by 6 dpi.
- Mo-AMs had low expression of genes related to oxidative phosphorylation and remained reliant on glycolysis at 3 and 6 dpi.
- the inventors believe that TR-AMs at 6 dpi were able survive through metabolic adaption to hypoxia in the injured lung, hence high glycolytic expression promotes survival of these cells which are normally reliant on oxidative phosphorylation under normoxia.
- FG-4592 in vitro, the inventors were able to stabilize HIF-la and promote glycolysis in TR-AMs in the absence of hypoxia.
- the inventors subsequently challenged FG-4592 treated TR-AMs with LPS the inventors found no significant changes in proinflammatory cytokine production compared to controls.
- HIF-la and inflammation are operating independently in TR-AMs, and that low oxygen levels, but not HIF- la leads to enhanced proinflammatory cytokine production in TR-AMs. It is also hard to compare the in vitro data to that of Zhu and colleagues in that they use GM-CSF in all of their experiments. GM-CSF induces rapid proliferation of TR-AMs in vitro and the use of GM-CSF is outside the scope of this study. The inventors find that treating mice with FG-4592 at the time of infection increases TR-AM survival and alleviates influenza-induced lung injury. These findings suggest that HIF-la is essential for TR-AM cell survival, and that increasing TR-AM cell number during infection reduces inflammation.
- Glycolytic and mitochondrial respiration rates were measured using the XFe24 Extracellular Flux Analyzer (Agilent, Santa Clara, MA). BMDMs and TR-AMs were seeded at 4.0 X 10 4 /well onto Seahorse XF24 Cell Culture Microplates. Cells were equilibrated with XF Base media (Agilent, catalog number 103334-100) at 37 °C for 30 minutes in the absence of C02. Glycolytic rate was assessed using the manufacturers’ protocol for the Seahorse XF Glycolysis Stress Test followed by sequential injections with glucose (lOmM), oligomycin (LOpM), and 2- DG (lOOmM).
- Mitochondrial respiration rate was measured using the Seahorse XF Mito Stress Test according to the manufacturer’s protocol followed by sequential injections with oligomycin (l.OpM), FCCP (l.OpM for BMDMs and 4.0pM for TR-AMs), and rotenone/antimycin A (l.OpM). Assessment of real-time metabolic responses to LPS was performed using the protocol detailed in an application note provided by the Agilent (45).
- cells were equilibrated in XF base media supplemented with 10 mM glucose, 2 mM L-glutamine, 1 mM sodium pyruvate (Sigma, catalog number 11360070) and 5 mM HEPES (Sigma, catalog number 15630080), pH 7.4 and incubated at 37 °C without CO2 for 30 minutes prior to XF assay.
- Baseline metabolic rates were measured followed by direct injection of LPS (final concentration:20ng/ml). Bioenergetic rates were subsequently measured every three minutes for approximately 5 hours in total.
- Lysate protein concentration was determined using the PierceTM BCA Protein Assay Kit (ThermoFisher, catalog number 23225). Equal concentrations of samples (15pg for whole cell lysates and 5pg for subcellular fractions) were resolved on Criterion gels (Bio-Rad, catalog number 5671093 and 5671094) and transferred to nitrocellulose (Bio-Rad, catalog number 1620167).
- rlpl9 served as a housekeeping gene, and gene expression was quantified using the AAct method to determine relative fold-change
- the following mouse-specific primer sequences were used: rlpl9 (5’-CCGACGAAAGGGTATGCTCA-3’ (SEQ ID NO: 1), 5’-GACCTTCTTTTTCCCGCAGC-3’ (SEQ ID NO:2)), 116 (5’-TTCCATCCAGTTGCCTTCTTGG-3’ (SEQ ID NO:3), 5’- TTCCTATTTCCACGATTTCCCAG-3’ (SEQ ID NO:4)), tnfa (5’- AGGGGATTATGGCTCAGGGT-3’ (SEQ ID NO: 5), 5’-CCACAGTCCAGGTCACTGTC-3’ (SEQ ID NO:6)), ill/3 (5’-GCCACCTTTTGACAGTGATGAG, (SEQ ID NO:7) 5’- GACAGCCCAGGTCAAAGGTT-3’ (SEQ ID NO:8)), kc (5'-AGACCAT
- ETC inhibitor concentration in BMDMs were as follows: IpM rotenone, and IpM antimycin A.
- ETC inhibitor concentration in TR-AMs were as follows: 500nM rotenone, and lOOnM antimycin A.
- Lactate colorimetric assay kit Sigma, catalog number MAK064-1KT. Cells were plated in complete DMEM media (RPMI interferes with assay), allowed to adhere, washed with phosphate buffer saline, and exposed to normoxia or 1.5% O2. Samples were collected at 16 hours post treatment and manufacturer’s protocol was followed to measure lactate.
- mice were euthanized and a single 0.5ml saline wash was instilled into the lungs via the trachea and subsequently collected.
- BALF protein concentration was determined using the PierceTM BCA Protein Assay Kit (ThermoFisher, catalog number 23225).
- BALF TNFa, IL-6, and IL- 10 were measured using sandwich ELISA.
- BAL cells were first treated with Fc Block (clone 2.4G2, catalog number 553141; BD Biosciences) and stained with fluorochrome-conjugated antibodies.
- the antibodies used were AlexaFluor 700 antimouse Ly-6G (Clone 1A8, catalog number 127621, 1 :250; BioLegend).
- sorting buffer (0.2% BSA in PBS) containing 5 nM SYTOX Green Nucleic Acid Stain (catalog number S7020; ThermoFisher) to distinguish between live and dead cells.
- Cell sorting was performed on a FACS Aria II instrument and data were acquired using BDFACS Diva software and analyzed with FCS Express 7 software.
- Semenza GL Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148(3):399-408.
- Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. Journal of Experimental Medicine. 2013;210(10): 1977-92.
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Abstract
Les inventeurs ont découvert que les modulateurs de HIF1α peuvent traiter l'inflammation des voies respiratoires. La présente invention concerne des procédés de traitement d'une maladie pulmonaire chez un sujet, le procédé consistant à administrer au sujet une quantité efficace d'un facteur induit par l'hypoxie-1α (HIF-1α). D'autres procédés comprennent une méthode de traitement de l'inflammation des voies respiratoires chez un sujet, le procédé comprenant l'administration d'une quantité efficace d'un inducteur de facteur HIF-1α au sujet. Sont également décrites des compositions comprenant i) un inducteur de facteur HIF-1α et ii) une thérapie antivirale, un agent anti-inflammatoire ou leurs combinaisons. D'autres aspects concernent un nébuliseur ou un dispositif d'inhalation comprenant un inducteur du HIF-1α.
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US20190298709A1 (en) * | 2016-02-19 | 2019-10-03 | Cornell University | Hif-stabilization and prevention of hyperoxia-induced neonatal lung disease |
US20200277262A1 (en) * | 2017-09-25 | 2020-09-03 | Takeda Pharmaceutical Company Limited | N-(cyano-substituted benzyl or pyridinylmethyl)-3-hydroxypicolinamide derivatives |
US20200397777A1 (en) * | 2018-01-09 | 2020-12-24 | Cornell University | Prevention and treatment of organ fibrosis |
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- 2022-12-07 WO PCT/US2022/081056 patent/WO2023107977A1/fr unknown
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US20190298709A1 (en) * | 2016-02-19 | 2019-10-03 | Cornell University | Hif-stabilization and prevention of hyperoxia-induced neonatal lung disease |
US20200277262A1 (en) * | 2017-09-25 | 2020-09-03 | Takeda Pharmaceutical Company Limited | N-(cyano-substituted benzyl or pyridinylmethyl)-3-hydroxypicolinamide derivatives |
US20200397777A1 (en) * | 2018-01-09 | 2020-12-24 | Cornell University | Prevention and treatment of organ fibrosis |
Non-Patent Citations (1)
Title |
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HUANG LIANG-TI, CHOU HSIU-CHU, CHEN CHUNG-MING: "Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice", PEDIATRICS & NEONATOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 62, no. 4, 1 July 2021 (2021-07-01), AMSTERDAM, NL , pages 369 - 378, XP093073086, ISSN: 1875-9572, DOI: 10.1016/j.pedneo.2021.03.012 * |
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