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WO2025151774A1 - Traitement de réponses inflammatoires - Google Patents

Traitement de réponses inflammatoires

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Publication number
WO2025151774A1
WO2025151774A1 PCT/US2025/011176 US2025011176W WO2025151774A1 WO 2025151774 A1 WO2025151774 A1 WO 2025151774A1 US 2025011176 W US2025011176 W US 2025011176W WO 2025151774 A1 WO2025151774 A1 WO 2025151774A1
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WO
WIPO (PCT)
Prior art keywords
reverse transcriptase
mammal
tenofovir
nucleoside
transcriptase inhibitor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/011176
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English (en)
Inventor
Matthew K. Waldor
Karthik HULLAHALLI
Katherine G. DAILEY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Brigham and Womens Hospital Inc
Original Assignee
Brigham and Womens Hospital Inc
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Filing date
Publication date
Application filed by Brigham and Womens Hospital Inc filed Critical Brigham and Womens Hospital Inc
Publication of WO2025151774A1 publication Critical patent/WO2025151774A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/10021—Viruses as such, e.g. new isolates, mutants or their genomic sequences
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/10022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • This invention relates to inflammatory responses and methods and compositions for treating the same.
  • Inflammatory responses may exacerbate damage to host tissues due to an overactive immune system that is concomitant with autoimmune disease or infection. These diseases may drive inflammation to the point of severe organ damage, sepsis, the formation of abscesses, or even death. Understanding pathways involved in inflammatory responses is useful for developing therapeutics and treatments for autoimmune diseases and pathogenic infections.
  • the present invention provides methods and compositions for treating inflammation.
  • the invention provides methods for treating tissue damage in a subject experiencing endogenous retrovirus (ERV)-induced reverse transcription or, alternatively, long interspersed nuclear element (LINE)-induced reverse transcription.
  • ERP retrovirus
  • LINE long interspersed nuclear element
  • a method of treating inflammation in a mammal in need thereof including:
  • step (ii) following step (i), contacting in vivo the reverse transcriptase with a reverse transcriptase inhibitor in an amount sufficient to ameliorate the pathogen-induced inflammation.
  • the host endogenous reverse transcriptase is produced by a retroelement.
  • the retroelement is an endogenous retrovirus (ERV) or a long interspersed nuclear element (LINE).
  • ERP endogenous retrovirus
  • LINE long interspersed nuclear element
  • the pathogen-induced inflammation is concomitant with bacterial or fungal or non-retrovirus infection in the mammal.
  • the reverse transcriptase inhibitor is a nucleoside/nucleotide reverse transcriptase inhibitor.
  • the nucleoside/nucleotide reverse transcriptase inhibitor is tenofovir, abacavir, adefovir, alovudine, azvudine, censavudine, didanosine, emtricitabine, entecavir, islatravir, lamivudine, stavudine, zalcitabine, or zidovudine.
  • the nucleoside/nucleotide reverse transcriptase inhibitor is tenofovir.
  • the reverse transcriptase inhibitor includes two or more nucleoside/nucleotide reverse transcriptase inhibitors.
  • the reverse transcriptase inhibitor is a non-nucleoside/non-nucleotide reverse transcriptase inhibitor.
  • analogs of any of the above compounds may be utilized in the methods of the present disclosure.
  • Such analogs include, but are not limited to, stereoisomers, geometric isomers, tautomers, or alternative isotopic forms (e.g. where one or more atoms has been substituted with a different isotope of the same atom, such as hydrogen substituted for deuterium).
  • one or more compounds for use in the methods of the present disclosure may exist in different tautomeric forms.
  • references to such compounds encompass all such tautomeric forms.
  • tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton.
  • a tautomeric form may be a prototropic tautomer, which is an isomeric protonation states having the same empirical formula and total charge as a reference form.
  • moieties with prototropic tautomeric forms are ketone — enol pairs, amide — imidic acid pairs, lactam — lactim pairs, amide — imidic acid pairs, enamine — imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1 H- and 3H-imidazole, 1 H-, 2H- and 4H- 1 ,2,4-triazole, 1 H- and 2H-isoindole, and 1 H- and 2H-pyrazole.
  • tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • synthetic nucleotide analogs may be present in multiple tautomeric forms, and it is contemplated that any tautomer from such compound is within the scope of the present methods.
  • prodrugs include the use of protecting groups which may be removed in situ releasing active compounds or serve to inhibit clearance of the drug in vivo.
  • Prodrugs can take on many different functional forms, and may include, but are not limited to, acetals, esters, or phosphates.
  • compounds including, but not limited to, adefovir, tenofovir, adefovir dipivoxil, tenofovir disoproxil, tenofovir disoproxil hemifumarate, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, tenofovir alafenamide fumarate, and tenofovir amibufenamide are suitable for use in the methods of treatment described herein, regardless of the compound being in free base or salt form.
  • compositions and methods of treatment of the disclosure are not intended to be limited to a single active agent. Multiple reverse transcriptase inhibitors are thought to be appropriate for inhibiting transcription of retroelements and reducing or treating inflammation as described herein, and the effects of administering more than one single compound may be greater than administering an individual compound.
  • a compound of the disclosure may be administered with one or more further active agents, wherein the one or more further active agents is another compound of the disclosure.
  • Such combinations may indicate two or more total active agents, e.g., two compounds, three compounds, four compounds, five compounds, six compounds, seven compounds, eight compounds, nine compounds, or ten compounds suitable for use in the methods of treatment described herein.
  • tenofovir may be administered alone or in combination with emtricitabine (or any other compounds described herein) in accordance with the present methods.
  • one may administer at least a second, if not more preferrable two or more additional active agents, for the purposes of inhibiting a broad spectrum of isoforms and improving inhibitory activity and the therapeutic result achieved.
  • Administering two or more compounds of the disclosure as part of a combination therapy is not limited to a single pharmaceutical composition and may include the active agents within the same or in separate compositions.
  • the first reverse transcriptase inhibitor may be administered substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions) as any additional reverse transcriptase inhibitor or may be administered prior to or following the administration of the first reverse transcriptase inhibitor (e.g., within a period of 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, or more).
  • Methods of the present disclosure may include administering compounds that can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.). While it is possible that, for use in the prophylaxis or treatment, a compound of the disclosure may, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising at least one pharmaceutically acceptable excipient.
  • Formulations comprising the active compounds described herein alongside one or more inert reagents (excipients) that improve the bioavailability, pharmacokinetic properties, ease of administration, or processability during manufacture are envisioned to be used for the methods of the present disclosure.
  • Pharmaceutically acceptable excipients that may be present in the compositions of the present invention include, but are not limited to, diluents, binders, disintegrants, fillers, lubricants, colorants, flavors, pH adjusters, buffers, stabilizers, viscolizers, antiadherents, preservatives, glidants, acidulants, artificial and natural sweeteners, and the like.
  • compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, pill, capsule, caplet, gelcap, suspension, solution, or syrup); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.
  • unit dosage form e.g., a tablet, pill, capsule, caplet, gelcap, suspension, solution, or syrup
  • intravenous administration e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use
  • Some embodiments include methods for treatment of diseases or disorders in a subject which include administering compounds of the present disclosure in combination with at least one pharmaceutically acceptable excipient.
  • Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions.
  • Fillers employed in the compositions of the present invention include, but are not limited to, microcrystalline cellulose, maltodextrin, calcium hydrogen phosphate, polyethylene glycol, polyvinylpyrrolidone, maize starch, xanthan gum, corn starch, Cutina HR, pregelatinized starch, partially pregelatinized starch, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, lactose monohydrate, or combinations thereof.
  • Disintegrants employed in the compositions of the present invention include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, cross-linked alginic acid, crospovidone, polyvinylpyrrolidone, methyl cellulose, starch, crosslinked starch, pregelatinized starch, partially pregelatinized starch, glycerin fatty acid ester, or combinations thereof.
  • Lubricants that may be employed in the compositions of the present invention include, but are not limited to, magnesium stearate, sodium stearate, hydrogenated vegetable oils, silicon dioxide, Aerosil 200, talc, boric acid, sodium benzoate, sodium acetate, sodium chloride, DL-leucine, polyethylene glycol, waxes, calcium stearate, zinc stearate, sodium stearyl fumarate, sodium oleate, sodium lauryl sulfate, magnesium lauryl sulfate, or combinations thereof.
  • a glidant is an excipient that improves the flow properties powders or granulates by decreasing interparticle friction and cohesion.
  • Potentially suitable glidants include, without limitation, silicon dioxide, in particular colloidal silicon dioxide, anhydrous colloidal silica, peptized silica, talc, magnesium trisilicate, powdered cellulose, or combinations thereof.
  • the glidant is colloidal silicon dioxide. If two or more glidants are present in the tablet, these amounts refer to the total amount of the glidants.
  • compositions are sometimes in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules and powders in vials, sachets or ampoules.
  • the unit dosage form can be a capsule, tablet, a pill, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the compounds of the disclosure may be prepared as liquid formulations to be suitable for the methods described herein, such as in the form of a solution, suspension, or emulsion.
  • Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants may be added to the liquid preparations.
  • Formulations suitable for oral administration can consist of (a) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (b) powders; (c) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • solid oral dosage forms such as capsule forms, tablet forms, and powder forms.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient and a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, other carriers.
  • the composition is administered as a dry powder that is reconstituted as a liquid prior to administration to the subject, thereby forming a solution or suspension.
  • Parenteral (e.g. injectable) dosage forms may be prepared by dissolving a compound of the disclosure in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule. The solutions may then be administered to a subject to treat a disease or condition by injection into a blood vessel or to the target site, as appropriate.
  • dosage amounts and regimens for administration of reverse transcriptase inhibitors in appropriate amounts to treat a disorder in a subject may be selected from a range as is customary and known to the physician and is to be tailored to an individual subject in each case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the subject, on the compound (or compounds or compositions) employed, on whether an acute or chronic disease state is treated, if prophylactic administration is conducted, or on whether further active compounds are administered in addition to the compounds and compositions described by the present disclosure.
  • Representative doses of the present disclosure include, but are not limited to, from 0.1 to 1000 mg.
  • the dose administered to the subject may be about 0.1 mg (100 pg), about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 .0 mg, about 1 .5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 4.0 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg.
  • Gram-positive bacteria possess a thick cell wall containing multiple layers of peptidoglycan and teichoic acids
  • Gram-negative bacteria have a relatively thin cell wall containing fewer layers of peptidoglycan that are surrounded by a second lipid membrane containing lipopolysaccharides (LPS) and lipoproteins.
  • LPS also called endotoxins, are composed of polysaccharides and lipid A. Molecules such as LPS are the dominant immunostimulatory molecule from E.
  • Gram-positive bacteria include, but are not limited to, bacteria in the genus Streptococcus (e.g., Streptococcus pyogenes), bacteria in the genus Staphylococcus (e.g., Staphylococcus aureus), bacteria in the genus Corynebacterium (e.g., Corynebacterium auris), bacteria in the genus Listeria (e.g., Listeria monocytogenes), bacteria in the genus Bacillus (e.g., Bacillus anthracis), and bacteria in the genus Clostridium (e.g., Clostridium perle).
  • Streptococcus e.g., Streptococcus pyogenes
  • Staphylococcus e.g., Staphylococcus aureus
  • Corynebacterium e.g., Corynebacterium auris
  • bacteria in the genus Listeria e
  • Gram-negative bacteria examples include, but are not limited to, bacteria in the genus Escherichia (e.g., Escherichia coli), bacteria in the genus Enterobacter (e.g. Enterobacter cloacae, Enterobacter aerogenes, Enterobacter gergoviae, Enterobacter asburiae, and Enterobacter hormaechei), bacteria in the genus Serratia (e.g. Serratia marcescens, Serratia plymuthica, Serratia liquefaciens, Serratia rubidaea, Serratia odorifera, and Serratia fonticola), bacteria in the genus Proteus (e.g.
  • Exemplary viruses include, but are not limited to, coronaviruses, pneumoviridae viruses, picornaviridae viruses, enteroviruses, flaviviridae viruses, filoviridae viruses, orthomyxoviruses, or paramyxoviridae viruses.
  • autoimmune diseases include autoimmune disease is selected from the list consisting of inflammatory bowel disease, type I diabetes, aplastic anemia, Graves’ disease, systemic lupus erythematosus, celiac disease, multiple sclerosis, psoriasis, scleroderma, chronic inflammatory demyelinating polyneuropathy, pernicious anemia, polyarteritis nodosa, Sjogren’s syndrome, premature ovarian failure, alopecia (baldness), polyglandular failure, hypothyroidism, polymyosititis, Crohn’s disease, ulcerative colitis, autoimmune hepatitis, hypopituitarism, myocardititis, Addison’s disease, autoimmune skin diseases, uveititis, polymyalgia rheumatica, Goodpasture’s syndrome, hypo
  • inflammatory cytokines may become altered in response to the methods of treatment disclosed herein.
  • Host inflammatory pathways become activated in response to infection, causing an increase in the expression of cytokines.
  • Administration of reverse transcriptase inhibitors, such as NRTIs causes a reduction in the expression in many inflammatory cytokines, with the notable exception being IL- 10.
  • cytokines such as IFN-y, CXCL1 , TNF-a, MIP-1 a, MIP-1 p, MCP-1 , KC, IP-10, IL-6, or IL-1 p had statistically significant reductions in expression. This trend held following infection with either the gram-positive bacteria E. coli or the gram-negative bacteria S. aureus, indicating that the signaling pathways effected by reverse transcriptase administration broadly diminish inflammatory responses regardless of the pathogenic species.
  • Example 1 Expression of endogenous retroviruses correlates with abscess susceptibility.
  • ERVs are integrated proviruses from past retroviral infections and have coevolved with eukaryotic genomes for millennia (Johnson, WE Nat Rev Microbiol 2018, 17, 355-370). Functional ERVs can be transcribed, packaged, and secreted as mature viral particles, as well as reverse- transcribed to DNA and reintegrated into the chromosome. Mice possess several classes of ERVs that reflect varying histories of viral infections (Stocking, et al. Cell Mai Life Sci 2008, 65, 3383-3398; Young, et al. Nature 2012, 491 , 774-778).
  • ERV reverse transcription can generate cytosolic cDNA or DNA:RNA hybrids, which can induce immune signaling through cytoplasmic nucleic acid sensors (Lima-Junior, et al. Cell 2021 , 184, 3794- 3811 ).
  • cytoplasmic nucleic acid sensors Lia-Junior, et al. Cell 2021 , 184, 3794- 3811 .
  • NRTIs nucleoside/nucleotide reverse transcriptase inhibitors
  • mice treated mice with tenofovir/emtricitabine (which are used together clinically), zidovudine, or abacavir alone. Surprisingly, no individual constituent phenocopied the high efficacy of the NRTI cocktail ( Figure 2A, columns 7-9). However, at higher doses equal to the total dose of the NRTI cocktail, both tenofovir/emtricitabine and abacavir alone significantly reduced abscess formation ( Figure 2A, columns 10-11 ). Timing was critical, as administration of both drugs 1 dpi did not prevent abscess formation ( Figure 2A, columns 12-13).
  • mice were used for all experiments. Mice were obtained from Jackson Laboratories (C57BL/6J (B6J, #000664), C57BL/6NJ (B6N, #005304), BALB/cJ (#000651 )). Animals were maintained at 68-75QC with 50% humidity in 12 hour day-night cycles.
  • NRTIs were dissolved in PBS and administered at doses indicated by intraperitoneal injection in a total volume of 200p1 (Tenofovir disoproxil fumarate: Fisher Scientific AC461250010, Emtricitabine: Sigma PHR2120-500MG, Zidovudine: Sigma PHR1292-1 G, Abacavir: Fisher Scientific AC458860010).
  • animals were restrained using a Broome-style restrainer (Plas- Labs) and inoculated via the lateral tail vein with 100p1 using a 27G needle. A heating pad was used to facilitate dilation of the tail vein.
  • animals were injected with 200p1 into the abdominal cavity with a 25G needle.
  • Bioinformatics 2014, 30, 923-930 was used to quantify transcript abundance. Only uniquely mapped reads were counted, and therefore highly repetitive loci with no unique sequences were excluded. ERV loci were counted using .gtf files from the Genome-based Endogenous Viral Element (gEVE) database (2). Counts were analyzed using DESeq2 for differential expression analysis (Love, et al. Genome Biol 20 4, 15, 550).
  • Nucleotide sequences correspond to MLV genomes and MLV-related ERV loci were aligned using CLUSTAL-omega.
  • a segment corresponding to the start of the gag gene through the end of the envgene was extracted and used to identify the best-fit tree by maximum likelihood using PHYML, as implemented in Geneious Prime (2023.1 .2).
  • the tree image was created in FigTree (v.1 .4.4).
  • HEMV an ERV from Mus spiceligus, was designated as an outgroup based on previously reported relationship to MLVs (Tipper, et al. J Viral 2005, 79, 8316-8329).
  • NRTIs diminish proinflammatory gene expression in the liver
  • mice infected with E. coli and administered vehicle control were clearly separated along the first principal component (79.4% of variance) from mice infected with E. coli and subsequently administered the NRTI cocktail (Fig. 3B).
  • Differential expression analysis revealed that 221 genes had higher expression (adjusted R value ⁇ 0.001 , Iog2 fold change >0.9) and 469 genes had lower expression following NRTI treatment in infected mice (Fig. 3C).
  • RNA sequencing described above identified hepatic genes induced by E. coli infection (Hullahalli, et al. Proc Natl Acad Sci 2024, 121 , e2319162121 ). By intersecting the genes that are differentially regulated by E. coli infection and those that are sensitive to NRTIs in infected mice, we assessed how NRTI treatment modulates E. co//-induced gene expression in the liver (Fig. 3E). Among the 3,078 genes that are upregulated by E. coli infection, 275 (9%) had reduced expression following NRTI treatment, while only 5 (0.16%) had increased expression following NRTI treatment. Among the 2,984 genes that are downregulated by E.
  • NRTI treatment partially reverses the hepatic differential gene expression profile resulting from E. coli infection, where among the 483 genes differentially regulated by both NRTIs and E. coli, 93% are inversely correlated in their expression. In particular, the expression of numerous components of the inflammatory response is diminished in the presence of NRTIs.
  • Flow cytometry on mice infected with E. coli and administered NRTIs or vehicle control was used to determine whether the number of liver-infiltrating cells is altered following NRTI administration (Fig. 3F).
  • NRTIs The numbers of monocytes (CD11 b+, Ly6C+, Ly6G-), monocyte-derived macrophages (CD11 bhi, F4/80+, Ly6C-, Ly6G-), and neutrophils (CD11 b+, Ly6C+, Ly6G+) relative to total CD45+ immune cells were identical in vehicle- and NRTI-treated infected mice.
  • NRTIs appear to diminish inflammatory gene expression in the liver without altering the number of infiltrating cells, potentially accounting for the fact that NRTI treatment does not impair E. coli clearance from the liver (Hullahalli, et al. Proc Natl Acad Sci 2024, 121 , e2319162121 ).
  • NRTIs diminish systemic proinflammatory responses
  • NRTIs diminish inflammatory responses induced by the Gram-positive pathogen Staphylococcus aureus. Although the stimulation of inflammatory cytokines by S. aureus was not as broad or pronounced as observed with E. coli, NRTIs significantly reduced the abundance of MCP-1 , IP-10, and MIP-i p (Fig. 4A, brown points). Finally, we examined whether NRTI treatment could improve clinical outcomes during lethal LPS shock, a commonly used model for sepsis (Stortz, et al. ILAR J, 2017, 58, 90-105). Mice were administered 200 pg of LPS i.v. (50% lethal dose) and either NRTIs or vehicle control.
  • NRTIs prevented LPS-induced hypothermia (Fig. 4B) and death (Fig. 4C). Together, these data indicate that NRTIs broadly diminish inflammatory responses to bacteria and can protect mice from lethal endotoxin shock. Since NRTIs diminish inflammatory cytokine production in the context of both Gram-negative and Gram-positive infection, the molecular mechanisms underlying the anti-inflammatory effects of NRTIs may be shared between diverse immune signaling pathways.
  • NRTI cocktail consisting of tenofovir disoproxil fumarate, emtricitabine, zidovudine, and abacavir reduces the expression of Nos2 in infected mice.
  • Nos2 encodes inducible nitric oxide synthase (iNOS) and is notable since it is also a classical marker for the activation of macrophages by proinflammatory signals such as bacteria, raising the possibility that NRTIs elicit their anti-inflammatory functions in mice in part by directly modulating the activation of macrophages during bacterial infections.
  • iNOS inducible nitric oxide synthase
  • BMDMs bone-marrow derived macrophages
  • LPS lipopolysaccharide
  • mice used in this study were 8- to 10-week-old females obtained from The Jackson Laboratories (C57BL/6NJ — #5304 and BALB/cJ — #651 ).
  • mice were restrained in a Broome-style restrainer and 100 pL of inoculum was injected into the tail vein with a 27G needle. A heating pad was used to facilitate the dilation of the tail vein.
  • PBS was used as a vehicle for all inocula in this study.
  • NRTIs were prepared from 100 mg/mL stocks in PBS and freshly diluted to 8 mg/mL for each drug (Tenofovir disoproxil fumarate, emtricitabine, zidovudine, and abacavir).
  • E. coli strain CHS7- STAMP
  • S. aureus strain HG003
  • E. coli strain CHS7- STAMP
  • S. aureus strain HG003
  • LPS Sigma L2630
  • RNA-sequencing Livers were harvested and the right lobe was flash frozen in liquid nitrogen. RNA was extracted with Trizol and the Direct Zol RNA Miniprep Kit (Zymo). Illumina-compatible libraries were prepared with the NEBNext Poly(A) mRNA Magnetic Isolation Module and the NEBNext Ultra II Directional RNA Library Prep Kit for Illumina (New England Biolabs). Libraries were sequenced on a NextSeq 1000 as 1 x 101 nt reads. Reads were processed with TrimGalore and mapped to the reference C57BL/6J chromosome (mm10, GRCm38) using HISAT2 (Kim, et al. Nat. Biotech. 2019, 37, 907-915).
  • Embodiment 5 The method of embodiment 3 wherein the administering of the reverse transcriptase inhibitory composition prevents the formation of liver abscesses.
  • Embodiment 6 A method of reducing the levels of proinflammatory cytokines in a patient comprising administering a reverse transcriptase inhibitory composition to the patient in an amount effective to cause reduction in the levels.
  • Embodiment 8 The method of any of embodiment 6 wherein the nucleotide/nucleoside reverse transcriptase inhibitory composition is selected from tenofovir, emtricitabine, abacavir, zidovudine, zalcitabine, stavudine, lamivudine, entecavir truada, azvudine, tenofovir, adefovir, and islatravir.
  • Embodiment 9 The method of any of embodiments 1-5 wherein the reverse transcriptase inhibitory composition is a non-nucleotide/nucleoside reverse transcriptase inhibitory composition.
  • non-nucleotide/nucleoside reverse transcriptase inhibitory composition is selected from efavirenz, nevirapine, delavirdine, etravirine, rilpivirine, doravirine, and elsulfavirine.
  • Embodiment 11 Any and all compositions, articles of manufacture, methods, and uses disclosed and/or described in the above specification.
  • Embodiment 12 A method of reducing an inflammatory response or reducing the risk of developing inflammation resulting from a pathogen or the presence of a toxin in a mammal, the method comprising administering to the mammal a composition comprising at least one reverse transcriptase inhibitor, in an amount sufficient to reduce the inflammatory response or reduce the risk of developing the inflammation.
  • Embodiment 13 The method of embodiment 12, wherein the composition comprises two or more reverse transcriptase inhibitors.
  • Embodiment 14 The method of embodiment 12, wherein the inflammation or inflammatory response causes tissue damage.
  • Embodiment 15 The method of embodiment 12, wherein the inflammatory response or inflammation causes sepsis.
  • Embodiment 16 The method of embodiment 12, wherein the inflammatory response or the inflammation results from the presence of a bacterial toxin.
  • Embodiment 25 The method of embodiment 12, wherein the pathogen is a bacterial, fungal, or viral pathogen.
  • Embodiment 28 The embodiment of claim 12, wherein the composition comprises tenofovir, tenofovir alafenamide fumarate, tenofovir disoproxil fumarate, or tenofovir exalidex.
  • Embodiment 29 The method of embodiment 12, wherein the composition comprises censavudine.
  • Embodiment 30 The method of embodiment 12, wherein the composition comprises tenofovir.
  • Embodiment 31 The method of embodiment 12, wherein the composition comprises abacavir.
  • Embodiment 32 The method of embodiment 13, wherein the composition comprises emtricitabine and tenofovir.

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Abstract

La présente invention concerne une méthode de traitement d'une inflammation chez un mammifère en ayant besoin qui consiste à fournir à un mammifère une transcriptase inverse endogène hôte élevée produite par des rétrovirus endogènes hôtes (ERVs), puis à mettre en contact in vivo la transcriptase inverse avec un inhibiteur de transcriptase inverse en quantité suffisante pour améliorer la réponse inflammatoire induite par ERV.
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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HULLAHALLI KARTHIK , KATHERINE G DAILEY, YUKO HASEGAWA, WELKIN E JOHNSON, MATTHEW K WALDOR : "Reverse transcriptase inhibitors prevent liver abscess formation during Escherichia coli bloodstream infection", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 121, no. 4, 16 January 2024 (2024-01-16), pages 1 - 3, XP093336862 *
LIMA-JUNIOR DJALMA S., KRISHNAMURTHY SIDDHARTH R., BOULADOUX NICOLAS, COLLINS NICHOLAS, HAN SEONG-JI, CHEN ERIN Y., CONSTANTINIDES: "Endogenous retroviruses promote homeostatic and inflammatory responses to the microbiota", CELL, ELSEVIER, AMSTERDAM NL, vol. 184, no. 14, 1 July 2021 (2021-07-01), Amsterdam NL , pages 3794 - 3811.e19, XP093336851, ISSN: 0092-8674, DOI: 10.1016/j.cell.2021.05.020 *
MARINE MOMMERT, TABONE OLIVIER, GUICHARD AUDREY, ORIOL GUY, CERRATO ELISABETH, DENIZOT MéLANIE, CHEYNET VALéRIE, PACHOT : "Dynamic LTR retrotransposon transcriptome landscape in septic shock patients", CRITICAL CARE, vol. 24, no. 1, 18 March 2020 (2020-03-18), XP055722526, DOI: 10.1186/s13054-020-2788-8 *

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