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WO2023239728A1 - Compositions et méthodes de traitement d'une inflammation à l'aide de vésicules extracellulaires de prevotella histicola - Google Patents

Compositions et méthodes de traitement d'une inflammation à l'aide de vésicules extracellulaires de prevotella histicola Download PDF

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Publication number
WO2023239728A1
WO2023239728A1 PCT/US2023/024590 US2023024590W WO2023239728A1 WO 2023239728 A1 WO2023239728 A1 WO 2023239728A1 US 2023024590 W US2023024590 W US 2023024590W WO 2023239728 A1 WO2023239728 A1 WO 2023239728A1
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Prior art keywords
evs
subject
prevotella
particles
solid dosage
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English (en)
Inventor
Duncan MCHALE
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Evelo Biosciences Inc
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Evelo Biosciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • therapeutic compositions comprising extracellular vesicles (EVs) from Prevotella histicola bacteria useful for the treatment and/or prevention of an inflammatory disease, and methods of using such therapeutic compositions (e.g., for the treatment and/or prevention of an inflammatory disease).
  • the inflammatory disease is a Th1, Th2, or Th17 inflammatory disease.
  • therapeutic compositions e.g., pharmaceutical compositions
  • the therapeutic compositions comprise secreted Prevotella histicola EVs (smEVs).
  • the therapeutic compositions are used for at least 8 weeks.
  • therapeutic compositions e.g., pharmaceutical compositions
  • Prevotella histicola EVs useful for the treatment and/or prevention of psoriasis (e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis) (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for the treatment of psoriasis, for the reduction of Lesion Severity Scores (LSS), and/or for the reduction of Psoriasis Area Severity Index (PASI) scores).
  • LSS Lesion Severity Scores
  • PASI Psoriasis Area Severity Index
  • the therapeutic compositions comprise secreted Prevotella histicola EVs (smEVs). In some embodiments, the therapeutic compositions are used for at least 8 weeks.
  • therapeutic compositions e.g., pharmaceutical compositions
  • Prevotella histicola EVs useful for the treatment and/or prevention of atopic dermatitis (e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis) (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for the treatment of atopic dermatitis and/or for an improvement in EASI score).
  • the therapeutic compositions comprise secreted Prevotella histicola EVs (smEVs). In some embodiments, the therapeutic compositions are used for at least 8 weeks.
  • therapeutic compositions e.g., pharmaceutical compositions
  • Prevotella histicola EVs useful for the treatment and/or prevention of psoriatic arthritis (e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis), (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for the treatment of psoriatic arthritis).
  • the therapeutic compositions comprise secreted Prevotella histicola EVs (smEVs). In some embodiments, the therapeutic compositions are used for at least 8 weeks.
  • therapeutic compositions e.g., pharmaceutical compositions
  • Prevotella histicola EVs useful for the treatment and/or prevention of an autoimmune disease, (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for the treatment of an autoimmune disease).
  • the therapeutic compositions comprise secreted Prevotella histicola EVs (smEVs). In some embodiments, the therapeutic compositions are used for at least 8 weeks.
  • compositions comprising Prevotella histicola EVs useful for the treatment and/or prevention of a metabolic disease, (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for the treatment of a metabolic disease).
  • the therapeutic compositions comprise secreted Prevotella histicola EVs (smEVs).
  • the therapeutic compositions are used for at least 8 weeks.
  • compositions comprising Prevotella histicola EVs useful for the treatment and/or prevention of a dysbiosis, (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for the treatment of a dysbiosis).
  • the therapeutic compositions comprise secreted Prevotella histicola EVs (smEVs).
  • the therapeutic compositions are used for at least 8 weeks.
  • compositions comprising Prevotella histicola useful for decreasing inflammatory cytokine expression (e.g., decreased TNF ⁇ expression levels), (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for decreasing inflammatory cytokine expression (e.g., decreased TNF ⁇ expression levels)).
  • the therapeutic compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-live bacteria, killed bacteria, and/or attenuated bacteria).
  • the therapeutic compositions are used for at least 8 weeks.
  • compositions comprising Prevotella histicola EVs useful for the treatment and/or prevention of bacterial septic shock, cytokine storm and/or viral infection, (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for the treatment of bacterial septic shock, cytokine storm and/or viral infection).
  • the therapeutic compositions comprise secreted Prevotella histicola EVs (smEVs).
  • the therapeutic compositions are used for at least 8 weeks.
  • compositions comprising Prevotella histicola EVs useful for the treatment and/or prevention of a viral infection, (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for the treatment of a viral infection).
  • the viral infection is a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection.
  • the viral infection is a SARS-CoV-2 infection.
  • the therapeutic compositions comprise secreted Prevotella histicola EVs (smEVs).
  • the therapeutic compositions are used for at least 8 weeks.
  • the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for at least 8 weeks.
  • the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for at least 12 weeks.
  • the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for at least 16 weeks.
  • the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for at least 20 weeks.
  • the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for at least 24 weeks. In some embodiments, therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for at least 28 weeks. In some embodiments, the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for at least 32 weeks. In some embodiments, the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for at least 36 weeks.
  • the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for at least 40 weeks. In some embodiments, the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for at least 44 weeks. In some embodiments, the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for at least 48 weeks. In some embodiments, the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for at least 52 weeks.
  • the therapeutic composition comprising Prevotella histicola EVs is administered to the subject once daily for the given number of weeks.
  • the therapeutic composition e.g., pharmaceutical composition
  • the therapeutic composition comprising Prevotella histicola EVs is administered to the subject twice daily for the given number of weeks.
  • the therapeutic composition e.g., pharmaceutical composition
  • the therapeutic composition comprising Prevotella histicola EVs is administered to the subject for 8 weeks.
  • the therapeutic composition e.g., pharmaceutical composition
  • the therapeutic composition comprising Prevotella histicola EVs is administered to the subject for 12 weeks.
  • the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for 16 weeks. In some embodiments, the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for 20 weeks. In some embodiments, the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for 24 weeks. In some embodiments, the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for 28 weeks.
  • the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for 32 weeks. In some embodiments, the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for 36 weeks. In some embodiments, the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for 40 weeks. In some embodiments, the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for 44 weeks.
  • the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for 48 weeks. In some embodiments, the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject for 52 weeks. For example, the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject once daily for the given number of weeks. For example, the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is administered to the subject twice daily for the given number of weeks.
  • the Prevotella histicola EVs are from Prevotella Strain B 50329 (NRRL accession number B 50329; Strain B).
  • the Prevotella EVs are from a strain that is a strain comprising at least at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, or CRISPR sequence) of the Prevotella Strain B 50329.
  • sequence identity e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.
  • the therapeutic composition comprises EVs from one strain of bacteria, wherein the one strain of bacteria is a strain comprising at least 99.9% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
  • the therapeutic composition comprises EVs from one strain of bacteria, wherein the one strain of bacteria is the Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 1 x 10 11 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 1 x 10 12 to about 1 x 10 15 -.
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 1 x 10 12 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 2 x 10 12 to about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 3 x 10 12 to about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 2 x 10 13 to about 2 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 5 x 10 13 to about 5 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 1 x 10 13 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 1 x 10 11 to about 1 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 4 x 10 11 to about 4 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 1 x 10 11 to about 1 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 4 x 10 11 to about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein). In some embodiments, the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 1.6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein). In some embodiments, the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • solid dosage forms comprising the Prevotella histicola EVs.
  • the solid dosage form comprises an enteric coating.
  • the solid dosage form is a tablet, e.g., an enteric coated tablet.
  • each tablet comprises Prevotella histicola EVs at a dose of about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • each tablet comprises Prevotella histicola EVs at a dose of about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein). In some embodiments, each tablet comprises Prevotella histicola EVs at a dose of about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • each capsule comprises Prevotella histicola EVs at a dose of about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein). In some embodiments, each capsule comprises Prevotella histicola EVs at a dose of about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • about 5 x 10 13 to about 5 x 10 14 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola EVs are administered to the subject daily, e.g., in one or more solid dosage forms.
  • about 1 x 10 13 to about 1 x 10 14 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola EVs are administered to the subject daily, e.g., in one or more solid dosage forms.
  • about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of Prevotella histicola EVs are administered to the subject daily, e.g., in one or more solid dosage forms.
  • about 1.6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of Prevotella histicola EVs are administered to the subject daily, e.g., in one or more solid dosage forms.
  • the therapeutic composition comprises about 1 x 10 11 to about 1 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 4 x 10 11 to about 4 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the enteric coating is at a coating level of about 2.7 mg/cm 2 (e.g., about 14 mg per size 0 capsule) total weight gain (a polymer weight gain of about 1.7 mg/cm 2 ).
  • the solid dosage form comprises about 1 x 10 12 to about 1 x 10 15 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 2 x 10 13 to about 2 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 5 x 10 13 to about 5 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 1 x 10 11 to about 1 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 4 x 10 11 to about 4 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 4 x 10 11 to about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the Prevotella EVs in the solid dosage form are spray dried.
  • the dried form comprises Prevotella EVs and mannitol.
  • the dried form comprises Prevotella EVs and trehalose.
  • the dried form comprises Prevotella EVs, mannitol, and trehalose.
  • the dried form consists essentially of Prevotella EVs, mannitol, and trehalose.
  • the solid dosage form comprises about 1 x 10 12 to about 1 x 10 15 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 4 x 10 11 to about 4 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 4 x 10 11 to about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 1.6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • 2 solid dosage forms e.g., each comprising about 4 x 10 11 particles
  • 3 solid dosage forms e.g., each comprising about 4 x 10 11 particles
  • 4 solid dosage forms e.g., each comprising about 4 x 10 11 particles
  • 5 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 6 solid dosage forms e.g., each comprising about 4 x 10 11 particles
  • 8 solid dosage forms e.g., each comprising about 4 x 10 11 particles
  • 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • each solid dosage form comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 1 solid dosage form e.g., comprising about 4 x 10 12 particles
  • 2 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 3 solid dosage forms e.g., each comprising about 4 x 10 12 particles
  • 4 solid dosage forms e.g., each comprising about 4 x 10 12 particles
  • 5 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 6 solid dosage forms e.g., each comprising about 4 x 10 12 particles
  • 8 solid dosage forms e.g., each comprising about 4 x 10 12 particles
  • 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • each solid dosage form comprises about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 1 solid dosage form e.g., comprising about 6 x 10 13 particles
  • 2 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 3 solid dosage forms e.g., each comprising about 6 x 10 13 particles
  • 4 solid dosage forms e.g., each comprising about 6 x 10 13 particles
  • 5 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 6 solid dosage forms e.g., each comprising about 6 x 10 13 particles
  • 8 solid dosage forms e.g., each comprising about 6 x 10 13 particles
  • 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • each solid dosage form comprises about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 1 solid dosage form e.g., comprising about 8 x 10 13 particles
  • 2 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 3 solid dosage forms e.g., each comprising about 8 x 10 13 particles
  • 4 solid dosage forms e.g., each comprising about 8 x 10 13 particles
  • 5 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • solid dosage forms e.g., each comprising about 8 x 10 13 particles
  • 6 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 8 solid dosage forms e.g., each comprising about 8 x 10 13
  • 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • the solid dosage form comprises a capsule.
  • the capsule is a size 0 capsule.
  • the capsule is an enteric coated capsule.
  • the Prevotella EVs in the capsule are in a dried form.
  • the Prevotella EVs in the capsule are lyophilized.
  • the Prevotella EVs in the capsule are spray dried.
  • the dried form comprises Prevotella EVs and mannitol.
  • the dried form comprises Prevotella EVs and trehalose.
  • the capsule comprises about 1 x 10 12 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a capsule or plurality of capsules).
  • particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329 (e.g., total dose of a capsule or plurality of capsules).
  • the capsule comprises about 2 x 10 12 to about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a capsule or plurality of capsules).
  • particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329 (e.g., total dose of a capsule or plurality of capsules).
  • the capsule comprises about 1 x 10 13 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a capsule or plurality of capsules).
  • particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329 (e.g., total dose of a capsule or plurality of capsules).
  • the capsule comprises about 4 x 10 11 to about 4 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a capsule or plurality of capsules).
  • particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329 (e.g., total dose of a capsule or plurality of capsules).
  • the capsule comprises about 1.6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a capsule or plurality of capsules).
  • the capsule comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a capsule or plurality of capsules).
  • particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329 (e.g., total dose of a capsule or plurality of capsules).
  • 6 capsules e.g., each comprising about 4 x 10 11 particles
  • 8 capsules e.g., each comprising about 4 x 10 11 particles
  • 10 capsules e.g., each comprising about 4 x 10 11 particles
  • 2 capsules e.g., each comprising about 4 x 10 12 particles
  • 3 capsules e.g., each comprising about 4 x 10 12 particles
  • 4 capsules e.g., each comprising about 4 x 10 12 particles
  • 5 capsules are administered, e.g., once or twice daily to a subject.
  • 2 capsules e.g., each comprising about 6 x 10 13 particles
  • 3 capsules e.g., each comprising about 6 x 10 13 particles
  • 4 capsules e.g., each comprising about 6 x 10 13 particles
  • 5 capsules are administered, e.g., once or twice daily to a subject.
  • 2 capsules e.g., each comprising about 8 x 10 13 particles
  • 3 capsules e.g., each comprising about 8 x 10 13 particles
  • 4 capsules e.g., each comprising about 8 x 10 13 particles
  • 5 capsules are administered, e.g., once or twice daily to a subject.
  • the enteric coating comprises a polymethacrylate- based copolymer. In some embodiments, the enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1). In some embodiments, the enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P or Eudragit L30-D55). [44] In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 tablets are administered, e.g., once or twice daily to a subject. In some embodiments, 1 tablet is administered, e.g., once or twice daily to a subject.
  • the tablet comprises about 5 x 10 13 to about 5 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a tablet or plurality of tablets).
  • particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329 (e.g., total dose of a tablet or plurality of tablets).
  • the tablet comprises about 1 x 10 13 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a tablet or plurality of tablets).
  • particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329 (e.g., total dose of a tablet or plurality of tablets).
  • the tablet comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a tablet or plurality of tablets).
  • the tablet comprises about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a tablet or plurality of tablets).
  • particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329 (e.g., total dose of a tablet or plurality of tablets).
  • 2 tablets are administered, e.g., once or twice daily to a subject.
  • 3 tablets e.g., each comprising about 4 x 10 12 particles
  • 4 tablets are administered, e.g., once or twice daily to a subject.
  • 5 tablets are administered, e.g., once or twice daily to a subject.
  • 2 tablets are administered, e.g., once or twice daily to a subject.
  • 3 tablets e.g., each comprising about 6 x 10 13 particles
  • 4 tablets e.g., each comprising about 6 x 10 13 particles
  • 5 tablets are administered, e.g., once or twice daily to a subject.
  • 6 tablets are administered, e.g., once or twice daily to a subject.
  • 8 tablets e.g., each comprising about 6 x 10 13 particles
  • 10 tablets are administered, e.g., once or twice daily to a subject.
  • the therapeutic composition comprising Prevotella EVs is prepared as a dried form (e.g., for resuspension or for use in a solid dosage form (such as a capsule)) or as a solid dosage form, such as a tablet, a mini-tablet, a capsule, a pill, or a powder; or a combination of these forms (e.g., mini-tablets comprised in a capsule).
  • the Prevotella EVs in the therapeutic composition are in a dried form.
  • the Prevotella EVs in the therapeutic composition are lyophilized.
  • the Prevotella EVs in the therapeutic composition are spray dried.
  • the dried form comprises Prevotella EVs and mannitol. In some embodiments, the dried form comprises Prevotella EVs and trehalose. In some embodiments, the dried form comprises Prevotella EVs, mannitol, and trehalose.
  • the therapeutic composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola, e.g., Prevotella Strain B 50329.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the therapeutic composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola, e.g., Prevotella Strain B 50329.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the therapeutic composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola, e.g., Prevotella Strain B 50329.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the therapeutic composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1 x 10 11 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola, e.g., Prevotella Strain B 50329.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the therapeutic composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1 x 10 11 to about 1 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola, e.g., Prevotella Strain B 50329.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the therapeutic composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 4 x 10 11 to about 4 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola, e.g., Prevotella Strain B 50329.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the therapeutic composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1 x 10 11 to about 1 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola, e.g., Prevotella Strain B 50329.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the therapeutic composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 4 x 10 11 to about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola, e.g., Prevotella Strain B 50329.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the therapeutic composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1 x 10 12 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola, e.g., Prevotella Strain B 50329.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the therapeutic composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 2 x 10 12 to about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola, e.g., Prevotella Strain B 50329.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the therapeutic composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 3 x 10 12 to about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola, e.g., Prevotella Strain B 50329.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the therapeutic composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 2 x 10 13 to about 2 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola, e.g., Prevotella Strain B 50329.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the therapeutic composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1 x 10 13 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola, e.g., Prevotella Strain B 50329.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • the solid dosage form comprises about 4 x 10 11 particles per solid dosage form (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the solid dosage form comprises about 4 x 10 12 particles per solid dosage form (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the solid dosage form comprises about 6 x 10 13 particles per solid dosage form (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the solid dosage form comprises about 8 x 10 13 particles per solid dosage form (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • one solid dosage form is administered to the subject once daily.
  • one solid dosage form is administered to the subject twice daily.
  • two solid dosage forms are administered to the subject once daily.
  • two solid dosage forms are administered to the subject twice daily.
  • three solid dosage forms are administered to the subject once daily.
  • three solid dosage forms are administered to the subject twice daily.
  • four solid dosage forms are administered to the subject once daily.
  • four solid dosage forms are administered to the subject twice daily.
  • five solid dosage forms are administered to the subject once daily.
  • five solid dosage forms are administered to the subject twice daily.
  • 1 solid dosage form e.g., tablet or capsule
  • is administered e.g., is for administration
  • the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • 2 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject
  • the solid dosage form e.g., each solid dose form
  • 3 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 4 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 5 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 6 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 8 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 10 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 1 solid dosage form e.g., tablet or capsule
  • is administered e.g., is for administration
  • the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • 2 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject
  • the solid dosage form e.g., each solid dose form
  • 3 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 4 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 5 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 6 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 8 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 10 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 1 solid dosage form e.g., tablet or capsule
  • is administered e.g., is for administration
  • the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • 2 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject
  • the solid dosage form e.g., each solid dose form
  • 3 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 5 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 6 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 8 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 10 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 1 solid dosage form e.g., tablet or capsule
  • is administered e.g., is for administration
  • the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • 2 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject
  • the solid dosage form e.g., each solid dose form
  • 3 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • solid dosage forms e.g., tablets or capsules
  • the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • 5 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 6 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 8 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • Prevotella histicola bacteria e.g., Prevotella Strain B 50329
  • 10 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, of about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the solid dosage form is a tablet, e.g., an enteric coated tablet.
  • the solid dosage form is a mini-tablet, e.g., an enteric coated mini-tablet.
  • the solid dosage form is a capsule, e.g., an enteric coated capsule.
  • the enteric coating comprises a polymethacrylate-based copolymer.
  • the enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1).
  • the enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P or Eudragit L30-D55).
  • the therapeutic composition comprising Prevotella EVs is prepared as a dried form.
  • the dried form is a powder.
  • the dried form can comprise lyophilized EVs.
  • the dried form further comprises mannitol and/or trehalose.
  • the therapeutic composition comprises a dried form comprising Prevotella EVs.
  • the dried form comprising Prevotella EVs (e.g., at a dose provided herein) is resuspended (e.g., in a liquid such as a solution, buffer, water or other beverage, or a food), e.g., for use in the methods provided herein.
  • the Prevotella histicola EVs are administered in a therapeutic composition (e.g., a therapeutic composition provided herein).
  • the therapeutic composition is a solid dose form provided herein.
  • the therapeutic composition comprises a dried form (such as a powder) of the Prevotella histicola EVs and excipients (e.g., an encapsulated dried form of a Prevotella histicola strain provided herein and excipients).
  • the therapeutic composition comprises a blend of freeze-dried (that is, lyophilized) powder of Prevotella histicola EVs and excipients (e.g., an encapsulated freeze-dried powder of a Prevotella histicola EVs provided herein and excipients).
  • the therapeutic composition comprises freeze-dried (e.g., lyophilized) powder of Prevotella histicola EVs in a capsule.
  • the capsule is enteric coated.
  • the therapeutic composition comprises an enteric coated hydroxylpropyl methylcellulose (HPMC) capsule.
  • the therapeutic composition comprises a formulation of Prevotella histicola Strain B EVs comprising freeze- dried powder of Prevotella histicola EVs and an excipient.
  • the excipient comprises mannitol.
  • the excipient comprises magnesium stearate.
  • the excipient comprises colloidal silicon dioxide.
  • the excipient comprises mannitol, magnesium stearate and/or colloidal silicon dioxide.
  • each capsule contains about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B).
  • a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B).
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules are administered to a subject daily.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules e.g., each containing about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B)) are administered to a subject once daily.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules e.g., each containing about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B)) are administered to a subject twice daily.
  • each capsule contains about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B).
  • a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B).
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules are administered to a subject daily.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules e.g., each containing about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B)) are administered to a subject once daily.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules e.g., each containing about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B)) are administered to a subject twice daily.
  • each capsule contains about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B).
  • a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B).
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules are administered to a subject daily.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules e.g., each containing about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B)) are administered to a subject once daily.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules e.g., each containing about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B)) are administered to a subject twice daily.
  • each capsule contains about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B).
  • a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B).
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules are administered to a subject daily.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules e.g., each containing about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B)) are administered to a subject once daily.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules e.g., each containing about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B)) are administered to a subject twice daily.
  • the therapeutic composition comprising Prevotella EVs is prepared as a solid dose form, such as a tablet, capsule, or a dried form, such as a powder.
  • the dried form can comprise lyophilized EVs.
  • the powder further comprises mannitol.
  • the powder further comprises trehalose.
  • the powder further comprises mannitol and trehalose.
  • the powder consists essentially of EVs, mannitol and trehalose.
  • the therapeutic composition comprises a dried form, such as a powder, comprising Prevotella EVs.
  • the dried form such as a powder, comprising Prevotella EVs (e.g., at a dose provided herein) is resuspended (e.g., in a liquid such as a solution, buffer, water or other beverage, or a food), e.g., for use in the methods provided herein.
  • the dried form, such as a powder, comprising Prevotella EVs is prepared as a solid dosage form, e.g., for use in the methods provided herein.
  • the therapeutic composition is administered orally. In some embodiments, the administration to the subject is daily.
  • the administration to the subject is once daily. In some embodiments, the administration to the subject is twice daily. [98] In some embodiments, the therapeutic composition is administered once daily for 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks. In some embodiments, the therapeutic composition is administered once daily for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks. In some embodiments, the therapeutic composition is administered once daily for at least 8 weeks. In some embodiments, the therapeutic composition is administered once daily for at least 12 weeks. In some embodiments, the therapeutic composition is administered once daily for at least 16 weeks. In some embodiments, the therapeutic composition is administered once daily for at least 20 weeks.
  • the therapeutic composition is administered once daily for at least 24 weeks.
  • the therapeutic composition comprises lyophilized Prevotella EVs e.g., in a powder.
  • the powder comprises mannitol.
  • the powder comprises trehalose.
  • the powder comprises mannitol and trehalose.
  • the powder consists essentially of EVs, mannitol and trehalose.
  • the powder is formulated into a solid dose form, such as a tablet or capsule.
  • the solid dose form comprises an excipient.
  • the excipient comprises mannitol.
  • the excipient comprises magnesium stearate. In some embodiments, the excipient comprises colloidal silicon dioxide. In some embodiments, the excipient comprises mannitol, magnesium stearate and/or colloidal silicon dioxide.
  • the therapeutic composition is formulated as a tablet. In some embodiments, the tablet comprises an enteric coating or micro encapsulation. [101] In some embodiments, the therapeutic composition is formulated as a capsule. In some embodiments, the capsule comprises an enteric coating or micro encapsulation. [102] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
  • the subject is a non-human mammal (e.g., a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla, or a chimpanzee).
  • a non-human mammal e.g., a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla, or a chimpanzee.
  • a therapeutic composition e.g., a pharmaceutical composition and/or a solid dosage form
  • the disclosure provides Prevotella histicola EVs provided herein and/or a therapeutic composition (e.g., a pharmaceutical composition and/or a solid dosage form) described herein (e.g., in an amount described herein) for use in the performance of a therapeutic method provided herein.
  • a therapeutic composition e.g., a pharmaceutical composition and/or a solid dosage form
  • provided herein are methods of treating a subject who has a Th1 mediated inflammatory disease comprising administering to the subject a therapeutic composition described herein.
  • a method of treating a Th1 mediated inflammatory disease comprising administering (e.g., orally administering) to a human subject (e.g., a subject with a Th1 mediated inflammatory disease) Prevotella histicola EVs and/or a composition (e.g., a therapeutic composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising Prevotella histicola EVs provided herein.
  • a Th2 mediated inflammatory disease such as asthma or atopic dermatitis
  • a method of treating a Th2 mediated inflammatory disease comprising administering (e.g., orally administering) to a human subject (e.g., a subject with a Th2 mediated inflammatory disease (such as asthma or atopic dermatitis))
  • a human subject e.g., a subject with a Th2 mediated inflammatory disease (such as asthma or atopic dermatitis)
  • Prevotella histicola EVs and/or a composition e.g., a therapeutic composition (e.g., pharmaceutical composition) and/or a solid dosage form
  • a composition e.g., a therapeutic composition (e.g., pharmaceutical composition) and/or a solid dosage form
  • provided herein are methods of treating a subject who has a Th17 mediated inflammatory disease (such as psoriasis) comprising administering to the subject a therapeutic composition described herein.
  • a method of treating a Th17 mediated inflammatory disease comprising administering (e.g., orally administering) to a human subject (e.g., a subject with a Th17 mediated inflammatory disease (such as psoriasis))
  • Prevotella histicola EVs and/or a composition e.g., a therapeutic composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising Prevotella histicola EVs provided herein.
  • provided herein are methods of treating a subject who has psoriasis (e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis) comprising administering to the subject a therapeutic composition (e.g., pharmaceutical composition) described herein.
  • a therapeutic composition e.g., pharmaceutical composition
  • methods of decreasing Lesion Severity Score e.g., mean LSS
  • a subject e.g., a subject with psoriasis
  • the LSS in the subject is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more (e.g., by week 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 of treatment).
  • Psoriasis Area and Severity Index (PASI) score (e.g., mean PASI score) (e.g., as compared to baseline or placebo control) in a subject (e.g., a subject with psoriasis) comprising administering to the subject a therapeutic composition described herein.
  • PASI Psoriasis Area and Severity Index
  • the PASI score in the subject is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more (e.g., by week 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 of treatment).
  • provided herein are methods of enhancing anti-inflammatory cytokine production (e.g., increasing as compared to amount produced (e.g., mRNA and/or protein) in the absence of the therapeutic composition) in a subject, the method comprising administering a therapeutic composition described herein.
  • the anti- inflammatory cytokine is IL-10.
  • the anti-inflammatory cytokine is expressed by immune cells.
  • enhancing anti-inflammatory cytokine production comprises an increase in anti-inflammatory cytokine (e.g., IL-10) mRNA levels (e.g., by immune cells, e.g., by peripheral blood mononuclear cells (PBMCs), dendritic cells (DCs), macrophages and/or by antigen presenting cells (APCs)).
  • PBMCs peripheral blood mononuclear cells
  • DCs dendritic cells
  • APCs antigen presenting cells
  • enhancing anti-inflammatory cytokine production comprises an increase in anti-inflammatory cytokine (e.g., IL- 10) protein levels (e.g., by immune cells, e.g., by peripheral blood mononuclear cells (PBMCs), dendritic cells (DCs), macrophages and/or by antigen presenting cells (APCs)).
  • anti-inflammatory cytokine e.g., IL- 10
  • the anti-inflammatory cytokine is IL-27.
  • the anti- inflammatory cytokine is expressed by immune cells.
  • enhancing anti-inflammatory cytokine production comprises an increase in anti-inflammatory cytokine (e.g., IL- 27) mRNA levels (e.g., by immune cells, e.g., by antigen presenting cells (APCs)).
  • enhancing anti-inflammatory cytokine production comprises an increase in anti- inflammatory cytokine (e.g., IL-27) protein levels (e.g., by immune cells, e.g., by antigen presenting cells (APCs)).
  • provided herein are methods of inhibiting pro-inflammatory cytokine production (e.g., decreasing as compared to amount produced (e.g., mRNA and/or protein) in the absence of the therapeutic composition) in a subject, the method comprising administering a therapeutic composition described herein.
  • the pro- inflammatory cytokine is TNF.
  • provided herein are methods of altering cytokine production or chemokine production (e.g., altering as compared to amount produced (e.g., mRNA and/or protein) in the absence of the therapeutic composition) in a subject, the method comprising administering a therapeutic composition described herein.
  • blood samples from the subject are stimulated ex vivo and analyzed for levels of cytokines and/or chemokines.
  • the level of IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-17A, TNF ⁇ (TNF alpha), and/or IFN ⁇ (IFN gamma) in the sample is analyzed.
  • mRNA levels of the cytokine are analyzed.
  • protein levels of the cytokine are analyzed.
  • kits for generating Prevotella histicola EV-specific IgA, IgG, and/or IgM antibodies e.g., as compared to amount of the antibody produced in the absence of the therapeutic composition
  • the method comprising administering a therapeutic composition described herein.
  • Prevotella histicola EVs are immobilized to a surface (e.g., a plate or bead), a serum (e.g., from blood) sample from the subject is contacted with the immobilized EVs to form an immobilized complex of the EVs and antibody present in the serum, and detecting and/or quantitating the presence and/or amount of antibody contacted with the immobilized EVs, e.g., by contacting an anti-human IgA, IgG, and/or IgM secondary antibody (as appropriate) (e.g., which may be detectably labeled) to the immobilized complex, and detecting the presence and/or amount of secondary antibody associated with the immobilized complex.
  • a surface e.g., a plate or bead
  • a serum (e.g., from blood) sample from the subject is contacted with the immobilized EVs to form an immobilized complex of the EVs and antibody present in the serum, and detecting and/
  • a method of treating psoriasis comprising administering (e.g., orally administering) to a human subject Prevotella histicola EVs and/or a composition (e.g., a therapeutic composition and/or a solid dosage form) comprising Prevotella histicola EVs provided herein.
  • the human subject has had mild to moderate plaque psoriasis with plaque covering BSA of ⁇ 5% and ⁇ 20% and meet both of the following additional criteria: (i) PASI score of ⁇ 5 and ⁇ 20, and (ii) PGA score of 3.
  • the method decreases the PASI (Psoriasis Area and Severity Index) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s PASI score prior to the commencement of treatment).
  • the method increases a PASI percentage response rate (e.g., PASI- 50, PASI-75, PASI-90, or PASI-100), e.g., as described herein.
  • the percentage of subjects who achieve a 75% or greater reduction in PASI score from baseline is represented by the PASI-75 value, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment.
  • the method decreases the LSS (Lesion Severity Score) in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s LSS prior to the commencement of treatment), e.g., as described herein.
  • the method decreases the PGA (Physician’s Global Assessment) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s PGA score prior to the commencement of treatment), e.g., as described herein.
  • the method decreases the percent of BSA (Body Surface Area) involvement in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s percent involvement prior to the commencement of treatment), e.g., as described herein.
  • the method decreases the mNAPSI (Modified Nail Psoriasis Severity Index) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s mNAPSI score prior to the commencement of treatment), e.g., as described herein.
  • mNAPSI Modified Nail Psoriasis Severity Index
  • the method improves (e.g., decreases) the DLQI (Dermatology Life Quality Index) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s DLQI score prior to the commencement of treatment), e.g., as described herein.
  • DLQI Density Life Quality Index
  • the method improves the product of PGA and BSA in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s product of PGA and BSA prior to the commencement of treatment), e.g., as described herein.
  • the method improves (e.g., decreases) the PSI (Psoriasis Symptom Inventory) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s PSI score prior to the commencement of treatment), e.g., as described herein.
  • PSI Psoriasis Symptom Inventory
  • the method improves (e.g., decreases) the PP-NRS (Peak Pruritus- Numeric Rating Scale) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s PP-NRS score prior to the commencement of treatment), e.g., as described herein.
  • PP-NRS Peak Pruritus- Numeric Rating Scale
  • the method improves the EQ-PSO (EuroQol-Psoriasis Bolt-On) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s EQ-PSO score prior to the commencement of treatment), e.g., as described herein.
  • the method decreases pain in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s pain prior to the commencement of treatment), e.g., as described herein.
  • the method decreases fatigue in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s fatigue prior to the commencement of treatment), e.g., as described herein, e.g., VAS fatigue.
  • provided herein are methods of treating a subject who has atopic dermatitis (e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis) comprising administering to the subject a therapeutic composition described herein.
  • atopic dermatitis e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis
  • a method of treating atopic dermatitis comprising administering (e.g., orally administering) to a human subject Prevotella histicola EVs and/or a composition (e.g., a therapeutic composition and/or a solid dosage form) comprising Prevotella histicola EVs.
  • the human subject has a confirmed diagnosis of mild to moderate atopic dermatitis for at least 6 months involving a minimum of 3% to a maximum of 15% body surface area. In some embodiments, the subject has had a confirmed diagnosis of mild to moderate atopic dermatitis with an IGA score of 2 or 3. In some embodiments, the human subject has moderate atopic dermatitis with a minimum of 5% and a maximum of 40% BSA involvement, and an IGA score of 2 or 3. In some embodiments, the human subject has severe atopic dermatitis. In some embodiments, the subject has at least 2 atopic dermatitis lesions with at least 1 in a site suitable for biopsy.
  • the subject is not receiving systemic non-biologic atopic dermatitis therapy (methotrexate (MTX), steroids, cyclophosphamide, or has received therapy within 4 weeks prior to dosing.
  • MTX systemic non-biologic atopic dermatitis therapy
  • the human subject is not receiving treatment with biologic agents within 12 months prior to first dose.
  • the human subject is not continuing to use topical or oral pharmacologically active agents 2 weeks prior to the start of dosing.
  • the method decreases the EASI (Eczema Area and Severity Index) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s EASI score prior to the commencement of treatment), e.g., as described herein.
  • EASI Equivalent Area and Severity Index
  • the percentage of subjects achieving EASI-50; EASI-75; or EASI-90 are examples of subjects achieving EASI-50; EASI-75; or EASI-90.
  • the method decreases the SCORAD (SCORing Atopic Dermatitis) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s SCORAD score prior to the commencement of treatment), e.g., as described herein. For example, the percentage of subjects achieving SCORAD-50 or SCORAD-75.
  • the method decreases the IGA (Investigator’s Global Assessment) (v-IGA) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s IGA score prior to the commencement of treatment), e.g., as described herein. For example, the percentage of subjects achieving an IGA score or 0 or 1.
  • the method decreases the Percentage of Body Surface Area (BSA) affected by disease in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s BSA percentage prior to the commencement of treatment), e.g., as described herein. For example, the percentage of subjects achieving BSA-50 or BSA-75; or the percentage of subjects achieving BSA reduction to 3% BSA or less.
  • BSA Body Surface Area
  • the method improves the product of IGA and BSA in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s IGA x BSA prior to the commencement of treatment), e.g., as described herein.
  • the method improves the Dermatology Life Quality Index (DLQI) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s DLQI score prior to the commencement of treatment), e.g., as described herein.
  • DLQI Dermatology Life Quality Index
  • the method improves the Patient-Oriented Eczema Measure (POEM) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s POEM score prior to the commencement of treatment), e.g., as described herein.
  • POEM Patient-Oriented Eczema Measure
  • the method improves the Pruritus Numerical Rating Scale (Pruritus NRS (e.g., Peak Pruritus Numerical Rating Scale (PP-NRS))) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s Pruritus NRS score prior to the commencement of treatment), e.g., as described herein.
  • Pruritus NRS e.g., Peak Pruritus Numerical Rating Scale (PP-NRS)
  • the method improves the number of courses or days of rescue therapy in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s SD-NRS score prior to the commencement of treatment), e.g., as described herein.
  • the method improves the Sleep Disturbance Numerical Rating Scale (SD-NRS) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s number of courses or days of rescue therapy) prior to the commencement of treatment), e.g., as described herein.
  • SD-NRS Sleep Disturbance Numerical Rating Scale
  • the method improves an AD rating scale score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s AD rating scale score prior to the commencement of treatment), e.g., as described herein.
  • the AD rating scale score comprises IGA, (e.g., vIGA), EASI, BSA, IGAxBSA, and/or SCORAD.
  • the method improves patient reported clinical rating scale score in the subject, e.g., after 8, 21, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s patient reported clinical rating scale score prior to the commencement of treatment), e.g., as described herein.
  • the patient reported clinical rating scale score comprises POEM, DLQI, ADCT, PP-NRS and/or SD-NRS.
  • the method improves the blood eosinophils in the subject, e.g., after 8, 21, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s blood eosinophils prior to the commencement of treatment), e.g., as described herein.
  • the method improves the Sleep Disturbance Numerical Rating Scale (SD-NRS) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s number of courses or days of rescue therapy) prior to the commencement of treatment), e.g., as described herein.
  • SD-NRS Sleep Disturbance Numerical Rating Scale
  • the Prevotella histicola EVs and/or a composition comprising Prevotella histicola EVs provided herein is administered with an additional therapy, wherein the additional therapy comprises an emollient.
  • the emollient is a bland additive-free, sodium lauryl sulfate (SLS)-free, and fragrance-free emollient cream, gel, or ointment.
  • the emollient is used at least daily. In some embodiments, the emollient is used at least twice daily.
  • provided herein are methods of treating a subject who has psoriatic arthritis (e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis) comprising administering to the subject a therapeutic composition described herein.
  • a method of treating psoriatic arthritis comprising administering (e.g., orally administering) to a human subject (e.g., a subject with psoriatic arthritis) Prevotella histicola EVs and/or a composition (e.g., a therapeutic composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising Prevotella histicola EVs provided herein.
  • the method improves (e.g., increases) the percentage of subjects with an ACR20 response, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the percentage prior to the commencement of treatment), e.g., as described herein.
  • the method improves (e.g., increases) the percentage of subjects with an ACR50 response, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the percentage prior to the commencement of treatment), e.g., as described herein.
  • the method improves (e.g., increases) the percentage of subjects with an ACR70 response, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the percentage prior to the commencement of treatment), e.g., as described herein.
  • the method improves (e.g., increases) the Modified Psoriatic Arthritis Response Criteria (PsARC) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s PsARC prior to the commencement of treatment), e.g., as described herein.
  • PsARC Modified Psoriatic Arthritis Response Criteria
  • the method decreases the dactylitis severity score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s dactylitis severity score prior to the commencement of treatment), e.g., as described herein.
  • the method decreases the Clinical Disease Activity Index (CDAI) score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s CDAI prior to the commencement of treatment), e.g., as described herein.
  • CDAI Clinical Disease Activity Index
  • the method decreases the DAS28 score in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s DAS28 prior to the commencement of treatment), e.g., as described herein.
  • the method decreases the Maastricht Ankylosing Spondylitis Enthesis Score (MASES) in the subject, e.g., after 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks of treatment (e.g., as compared to the subject’s MASES prior to the commencement of treatment), e.g., as described herein.
  • MASES Maastricht Ankylosing Spondylitis Enthesis Score
  • the disclosure provides a therapeutic composition described herein (e.g., in an amount described herein) for use in treating psoriasis (e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis).
  • psoriasis e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis.
  • the disclosure provides a therapeutic composition described herein (e.g., in an amount described herein) for use in treating atopic dermatitis (e.g., mild to moderate atopic dermatitis, or mild to moderate atopic dermatitis).
  • the disclosure provides a therapeutic composition described herein (e.g., in an amount described herein) for use in treating psoriatic arthritis (e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis).
  • psoriatic arthritis e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis.
  • the disclosure provides use of a therapeutic composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of psoriasis (e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis).
  • the disclosure provides use of a therapeutic composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of atopic dermatitis (e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis).
  • atopic dermatitis e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis.
  • the disclosure provides use of a therapeutic composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of psoriatic arthritis (e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis).
  • the disclosure provides a therapeutic composition described herein (e.g., in an amount described herein) for use in treating an inflammatory disease.
  • the inflammatory disease is a Th1, Th2, or Th17 inflammatory disease.
  • the disclosure provides a therapeutic composition described herein (e.g., in an amount described herein) for use in treating an immune disorder.
  • the disclosure provides use of a therapeutic composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of an inflammatory disease.
  • the inflammatory disease is a Th1, Th2, or Th17 inflammatory disease.
  • the disclosure provides use of a therapeutic composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of an immune disorder.
  • the disclosure provides use of a therapeutic composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of an autoimmune disease, (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for the treatment of an autoimmune disease).
  • the disclosure provides a therapeutic composition described herein (e.g., in an amount described herein) for use in treating an autoimmune disease.
  • the disclosure provides use of a therapeutic composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of an inflammatory disease, (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for the treatment of an inflammatory disease).
  • a therapeutic composition described herein e.g., in an amount described herein for use in treating an inflammatory disease.
  • the disclosure provides use of a therapeutic composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of a metabolic disease, (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for the treatment of a metabolic disease).
  • a therapeutic composition described herein e.g., in an amount described herein for use in treating a metabolic disease.
  • the disclosure provides use of a therapeutic composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of a dysbiosis, (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for the treatment of a dysbiosis).
  • a therapeutic composition described herein e.g., in an amount described herein for use in treating a dysbiosis.
  • the disclosure provides use of a therapeutic composition described herein (e.g., in an amount described herein) for the preparation of a medicament for decreasing IgE levels (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for decreasing IgE levels).
  • a therapeutic composition described herein e.g., in an amount described herein for use in decreasing IgE levels.
  • the disclosure provides use of a therapeutic composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of bacterial septic shock, cytokine storm and/or viral infection, (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for the treatment of bacterial septic shock, cytokine storm and/or viral infection).
  • the disclosure provides a therapeutic composition described herein (e.g., in an amount described herein) for use in treating bacterial septic shock, cytokine storm and/or viral infection.
  • the disclosure provides use of a therapeutic composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of a viral infection, (e.g., in a subject, e.g., a human subject) and methods of using such therapeutic compositions (e.g., for the treatment of a viral infection).
  • the viral infection is a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection.
  • the viral infection is a SARS-CoV-2 infection.
  • the disclosure provides a therapeutic composition described herein (e.g., in an amount described herein) for use in treating a viral infection.
  • the viral infection is a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection. In some embodiments the viral infection is a SARS-CoV-2 infection.
  • the disclosure provides a method of treating psoriasis (e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriasis e.g., mild to
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriasis (e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriasis e.g., mild to moderate psoriasis
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriasis (e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriasis e.g., mild to moderate psoriasis, or mild, moderate, or severe ps
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriasis (e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriasis e.g., mild to moderate psoriasis
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriasis (e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriasis e.g., mild to moderate psoriasis, or mild, moderate, or severe ps
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriasis (e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriasis e.g., mild to moderate psoriasis
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriasis (e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriasis e.g., mild to moderate psoriasis, or mild, moderate, or severe ps
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriasis (e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriasis e.g., mild to moderate psoriasis
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriatic arthritis (e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriatic arthritis e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriatic arthritis (e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis)in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriatic arthritis e.g., mild to moderate psoriatic arthritis, or mild, moderate
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriatic arthritis (e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriatic arthritis e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriatic arthritis (e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriatic arthritis e.g., mild to moderate psoriatic arthritis, or mild, moderate
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriatic arthritis (e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriatic arthritis e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriatic arthritis (e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriatic arthritis e.g., mild to moderate psoriatic arthritis, or mild, moderate
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriatic arthritis (e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriatic arthritis e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating psoriatic arthritis (e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • psoriatic arthritis e.g., mild to moderate psoriatic arthritis, or mild, moderate
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating atopic dermatitis (e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • atopic dermatitis e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating atopic dermatitis (e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating atopic dermatitis (e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • atopic dermatitis e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating atopic dermatitis (e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating atopic dermatitis (e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • atopic dermatitis e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating atopic dermatitis (e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating atopic dermatitis (e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • atopic dermatitis e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of treating atopic dermatitis (e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of reducing inflammation in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of reducing inflammation in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of reducing inflammation in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of reducing inflammation in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of reducing inflammation in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of reducing inflammation in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of reducing inflammation in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the disclosure provides a method of reducing inflammation in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two, three, four, or five solid dosage forms (e.g., tablet or capsule) and each solid dosage form comprises about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of the EVs.
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the dose is administered for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the inflammation comprises Th1 inflammation.
  • the inflammation comprises Th2 inflammation.
  • the inflammation comprises Th17 inflammation.
  • the disclosure provides use of a therapeutic composition described herein for use in treatment, as described herein.
  • the disclosure provides use of a therapeutic composition described herein for the preparation of a medicament for use in treatment, as described herein.
  • described herein is an oral therapy for treating inflammation, and/or a condition characterized by inflammation, with EVs from Prevotella histicola Strain B.
  • the inflammation is a Th1, Th2, or Th17 inflammation.
  • described herein is an oral therapy for treating an immune disorder with Prevotella histicola Strain B EVs.
  • described herein is an oral therapy for treating psoriasis with Prevotella histicola Strain B EVs.
  • described herein is an oral therapy for treating atopic dermatitis with Prevotella histicola Strain B EVs.
  • Described herein is an oral therapy for treating psoriatic arthritis with Prevotella histicola Strain B EVs.
  • Definitions [225] Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive (i.e., a composition “comprising elements A, B, or C” would not exclude a composition containing both elements A and B, a composition containing both elements B and C, a composition containing both elements A and C, or a composition containing all of elements A, B, and C). Unless specifically stated or obvious from context, as used herein, the terms “a,” “an,” and “the” are understood to be singular or plural.
  • Adjuvant or “Adjuvant therapy” broadly refers to an agent that affects an immunological or physiological response in a patient or subject. For example, an adjuvant might increase the presence of an antigen over time or help absorb an antigen presenting cell antigen, activate macrophages and lymphocytes and support the production of cytokines.
  • administering broadly refers to a route of administration of a composition to a subject. Examples of routes of administration include oral administration, rectal administration, topical administration, inhalation (nasal) or injection. Administration by injection includes intravenous (IV), intramuscular (IM), and subcutaneous (SC) administration.
  • IV intravenous
  • IM intramuscular
  • SC subcutaneous
  • compositions described herein can be administered in any form by any effective route, including but not limited to oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patch), intradermal, ophthalmic, (intra)nasally, local, non-oral, such as aerosol, inhalation, subcutaneous, intramuscular, buccal, sublingual, (trans)rectal, vaginal, intra-arterial, and intrathecal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), implanted, intravesical, intrapulmonary, intraduodenal, intragastrical, and intrabronchial.
  • transdermal e.g., using any standard patch
  • transdermal e.g., using any standard patch
  • intradermal e.g., using any standard patch
  • intradermal e.g
  • the therapeutic compositions described herein are administered orally, rectally, topically, intravesically, by injection into or adjacent to a draining lymph node, intravenously, by inhalation or aerosol, or subcutaneously. In some embodiments, the therapeutic compositions described herein are administered orally.
  • Cellular augmentation broadly refers to the influx of cells or expansion of cells in an environment that are not substantially present in the environment prior to administration of a composition and not present in the composition itself. Cells that augment the environment include immune cells, stromal cells, bacterial and fungal cells.
  • “Clade” refers to the OTUs or members of a phylogenetic tree that are downstream of a statistically valid node in a phylogenetic tree.
  • the clade comprises a set of terminal leaves in the phylogenetic tree that is a distinct monophyletic evolutionary unit and that share some extent of sequence similarity.
  • “Operational taxonomic units,” “OTU” (or plural, “OTUs”) refer to a terminal leaf in a phylogenetic tree and is defined by a nucleic acid sequence, e.g., the entire genome, or a specific genetic sequence, and all sequences that share sequence identity to this nucleic acid sequence at the level of species.
  • the specific genetic sequence may be the 16S sequence or a portion of the 16S sequence.
  • the entire genomes of two entities are sequenced and compared.
  • select regions such as multilocus sequence tags (MLST), specific genes, or sets of genes may be genetically compared.
  • MMT multilocus sequence tags
  • OTUs that share ⁇ 97% average nucleotide identity across the entire 16S or some variable region of the 16S are considered the same OTU (see e.g. Claesson M J, Wang Q, O'Sullivan O, Greene-Diniz R, Cole J R, Ros R P, and O'Toole P W.2010.
  • OTUs are frequently defined by comparing sequences between organisms. Generally, sequences with less than 95% sequence identity are not considered to form part of the same OTU.
  • OTUs may also be characterized by any combination of nucleotide markers or genes, in particular highly conserved genes (e.g., “house-keeping” genes), or a combination thereof. Such characterization employs, e.g., WGS data or a whole genome sequence.
  • a “combination” of two or more monoclonal microbial strains includes the physical co- existence of the two monoclonal microbial strains, either in the same material or product or in physically connected products, as well as the temporal co-administration or co-localization of the monoclonal microbial strains.
  • the term “decrease” or “deplete” means a qualitative or quantitative difference between a reference and a value that is less than the reference, such that the difference is, depending on circumstances, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the reference, or such that the value is 1/100, 1/1000, 1/10,000, 1/100,000, 1/1,000,000 of the reference, or such that the value is undetectable after a treatment when compared to a reference representative of a pre-treatment state.
  • a “dried form” that contains extracellular vesicles (EVs) refers to the product resulting from drying a solution that contains EVs.
  • the drying is performed, for example, by freeze drying (lyophilization) or spray drying.
  • the dried form is a powder.
  • a powder refers to a type of dried form and includes a lyophilized powder and a spray- dried powder, obtained by a method such as spray drying.
  • “Dysbiosis” refers to a state of the microbiota or microbiome of the gut or other body area, including, e.g., mucosal or skin surfaces (or any other microbiome niche) in which the normal diversity and/or function of the host gut microbiome ecological networks “microbiome”) are disrupted.
  • a state of dysbiosis may result in a diseased state, or it may be unhealthy under only certain conditions or only if present for a prolonged period.
  • Dysbiosis may be due to a variety of factors, including, environmental factors, infectious agents, host genotype, host diet and/or stress.
  • a dysbiosis may result in: a change (e.g., increase or decrease) in the prevalence of one or more bacteria types (e.g., anaerobic), species and/or strains, change (e.g., increase or decrease) in diversity of the host microbiome population composition; a change (e.g., increase or reduction) of one or more populations of symbiont organisms resulting in a reduction or loss of one or more beneficial effects; overgrowth of one or more populations of pathogens (e.g., pathogenic bacteria); and/or the presence of, and/or overgrowth of, symbiotic organisms that cause disease only when certain conditions are present.
  • a change e.g., increase or decrease
  • one or more bacteria types e.g., anaerobic
  • species and/or strains e.g., increase or decrease
  • change
  • engineered bacteria are any bacteria that have been genetically altered from their natural state by human intervention and the progeny of any such bacteria.
  • Engineered bacteria include, for example, the products of targeted genetic modification, the products of random mutagenesis screens and the products of directed evolution.
  • epitope means a protein determinant capable of specific binding to an antibody or T cell receptor. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains. Certain epitopes can be defined by a particular sequence of amino acids to which an antibody is capable of binding.
  • the term “gene” is used broadly to refer to any nucleic acid associated with a biological function.
  • genomic sequence refers to a specific genomic sequence, as well as to a cDNA or an mRNA encoded by that genomic sequence.
  • identity as between nucleic acid sequences of two nucleic acid molecules can be determined as a percentage of identity using known computer algorithms such as the “FASTA” program, using for example, the default parameters as in Pearson et al. (1988) Proc. Natl. Acad. Sci. USA 85:2444 (other programs include the GCG program package (Devereux, J., et al., Nucleic Acids Research 12(I):387 (1984)), BLASTP, BLASTN, FASTA Atschul, S.
  • the term “immune disorder” refers to any disease, disorder or disease symptom caused by an activity of the immune system, including autoimmune diseases, inflammatory diseases and allergies.
  • Immune disorders include, but are not limited to, autoimmune diseases (e.g., Lupus, Scleroderma, hemolytic anemia, vasculitis, type one diabetes, Grave’s disease, rheumatoid arthritis, multiple sclerosis, Goodpasture’s syndrome, pernicious anemia and/or myopathy), inflammatory diseases (e.g., acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis and/or interstitial cystitis), and/or an allergies (e.g., food allergies, drug allergies and/or environmental allergies).
  • autoimmune diseases e.g., Lupus, Scleroderma, hemolytic anemia
  • Immunotherapy is treatment that uses a subject’s immune system to treat disease (e.g., immune disease) and includes, for example, checkpoint inhibitors, cytokines, cell therapy, CAR- T cells, and dendritic cell therapy.
  • disease e.g., immune disease
  • the term “increase” means a qualitative or quantitative difference between a reference and a value that is more than the reference, such that the difference is, depending on circumstances, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 4-fold, 10- fold, 100-fold, 10 ⁇ 3 fold, 10 ⁇ 4 fold, 10 ⁇ 5 fold, 10 ⁇ 6 fold, and/or 10 ⁇ 7 fold of the reference, e.g., where the difference is between a reference representative of a pre-treatment state and a value that is representative of a post-treatment state.
  • “Innate immune agonists” or “immuno-adjuvants” are small molecules, proteins, or other agents that specifically target innate immune receptors including Toll-Like Receptors (TLR), NOD receptors, RLRs, C-type lectin receptors, STING-cGAS Pathway components, inflammasome complexes.
  • TLR Toll-Like Receptors
  • NOD receptors NOD receptors
  • RLRs C-type lectin receptors
  • STING-cGAS Pathway components inflammasome complexes.
  • LPS is a TLR-4 agonist that is bacterially derived or synthesized and aluminum can be used as an immune stimulating adjuvant.
  • Immuno-adjuvants are a specific class of broader adjuvant or adjuvant therapy.
  • STING agonists include, but are not limited to, 2'3'- cGAMP, 3'3'-cGAMP, c-di-AMP, c-di-GMP, 2'2'-cGAMP, and 2'3'-cGAM(PS)2 (Rp/Sp) (Rp, Sp-isomers of the bis-phosphorothioate analog of 2'3'- cGAMP).
  • TLR agonists include, but are not limited to, TLRl, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10 and TLR11.
  • NOD agonists include, but are not limited to, N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyldipeptide (MDP)), gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP), and desmuramylpeptides (DMP).
  • MDP N-acetylmuramyl-L-alanyl-D-isoglutamine
  • iE-DAP gamma-D-glutamyl-meso-diaminopimelic acid
  • DMP desmuramylpeptides
  • isolated or “enriched” encompasses a microbe, bacteria or other entity or substance that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature or in an experimental setting), and/or (2) produced, prepared, purified, and/or manufactured by the hand of man. Isolated microbes may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were initially associated.
  • isolated microbes are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure, e.g., substantially free of other components.
  • purify refer to a microbe or other material that has been separated from at least some of the components with which it was associated either when initially produced or generated (e.g., whether in nature or in an experimental setting), or during any time after its initial production.
  • a microbe or a microbial population may be considered purified if it is isolated at or after production, such as from a material or environment containing the microbe or microbial population, and a purified microbe or microbial population may contain other materials up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or above about 90% and still be considered “isolated.”
  • purified microbes or microbial population are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure.
  • the one or more microbial types present in the composition can be independently purified from one or more other microbes produced and/or present in the material or environment containing the microbial type.
  • Microbial compositions and the microbial components thereof are generally purified from residual habitat products.
  • “Metabolite” as used herein refers to any and all molecular compounds, compositions, molecules, ions, co-factors, catalysts or nutrients used as substrates in any cellular or microbial metabolic reaction or resulting as product compounds, compositions, molecules, ions, co-factors, catalysts or nutrients from any cellular or microbial metabolic reaction.
  • “Microbe” refers to any natural or engineered organism characterized as a bacterium, fungus, microscopic alga, protozoan, and the stages of development or life cycle stages (e.g., vegetative, spore (including sporulation, dormancy, and germination), latent, biofilm) associated with the organism.
  • “Microbiome” broadly refers to the microbes residing on or in body site of a subject or patient. Microbes in a microbiome may include bacteria, viruses, eukaryotic microorganisms, and/or viruses.
  • microbes in a microbiome may be metabolically active, dormant, latent, or exist as spores, may exist planktonically or in biofilms, or may be present in the microbiome in sustainable or transient manner.
  • the microbiome may be a commensal or healthy- state microbiome or a disease-state microbiome.
  • the microbiome may be native to the subject or patient, or components of the microbiome may be modulated, introduced, or depleted due to changes in health state or treatment conditions (e.g., antibiotic treatment, exposure to different microbes).
  • the microbiome occurs at a mucosal surface.
  • the microbiome is a gut microbiome.
  • a “microbiome profile” or a “microbiome signature” of a tissue or sample refers to an at least partial characterization of the bacterial makeup of a microbiome.
  • a microbiome profile indicates whether at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more bacterial strains are present or absent in a microbiome.
  • a microbiome profile indicates whether at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more bacterial strains are present in a sample.
  • the microbiome profile indicates the relative or absolute amount of each bacterial strain detected in the sample.
  • “Modified” in reference to a bacterium broadly refers to a bacterium that has undergone a change from its wild-type form. Examples of bacterial modifications include genetic modification, gene expression, phenotype modification, formulation, chemical modification, and dose or concentration. Examples of improved properties are described throughout this specification and include, e.g., attenuation, auxotrophy, homing, or antigenicity. Phenotype modification might include, by way of example, bacteria growth in media that modify the phenotype of a bacterium that increase or decrease virulence.
  • a gene is “overexpressed” in a bacterium if it is expressed at a higher level in an engineered bacterium under at least some conditions than it is expressed by a wild- type bacterium of the same species under the same conditions.
  • a gene is “underexpressed” in a bacterium if it is expressed at a lower level in an engineered bacterium under at least some conditions than it is expressed by a wild-type bacterium of the same species under the same conditions.
  • the terms “polynucleotide”, and “nucleic acid” are used interchangeably.
  • Polynucleotides refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof.
  • Polynucleotides may have any three-dimensional structure, and may perform any function.
  • polynucleotides coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), micro RNA (miRNA), silencing RNA (siRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers.
  • a polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs.
  • modifications to the nucleotide structure may be imparted before or after assembly of the polymer.
  • a polynucleotide may be further modified, such as by conjugation with a labeling component.
  • U nucleotides are interchangeable with T nucleotides.
  • “Operational taxonomic units” and “OTU(s)” refer to a terminal leaf in a phylogenetic tree and is defined by a nucleic acid sequence, e.g., the entire genome, or a specific genetic sequence, and all sequences that share sequence identity to this nucleic acid sequence at the level of species.
  • the specific genetic sequence may be the 16S sequence or a portion of the 16S sequence.
  • the entire genomes of two entities are sequenced and compared.
  • select regions such as multilocus sequence tags (MLST), specific genes, or sets of genes may be genetically compared.
  • MMT multilocus sequence tags
  • For 16S OTUs that share ⁇ 97% average nucleotide identity across the entire 16S or some variable region of the 16S are considered the same OTU. See e.g. Claesson MJ, Wang Q, O’Sullivan O, Greene-Diniz R, Cole JR, Ross RP, and O’Toole PW.2010. Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions. Nucleic Acids Res 38: e200.
  • OTUs are frequently defined by comparing sequences between organisms. Generally, sequences with less than 95% sequence identity are not considered to form part of the same OTU. OTUs may also be characterized by any combination of nucleotide markers or genes, in particular highly conserved genes (e.g., “house-keeping” genes), or a combination thereof. Operational Taxonomic Units (OTUs) with taxonomic assignments made to, e.g., genus, species, and phylogenetic clade are provided herein. [252] As used herein, a substance is “pure” if it is substantially free of other components.
  • purify refers to a microbe or other material that has been separated from at least some of the components with which it was associated either when initially produced or generated (e.g., whether in nature or in an experimental setting), or during any time after its initial production.
  • a microbe may be considered purified if it is isolated at or after production, such as from one or more other bacterial components, and a purified microbe or microbial population may contain other materials up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or above about 90% and still be considered “purified.”
  • purified microbes are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure.
  • Therapeutic compositions and the microbial components thereof are, e.g., purified from residual habitat products.
  • “Residual habitat products” refers to material derived from the habitat for microbiota within or on a subject. For example, microbes live in feces in the gastrointestinal tract, on the skin itself, in saliva, mucus of the respiratory tract, or secretions of the genitourinary tract (i.e., biological matter associated with the microbial community). Substantially free of residual habitat products means that the microbial composition no longer contains the biological matter associated with the microbial environment on or in the human or animal subject and is 100% free, 99% free, 98% free, 97% free, 96% free, or 95% free of any contaminating biological matter associated with the microbial community.
  • Residual habitat products can include abiotic materials (including undigested food) or it can include unwanted microorganisms. Substantially free of residual habitat products may also mean that the microbial composition contains no detectable cells from a human or animal and that only microbial cells are detectable. In one embodiment, substantially free of residual habitat products may also mean that the microbial composition contains no detectable viral (including microbial viruses (e.g., phage)), fungal, mycoplasmal contaminants.
  • microbial viruses e.g., phage
  • contamination may be reduced by isolating desired constituents through multiple steps of streaking to single colonies on solid media until replicate (such as, but not limited to, two) streaks from serial single colonies have shown only a single colony morphology.
  • reduction of contamination can be accomplished by multiple rounds of serial dilutions to single desired cells (e.g., a dilution of 10 -8 or 10 -9 ), such as through multiple 10-fold serial dilutions. This can further be confirmed by showing that multiple isolated colonies have similar cell shapes and Gram staining behavior.
  • Other methods for confirming adequate purity include genetic analysis (e.g., PCR, DNA sequencing), serology and antigen analysis, enzymatic and metabolic analysis, and methods using instrumentation such as flow cytometry with reagents that distinguish desired constituents from contaminants.
  • the terms “subject” or “patient” refers to any animal. A subject or a patient described as “in need thereof” refers to one in need of a treatment for a disease.
  • Mammals i.e., mammalian animals
  • mammals include humans, laboratory animals (e.g., primates, rats, mice), livestock (e.g., cows, sheep, goats, pigs), and household pets (e.g., dogs, cats, rodents).
  • the subject may be a non-human mammal including but not limited to of a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee.
  • strain refers to a member of a bacterial species with a genetic signature such that it may be differentiated from closely-related members of the same bacterial species.
  • the genetic signature may be the absence of all or part of at least one gene, the absence of all or part of at least on regulatory region (e.g., a promoter, a terminator, a riboswitch, a ribosome binding site), the absence (“curing”) of at least one native plasmid, the presence of at least one recombinant gene, the presence of at least one mutated gene, the presence of at least one foreign gene (a gene derived from another species), the presence at least one mutated regulatory region (e.g., a promoter, a terminator, a riboswitch, a ribosome binding site), the presence of at least one non- native plasmid, the presence of at least one antibiotic resistance cassette, or a combination thereof.
  • regulatory region e.g., a promoter, a terminator,
  • strains may be identified by PCR amplification optionally followed by DNA sequencing of the genomic region(s) of interest or of the whole genome. In the case in which one strain (compared with another of the same species) has gained or lost antibiotic resistance or gained or lost a biosynthetic capability (such as an auxotrophic strain), strains may be differentiated by selection or counter-selection using an antibiotic or nutrient/metabolite, respectively.
  • the term “treating” a disease in a subject or “treating” a subject having or suspected of having a disease refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of one or more agents, such that at least one symptom of the disease is decreased or prevented from worsening.
  • “treating” refers inter alia to delaying progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof.
  • the methods and compositions described herein can be used to treat any subject in need thereof.
  • a “subject in need thereof” includes any subject that has, or has been diagnosed as having, a disease or disorder disclosed herein and/or treatable by a method or composition disclosed herein, as well as any subject with an increased likelihood of acquiring a such a disease or disorder.
  • EVs Prevotella histicola extracellular vesicles
  • solutions and/or dried forms, and therapeutic compositions that comprise Prevotella histicola extracellular vesicles (EVs).
  • solutions and/or dried forms, and therapeutic compositions that comprise EVs obtained from Prevotella histicola bacteria.
  • compositions e.g., pharmaceutical compositions
  • solid dosage forms thereof comprising Prevotella histicola EVs useful for the treatment and/or prevention of inflammation (e.g., Th1, Th2, or Th17 inflammation) (e.g., inflammation associated with psoriasis or atopic dermatitis or psoriatic arthritis) and methods of using such therapeutic compositions (e.g., for the treatment of inflammation (e.g., Th1, Th2, or Th17 inflammation) (e.g., inflammation associated with psoriasis or atopic dermatitis or psoriatic arthritis), e.g., in a subject, e.g., in a human subject.
  • inflammation e.g., Th1, Th2, or Th17 inflammation
  • compositions e.g., pharmaceutical compositions
  • solid dosage forms thereof comprising Prevotella histicola EVs useful for the treatment and/or prevention of disease (for example, an immune disorder (e.g., an autoimmune disease, an inflammatory disease, an allergy), a dysbiosis, or a metabolic disease), as well as methods of making and/or identifying such EVs, and methods of using such therapeutic compositions (for example, for the treatment of an immune disorder (e.g., an autoimmune disease, an inflammatory disease, an allergy), a dysbiosis, or a metabolic disease, either alone or in combination with other therapeutics).
  • an immune disorder e.g., an autoimmune disease, an inflammatory disease, an allergy
  • a dysbiosis e.g., a metabolic disease
  • the therapeutic composition (e.g., pharmaceutical composition) comprises EVs from only one strain of bacteria, e.g., Prevotella histicola.
  • Prevotella histicola bacteria from which EVs are obtained are lyophilized.
  • Prevotella histicola bacteria from which EVs are obtained are gamma irradiated (e.g., at 17.5 or 25 kGy).
  • Prevotella histicola bacteria from which EVs are obtained are UV irradiated.
  • Prevotella histicola bacteria from which EVs are obtained are heat inactivated (e.g., at 50°C for two hours or at 90°C for two hours). [265] In some embodiments, Prevotella histicola bacteria from which EVs are obtained are acid treated. [266] In some embodiments, Prevotella histicola bacteria from which EVs are obtained are oxygen sparged (e.g., at 0.1 vvm for two hours). [267] In some embodiments, the Prevotella histicola EVs are lyophilized. [268] In some embodiments, the Prevotella histicola EVs are spray dried.
  • the Prevotella histicola EVs are gamma irradiated (e.g., at 17.5 or 25 kGy).
  • the Prevotella histicola EVs are UV irradiated.
  • the Prevotella histicola EVs are heat inactivated (e.g., at 50°C for two hours or at 90°C for two hours).
  • the Prevotella histicola EVs are acid treated.
  • the Prevotella histicola EVs are oxygen sparged (e.g., at 0.1 vvm for two hours).
  • the phase of growth can affect the amount or properties of bacteria and/or EVs produced by Prevotella histicola bacteria.
  • EVs can be isolated, e.g., from a culture, at the start of the log phase of growth, midway through the log phase, and/or once stationary phase growth has been reached.
  • the Prevotella histicola EVs are from one strain of bacteria, e.g., a strain provided herein.
  • the Prevotella histicola EVs are from one strain of bacteria (e.g., a strain provided herein) or from more than one strain.
  • the EVs are from Prevotella histicola bacteria, e.g., from a strain comprising at least 90% or at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329).
  • the EVs are from Prevotella histicola bacteria, e.g., from Prevotella Strain B 50329 (NRRL accession number B 50329).
  • the Prevotella histicola is Prevotella Strain B 50329 (NRRL accession number B 50329).
  • the EVs are from Prevotella histicola bacteria comprising at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, or CRISPR sequence) of the Prevotella Strain B 50329.
  • sequence identity e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity
  • nucleotide sequence e.g., genomic sequence, 16S sequence, or CRISPR sequence
  • the Prevotella histicola bacteria from which the EVs are obtained are modified (e.g., engineered) to reduce toxicity or other adverse effects, to enhance delivery) (e.g., oral delivery) of the EVs (e.g., by improving acid resistance, muco-adherence and/or penetration and/or resistance to bile acids, digestive enzymes, resistance to anti-microbial peptides and/or antibody neutralization), to target desired cell types (e.g., M-cells, goblet cells, enterocytes, dendritic cells, macrophages), to enhance their immunomodulatory and/or therapeutic effect of the EVs (e.g., either alone or in combination with another therapeutic agent), and/or to enhance immune activation or suppression by the EVs (e.g., through modified production of polysaccharides, pili, fimbriae, adhesins).
  • target desired cell types e.g., M-cells, goblet cells, enterocytes, dendritic cells, macro
  • the engineered bacteria described herein are modified to improve EV manufacturing (e.g., higher oxygen tolerance, stability, improved freeze-thaw tolerance, shorter generation times).
  • the engineered bacteria described include bacteria harboring one or more genetic changes, such change being an insertion, deletion, translocation, or substitution, or any combination thereof, of one or more nucleotides contained on the bacterial chromosome or endogenous plasmid and/or one or more foreign plasmids, wherein the genetic change may results in the overexpression and/or underexpression of one or more genes.
  • the engineered bacteria may be produced using any technique known in the art, including but not limited to site- directed mutagenesis, transposon mutagenesis, knock-outs, knock-ins, polymerase chain reaction mutagenesis, chemical mutagenesis, ultraviolet light mutagenesis, transformation (chemically or by electroporation), phage transduction, directed evolution, or any combination thereof.
  • Modified EVs [280] In some aspects, the Prevotella histicola EVs described herein are modified such that they comprise, are linked to, and/or are bound by a therapeutic moiety.
  • the Prevotella histicola EVs described herein are engineered such that they comprise, are linked to, and/or are bound by a magnetic and/or paramagnetic moiety (e.g., a magnetic bead).
  • the magnetic and/or paramagnetic moiety is comprised by and/or directly linked to the bacteria.
  • the magnetic and/or paramagnetic moiety is linked to and/or a part of an EV-binding moiety that that binds to the EV.
  • the EV-binding moiety is a fragment of or a full-length peptidoglycan recognition protein, such as PGRP.
  • the EV-binding moiety has binding specificity for the EV (e.g., by having binding specificity for a bacterial antigen).
  • the EV-binding moiety comprises an antibody or antigen binding fragment thereof.
  • the EV-binding moiety comprises a T cell receptor or a chimeric antigen receptor (CAR).
  • CAR chimeric antigen receptor
  • bacteria described herein are killed using a method that leaves the smEVs intact and the resulting bacterial components, including the smEVs, are used in the methods and compositions described herein.
  • the bacteria are killed using an antibiotic (for example, using an antibiotic described herein).
  • the bacteria are killed using UV irradiation.
  • the bacteria are heat-killed.
  • the smEVs described herein are purified from one or more other bacterial components. Methods for purifying smEVs from bacteria are known in the art.
  • smEVs are prepared from bacterial cultures using methods described in S. Bin Park, et al.
  • the bacteria are cultured to high optical density and then centrifuged to pellet bacteria (for example, at 10,000 x g for 30 min at 4°C, at 15,500 x g for 15 min at 4°C).
  • the culture supernatants are then passed through filters to exclude intact bacterial cells (for example, a 0.22 ⁇ m filter).
  • the supernatants are then subjected to tangential flow filtration, during which the supernatant is concentrated, species smaller than 100 kDa are removed, and the media is partially exchanged with PBS.
  • filtered supernatants are centrifuged to pellet bacterial smEVs (for example, at 100,000-150,000 x g for 1-3 hours at 4°C, at 200,000 x g for 1-3 hours at 4°C).
  • the smEVs are further purified by resuspending the resulting smEV pellets (for example, in PBS), and applying the resuspended smEVs to an Optiprep (iodixanol) gradient or gradient (for example, a 30-60% discontinuous gradient, a 0-45% discontinuous gradient), followed by centrifugation (for example, at 200,000 x g for 4-20 hours at 4°C).
  • Optiprep iodixanol gradient or gradient
  • centrifugation for example, at 200,000 x g for 4-20 hours at 4°C.
  • smEV bands can be collected, diluted with PBS, and centrifuged to pellet the smEVs (for example, at 150,000 x g for 3 hours at 4°C, at 200,000 x g for 1 hour at 4°C).
  • the purified smEVs can be stored, for example, at -80°C or -20°C until use.
  • the smEVs are further purified by treatment with DNase and/or proteinase K.
  • cultures of bacteria can be centrifuged at 11,000 x g for 20-40 min at 4°C to pellet bacteria.
  • Culture supernatants may be passed through a 0.22 ⁇ m filter to exclude intact bacterial cells. Filtered supernatants may then be concentrated using methods that may include, but are not limited to, ammonium sulfate precipitation, ultracentrifugation, or filtration.
  • ammonium sulfate precipitation 1.5-3 M ammonium sulfate can be added to filtered supernatant slowly, while stirring at 4oC. Precipitations can be incubated at 4oC for 8-48 hours and then centrifuged at 11,000 x g for 20- 40 min at 4oC. The resulting pellets contain bacteria smEVs and other debris. Using ultracentrifugation, filtered supernatants can be centrifuged at 100,000-200,000 x g for 1-16 hours at 4°C. The pellet of this centrifugation contains bacterial smEVs and other debris such as large protein complexes.
  • smEVs can be obtained from bacteria cultures continuously during growth, or at selected time points during growth, for example, by connecting a bioreactor to an alternating tangential flow (ATF) system (for example, XCell ATF from Repligen).
  • ATF alternating tangential flow
  • the ATF system retains intact cells (> 0.22 ⁇ m) in the bioreactor, and allows smaller components (for example, smEVs, free proteins) to pass through a filter for collection.
  • the system may be configured so that the ⁇ 0.22 ⁇ m filtrate is then passed through a second filter of 100 kDa, allowing species such as smEVs between 0.22 ⁇ m and 100 kDa to be collected, and species smaller than 100 kDa to be pumped back into the bioreactor.
  • the system may be configured to allow for medium in the bioreactor to be replenished and/or modified during growth of the culture. smEVs collected by this method may be further purified and/or concentrated by ultracentrifugation or filtration as described above for filtered supernatants.
  • smEVs obtained by methods provided herein may be further purified by size-based column chromatography, by affinity chromatography, by ion-exchange chromatography, and by gradient ultracentrifugation, using methods that may include, but are not limited to, use of a sucrose gradient or Optiprep gradient. Briefly, using a sucrose gradient method, if ammonium sulfate precipitation or ultracentrifugation were used to concentrate the filtered supernatants, pellets are resuspended in 60% sucrose, 30 mM Tris, pH 8.0.
  • the concentrate is buffer exchanged into 60% sucrose, 30 mM Tris, pH 8.0, using an Amicon Ultra column. Samples are applied to a 35-60% discontinuous sucrose gradient and centrifuged at 200,000 x g for 3-24 hours at 4°C. Briefly, using an Optiprep gradient method, if ammonium sulfate precipitation or ultracentrifugation were used to concentrate the filtered supernatants, pellets are resuspended in PBS and 3 volumes of 60% Optiprep are added to the sample.
  • the concentrate is diluted using 60% Optiprep to a final concentration of 35% Optiprep.
  • Samples are applied to a 0-45% discontinuous Optiprep gradient and centrifuged at 200,000 x g for 3-24 hours at 4°C, for example, 4-24 hours at 4°C.
  • smEVs are serially diluted onto agar medium used for routine culture of the bacteria being tested, and incubated using routine conditions. Non-sterile preparations are passed through a 0.22 ⁇ m filter to exclude intact cells.
  • isolated smEVs may be DNase or proteinase K treated.
  • purified smEVs are processed as described previously (G. Norheim, et al. PLoS ONE.10(9): e0134353 (2015)). Briefly, after sucrose gradient centrifugation, bands containing smEVs are resuspended to a final concentration of 50 ⁇ g/mL in a solution containing 3% sucrose or other solution suitable for in vivo injection known to one skilled in the art. This solution may also contain adjuvant, for example aluminum hydroxide at a concentration of 0-0.5% (w/v).
  • adjuvant for example aluminum hydroxide at a concentration of 0-0.5% (w/v).
  • smEVs in PBS are sterile- filtered to ⁇ 0.22 ⁇ m.
  • samples are buffer exchanged into PBS or 30 mM Tris, pH 8.0 using filtration (for example, Amicon Ultra columns), dialysis, or ultracentrifugation (200,000 x g, ⁇ 3 hours, 4oC) and resuspension.
  • the sterility of the smEV preparations can be confirmed by plating a portion of the smEVs onto agar medium used for standard culture of the bacteria used in the generation of the smEVs and incubating using standard conditions.
  • select smEVs are isolated and enriched by chromatography and binding surface moieties on smEVs.
  • select smEVs are isolated and/or enriched by fluorescent cell sorting by methods using affinity reagents, chemical dyes, recombinant proteins or other methods known to one skilled in the art.
  • smEVs are analyzed, for example, as described in Jeppesen, et al.
  • smEVs are lyophilized.
  • smEVs are spray dried.
  • smEVs are gamma irradiated (for example, at 17.5 or 25 kGy).
  • smEVs are UV irradiated.
  • smEVs are heat inactivated (for example, at 50°C for two hours or at 90°C for two hours).
  • smEVs are acid treated.
  • smEVs are oxygen sparged (for example, at 0.1 vvm for two hours).
  • the phase of growth can affect the amount or properties of bacteria and/or smEVs produced by bacteria.
  • smEVs can be isolated, for example, from a culture, at the start of the log phase of growth, midway through the log phase, and/or once stationary phase growth has been reached.
  • the growth environment (for example, culture conditions) can affect the amount of smEVs produced by bacteria.
  • the yield of smEVs can be increased by an smEV inducer, as provided in Table 1. Table 1: Culture Techniques to Increase smEV Production
  • the methods can optionally include exposing a culture of bacteria to an smEV inducer prior to isolating smEVs from the bacterial culture.
  • the culture of bacteria can be exposed to an smEV inducer at the start of the log phase of growth, midway through the log phase, and/or once stationary phase growth has been reached.
  • Processed EVs In some aspects, the EVs (such as processed EVs (pmEVs) described herein) are prepared (for example, artificially prepared) using any method known in the art.
  • the pmEVs are prepared without a pmEV purification step.
  • bacteria from which the pmEVs described herein are released are killed using a method that leaves the bacterial pmEVs intact, and the resulting bacterial components, including the pmEVs, are used in the methods and compositions described herein.
  • the bacteria are killed using an antibiotic (for example, using an antibiotic described herein).
  • the bacteria are killed using UV irradiation.
  • the pmEVs described herein are purified from one or more other bacterial components. Methods for purifying pmEVs from bacteria (and optionally, other bacterial components) are known in the art.
  • pmEVs are prepared from bacterial cultures using methods described in Thein et al. J.
  • the bacteria are cultured to high optical density and then centrifuged to pellet bacteria (for example, at 10,000-15,000 x g for 10-15 min at room temperature or 4°C).
  • the supernatants are discarded and cell pellets are frozen at -80oC.
  • cell pellets are thawed on ice and resuspended in 100 mM Tris-HCl, pH 7.5 supplemented with 1 mg/mL DNase I.
  • cells are lysed using an Emulsiflex C-3 (Avestin, Inc.) under conditions recommended by the manufacturer.
  • debris and unlysed cells are pelleted by centrifugation at 10,000 x g for 15 min at 4oC.
  • supernatants are then centrifuged at 120,000 x g for 1 hour at 4oC.
  • pellets are resuspended in ice-cold 100 mM sodium carbonate, pH 11, incubated with agitation for 1 hour at 4oC, and then centrifuged at 120,000 x g for 1 hour at 4oC.
  • pellets are resuspended in 100 mM Tris-HCl, pH 7.5, re-centrifuged at 120,000 x g for 20 min at 4oC, and then resuspended in 0.1 M Tris-HCl, pH 7.5 or in PBS. In some embodiments, samples are stored at -20oC.
  • pmEVs are obtained by methods adapted from Sandrini et al, 2014. In some embodiments, bacterial cultures are centrifuged at 10,000-15,500 x g for 10-15 min at room temp or at 4oC. In some embodiments, cell pellets are frozen at -80oC and supernatants are discarded.
  • cell pellets are thawed on ice and resuspended in 10 mM Tris- HCl, pH 8.0, 1 mM EDTA supplemented with 0.1 mg/mL lysozyme.
  • samples are incubated with mixing at room temp or at 37oC for 30 min.
  • samples are re-frozen at -80oC and thawed again on ice.
  • DNase I is added to a final concentration of 1.6 mg/mL and MgCl 2 to a final concentration of 100 mM.
  • samples are sonicated using a QSonica Q500 sonicator with 7 cycles of 30 sec on and 30 sec off.
  • debris and unlysed cells are pelleted by centrifugation at 10,000 x g for 15 min. at 4oC. In some embodiments, supernatants are then centrifuged at 110,000 x g for 15 min at 4oC. In some embodiments, pellets are resuspended in 10 mM Tris- HCl, pH 8.0, 2% Triton X-100 and incubated 30-60 min with mixing at room temperature. In some embodiments, samples are centrifuged at 110,000 x g for 15 min at 4oC. In some embodiments, pellets are resuspended in PBS and stored at -20oC.
  • a method of forming (for example, preparing) isolated bacterial pmEVs comprises the steps of: (a) centrifuging a bacterial culture, thereby forming a first pellet and a first supernatant, wherein the first pellet comprises cells; (b) discarding the first supernatant;(c) resuspending the first pellet in a solution; (d) lysing the cells; (e) centrifuging the lysed cells, thereby forming a second pellet and a second supernatant; (f) discarding the second pellet and centrifuging the second supernatant, thereby forming a third pellet and a third supernatant; (g) discarding the third supernatant and resuspending the third pellet in a second solution, thereby forming the isolated bacterial pmEVs.
  • the method further comprises the steps of: (h) centrifuging the solution of step (g), thereby forming a fourth pellet and a fourth supernatant; (i) discarding the fourth supernatant and resuspending the fourth pellet in a third solution. In some embodiments, the method further comprises the steps of: (j) centrifuging the solution of step (i), thereby forming a fifth pellet and a fifth supernatant; and (k) discarding the fifth supernatant and resuspending the fifth pellet in a fourth solution. [310] In some embodiments, the centrifugation of step (a) is at 10,000 x g. In some embodiments the centrifugation of step (a) is for 10-15 minutes.
  • step (b) further comprises freezing the first pellet at -80oC.
  • the solution in step (c) is 100 mM Tris-HCl, pH 7.5 supplemented with 1mg/ml DNaseI.
  • the solution in step (c) is 10 mM Tris-HCl, pH 8.0, 1 mM EDTA, supplemented with 0.1 mg/ml lysozyme.
  • step (c) further comprises incubating for 30 minutes at 37oC or room temperature.
  • step (c) further comprises freezing the first pellet at -80oC.
  • step (c) further comprises adding DNase I to a final concentration of 1.6 mg/ml. In some embodiments, step (c) further comprises adding MgCl 2 to a final concentration of 100 mM.
  • the cells are lysed in step (d) via homogenization. In some embodiments, the cells are lysed in step (d) via emulsiflex C3. In some embodiments, the cells are lysed in step (d) via sonication. In some embodiments, the cells are sonicated in 7 cycles, wherein each cycle comprises 30 seconds of sonication and 30 seconds without sonication. In some embodiments, the centrifugation of step (e) is at 10,000 x g.
  • the centrifugation of step (e) is for 15 minutes. In some embodiments, the centrifugation of step (e) is at 4oC or room temperature. [311] In some embodiments, the centrifugation of step (f) is at 120,000 x g. In some embodiments, the centrifugation of step (f) is at 110,000 x g. In some embodiments, the centrifugation of step (f) is for 1 hour. In some embodiments, the centrifugation of step (f) is for 15 minutes. In some embodiments, the centrifugation of step (f) is at 4oC or room temperature. In some embodiments, the second solution in step (g) is 100 mM sodium carbonate, pH 11.
  • the second solution in step (g) is 10 mM Tris-HCl pH 8.0, 2% triton X-100. In some embodiments, step (g) further comprises incubating the solution for 1 hour at 4oC. In some embodiments, step (g) further comprises incubating the solution for 30-60 minutes at room temperature. In some embodiments, the centrifugation of step (h) is at 120,000 x g. In some embodiments, the centrifugation of step (h) is at 110,000 x g. In some embodiments, the centrifugation of step (h) is for 1 hour. In some embodiments, the centrifugation of step (h) is for 15 minutes.
  • the centrifugation of step (h) is at 4oC or room temperature.
  • the third solution in step (i) is 100 mM Tris-HCl, pH 7.5.
  • the third solution in step (i) is PBS.
  • the centrifugation of step (j) is at 120,000 x g.
  • the centrifugation of step (j) is for 20 minutes.
  • the centrifugation of step (j) is at 4oC or room temperature.
  • the fourth solution in step (k) is 100 mM Tris-HCl, pH 7.5 or PBS.
  • pmEVs obtained by methods provided herein may be further purified by size based column chromatography, by affinity chromatography, and by gradient ultracentrifugation, using methods that may include, but are not limited to, use of a sucrose gradient or Optiprep gradient. Briefly, using a sucrose gradient method, if ammonium sulfate precipitation or ultracentrifugation were used to concentrate the filtered supernatants, pellets are resuspended in 60% sucrose, 30 mM Tris, pH 8.0. If filtration was used to concentrate the filtered supernatant, the concentrate is buffer exchanged into 60% sucrose, 30 mM Tris, pH 8.0, using an Amicon Ultra column.
  • Samples are applied to a 35-60% discontinuous sucrose gradient and centrifuged at 200,000 x g for 3-24 hours at 4°C. Briefly, using an Optiprep gradient method, if ammonium sulfate precipitation or ultracentrifugation were used to concentrate the filtered supernatants, pellets are resuspended in 35% Optiprep in PBS. In some embodiments, if filtration was used to concentrate the filtered supernatant, the concentrate is diluted using 60% Optiprep to a final concentration of 35% Optiprep. Samples are applied to a 35-60% discontinuous sucrose gradient and centrifuged at 200,000 x g for 3-24 hours at 4°C.
  • pmEVs are serially diluted onto agar medium used for routine culture of the bacteria being tested, and incubated using routine conditions. Non-sterile preparations are passed through a 0.22 ⁇ m filter to exclude intact cells. To further increase purity, isolated pmEVs may be DNase or proteinase K treated.
  • the sterility of the pmEV preparations can be confirmed by plating a portion of the pmEVs onto agar medium used for standard culture of the bacteria used in the generation of the pmEVs and incubating using standard conditions.
  • select pmEVs are isolated and enriched by chromatography and binding surface moieties on pmEVs.
  • select pmEVs are isolated and/or enriched by fluorescent cell sorting by methods using affinity reagents, chemical dyes, recombinant proteins or other methods known to one skilled in the art.
  • pmEVs are analyzed, for example, as described in Jeppesen et al. Cell 177:428 (2019).
  • pmEVs are lyophilized.
  • pmEVs are spray dried.
  • pmEVs are gamma irradiated (for example, at 17.5 or 25 kGy).
  • pmEVs are UV irradiated.
  • pmEVs are heat inactivated (for example, at 50°C for two hours or at 90°C for two hours).
  • pmEVs are acid treated.
  • pmEVs are oxygen sparged (for example, at 0.1 vvm for two hours).
  • the phase of growth can affect the amount or properties of bacteria.
  • pmEVs can be isolated, for example, from a culture, at the start of the log phase of growth, midway through the log phase, and/or once stationary phase growth has been reached.
  • Solutions and Dried Forms See PCT/US21/63266 (published as WO20221327380) and PCT/US22/13716 (published as WO2022164806) for examples of solutions and dried forms, and the preparation thereof, that can be used herewith.
  • solutions for example, liquid mixtures
  • Prevotella histicola EVs for example, Prevotella histicola EVs and/or a combination of EVs.
  • a solution includes Prevotella histicola EVs and an excipient that comprises a bulking agent.
  • a solution includes Prevotella histicola EVs and an excipient that comprises a bulking agent and a lyoprotectant.
  • a solution includes Prevotella histicola EVs and an excipient that comprises a lyoprotectant.
  • the disclosure also provides use of dried forms (in some embodiments, such as lyophilates) that comprise Prevotella histicola EVs (for example, Prevotella histicola EVs and/or a combination of EVs described herein), and an excipient.
  • a dried form can include Prevotella histicola EVs and an excipient that comprises a bulking agent.
  • a dried form can include Prevotella histicola EVs and an excipient that comprises a bulking agent and a lyoprotectant.
  • a dried form can include Prevotella histicola EVs and an excipient that comprises a lyoprotectant.
  • Prevotella histicola EVs are combined with an excipient that comprises a bulking agent and/or a lyoprotectant, for example, to prepare a solution.
  • the solution is dried, such as by lyophilization or spray drying.
  • the resulting dried form (for example, lyophilate) contains Prevotella histicola EVs and a component(s) of the excipient, for example, a bulking agent and/or a lyoprotectant (for example, in dried form).
  • the dried form is resuspended in a liquid.
  • the dried form is comprised in a solid dosage form.
  • the solutions and/or dried forms comprise Prevotella histicola EVs substantially or entirely free of whole Prevotella histicola bacteria (for example, live bacteria, killed bacteria, and/or attenuated bacteria).
  • the solutions and/or dried form comprise both Prevotella histicola EVs and Prevotella histicola whole bacteria (for example, live bacteria, killed bacteria, and/or attenuated bacteria).
  • the solutions and/or dried form comprise gamma irradiated Prevotella histicola EVs.
  • the Prevotella histicola EVs are gamma irradiated after the EVs are isolated (for example, prepared).
  • Prevotella histicola EVs are characterized by analytical methods known in the art (for example, Jeppesen, et al. Cell 177:428 (2019)).
  • the Prevotella histicola EVs are isolated away from one or more other bacterial components of the source bacteria.
  • the solution and/or dried form further comprises other bacterial components.
  • a Prevotella histicola EV liquid preparation obtained from the source bacteria may be fractionated into subpopulations based on the physical properties (for example, size, density, protein content, and/or binding affinity) of the subpopulations.
  • One or more of the EV subpopulations (for example, as a liquid preparation) can then be incorporated into the solutionsand/or dried forms of the invention.
  • solutions and/or dried forms (and therapeutic compositions thereof) comprising Prevotella histicola EVs from bacteria useful for the treatment and/or prevention of disease (for example, an immune disorder (e.g., an autoimmune disease, an inflammatory disease, an allergy), a dysbiosis, or a metabolic disease), as well as methods of making and/or identifying such EVs, and methods of using such solutions and/or dried forms (and therapeutic compositions thereof) (for example, for the treatment of an immune disorder (e.g., an autoimmune disease, an inflammatory disease, an allergy), a dysbiosis, or a metabolic disease, either alone or in combination with other therapeutics).
  • an immune disorder e.g., an autoimmune disease, an inflammatory disease, an allergy
  • a dysbiosis e.g., a inflammatory disease, an allergy
  • a metabolic disease for example, for the treatment of an immune disorder (e.g., an autoimmune disease, an inflammatory disease, an allergy), a dysbiosis, or a
  • solutions and/or dried forms comprising Prevotella histicola EVs from bacteria useful for the treatment and/or prevention of inflammation (such as inflammation associated with psoriasis or atopic dermatitis or psoriatic arthritis).
  • the therapeutic compositions comprise both Prevotella histicola EVs, and Prevotella histicola whole bacteria (for example, live bacteria, killed bacteria, and/or attenuated bacteria).
  • the solutions and/or dried forms comprise EVs from bacteria of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) taxonomic groups (e.g., class, order, family, genus, species or strain).
  • the solutions and/or dried forms comprise EVs from bacteria of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) bacteria strains or species.
  • the therapeutic compositions comprise Prevotella histicola EVs in the absence of bacteria (for example, at least about 85%, at least about 90%, at least about 95%, or at least about 99% free of bacteria).
  • the therapeutic compositions comprise EVs from bacteria of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) taxonomic groups (e.g., class, order, family, genus, species or strain). In some embodiments, the therapeutic compositions comprise EVs from bacteria of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) bacteria strains or species. In some embodiments, the therapeutic compositions comprise EVs from bacteria of one bacteria strain or species.
  • taxonomic groups e.g., class, order, family, genus, species or strain.
  • the therapeutic compositions comprise EVs from bacteria of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) bacteria strains or species. In some embodiments, the therapeutic compositions comprise EVs from bacteria of one bacteria strain or species.
  • the solution and/or dried form is added to or incorporated into (or is) a food product (for example, a food or beverage) such as a health food or beverage, a food or beverage for infants, a food or beverage for pregnant women, athletes, senior citizens or other specified group, a functional food, a beverage, a food or beverage for specified health use, a dietary supplement, a probiotic, a food or beverage for patients, or an animal feed.
  • a food product for example, a food or beverage
  • a food or beverage for infants such as a food or beverage for infants, a food or beverage for pregnant women, athletes, senior citizens or other specified group
  • a functional food such as a beverage, a food or beverage for specified health use, a dietary supplement, a probiotic, a food or beverage for patients, or an animal feed.
  • the foods and beverages include various beverages such as juices, refreshing beverages, tea beverages, drink preparations, jelly beverages, and functional beverages; alcoholic beverages such as beers; carbohydrate-containing foods such as rice food products, noodles, breads, and pastas; paste products such as fish hams, sausages, paste products of seafood; retort pouch products such as curries, food dressed with a thick starchy sauces, soups; dairy products such as milk, dairy beverages, ice creams, cheeses, and yogurts; fermented products such as fermented soybean pastes, yogurts, fermented beverages, and pickles; bean products; various confectionery products, including biscuits, cookies, and the like, candies, chewing gums, gummies, cold desserts including jellies, cream caramels, and frozen desserts; instant foods such as instant soups and instant soy-bean soups; microwavable foods; and the like.
  • beverages such as juices, refreshing beverages, tea beverages, drink preparations, jelly beverages, and functional beverages
  • alcoholic beverages such as be
  • the examples also include health foods and beverages prepared in the forms of powders, granules, tablets, capsules, liquids, pastes, and jellies.
  • the solution and/or dried form is added to (or is) a food product or food supplement for animals, including humans.
  • the animals, other than humans, are not particularly limited, and the composition can be used for various livestock, poultry, pets, experimental animals, and the like. Specific examples of the animals include pigs, cattle, horses, sheep, goats, chickens, ducks, ostriches, turkeys, dogs, cats, rabbits, hamsters, mice, rats, monkeys, and the like, but the animals are not limited thereto.
  • EV Quantification [335]
  • a sample e.g., of an EV preparation such as a dried form or therapeutic composition comprising EVs
  • electron microscopy for example, EM of ultrathin frozen sections
  • NTA nanoparticle tracking analysis
  • Coulter counting Coulter counting
  • DLS dynamic light scattering
  • the full range is 0.2-20 ⁇ m.
  • Coulter counting reveals the numbers of bacteria and/or EVs from bacteria in a given sample.
  • Coulter counting reveals the numbers of particles with diameters of 0.7-10 ⁇ m.
  • the Coulter counter alone can reveal the number of bacteria and/or EVs in a sample.
  • NTA a Nanosight instrument can be obtained from Malvern Pananlytical.
  • the NS300 can visualize and measure particles in suspension in the size range 10-2000 nm. NTA allows for counting of the numbers of particles that are, for example, 50-1000 nm in diameter.
  • the Prevotella histicola EVs are quantified based on particle count, e.g., of an EV preparation or sample thereof.
  • particle count of an EV preparation can be measured using NTA.
  • particle count of an EV preparation is measured using NTA with Zetaview.
  • the Prevotella histicola EVs are quantified based on the amount of protein, lipid, or carbohydrate, e.g., of an EV preparation or sample thereof.
  • total protein content of an EV preparation is measured using the Bradford assay or BCA.
  • Equivalent Total Particle Number eTPN
  • the Prevotella histicola EVs are quantified based on the eTPN, e.g., of an EV preparation or sample thereof. With this method, the quantification of EV content is based on measurement of EV lipid quantity with a fluorescent dye and comparing against a standard curve of an EV reference standard.
  • a key component of EVs is a lipid bilayer. The source of lipid in a composition is associated with the EVs.
  • This method utilizes a fluorescent-labeled dye (such as FM4-64) that specifically interacts with the lipid bilayer of the EVs.
  • the resulting fluorescent signal intensity correlates to the lipid content of EV and can be quantified by spectroscopy.
  • a representative EV reference standard with known correlation between the lipid content and EV particle numbers is used to generate a standard curve using the same fluorescent lipid assay. By comparing a sample lipid content and EV reference standard curve, the equivalent total particle number (ePTN) of the EVs can be determined.
  • a method of determining the lipid content of a composition comprising Prevotella histicola EVs can include the steps of: (a) contacting a test sample from a composition comprising the EVs with a lipophilic fluorescent dye (such as FM4-64) to obtain a mixture; (b) measuring a fluorescence signal from the mixture; and (c) determining the lipid content of the composition comprising the EVs based on the fluorescence signal.
  • a lipophilic fluorescent dye such as FM4-64
  • a method of determining a dose of a composition comprising Prevotella histicola EVs can include the steps of: (a) contacting a test sample from a composition comprising the EVs with a lipophilic fluorescent dye (such as FM4- 64) to obtain a mixture; (b) measuring a fluorescence signal from the mixture; and (c) determining a dose of the composition comprising the EVs based on the fluorescence signal.
  • a lipophilic fluorescent dye such as FM4- 64
  • fluorescent dyes used in the methods include, but are not limited to, N-(3- triethylammoniumpropyl)-4-(6-(4-(diethylamino)phenyl)hexatrienyl)pyridinium dibromide (FM4-64), a fixable analog of FM4-64 (FM4-64X (Thermo Fisher)), N-(3- Trimethylammoniumpropyl)-4-(6-(4-(Diethylamino)phenyl)hexatrienyl)Pyridinium Dibromide (FM 5-95), a slightly less lipophilic analog of FM 4-64, and SynaptoRed TM C2.
  • the fluorescent dyes used in the methods is N-(3-triethylammoniumpropyl)-4-(6- (4-(diethylamino)phenyl)hexatrienyl)pyridinium dibromide (FM4-64).
  • FM4-64 N-(3-triethylammoniumpropyl)-4-(6- (4-(diethylamino)phenyl)hexatrienyl)pyridinium dibromide
  • the methods provided herein comprise use of therapeutic compositions (e.g., pharmaceutical compositions) comprising Prevotella histicola EVs provided herein.
  • a solution and/or dried form containing Prevotella histicola EVs is formulated into a therapeutic composition.
  • therapeutic compositions comprising a solution and/or dried form described herein.
  • the therapeutic composition comprises a solution and/or dried form provided herein and a pharmaceutically acceptable carrier.
  • the therapeutic composition comprises a pharmaceutically acceptable excipient, such as a glidant, lubricant, and/or diluent.
  • compositions comprising Prevotella histicola EVs useful for the treatment and/or prevention of disease (for example, an immune disorder (e.g., an autoimmune disease, an inflammatory disease, an allergy), a dysbiosis, or a metabolic disease), as well as methods of making and/or identifying such EVs, and methods of using such therapeutic compositions (for example, for the treatment of an immune disorder (e.g., an autoimmune disease, an inflammatory disease, an allergy), a dysbiosis, or a metabolic disease, either alone or in combination with other therapeutics).
  • an immune disorder e.g., an autoimmune disease, an inflammatory disease, an allergy
  • a dysbiosis e.g., a inflammatory disease, an allergy
  • a metabolic disease for example, for the treatment of an immune disorder (e.g., an autoimmune disease, an inflammatory disease, an allergy), a dysbiosis, or a metabolic disease, either alone or in combination with other therapeutics).
  • compositions comprising Prevotella histicola EVs useful for the treatment and/or prevention of inflammation (e.g., Th1, Th2, or Th17 inflammation) (e.g., inflammation associated with psoriasis or atopic dermatitis or psoriatic arthritis) as well as methods of making such EVs, and methods of using such therapeutic compositions (for example, for the treatment of inflammation (e.g., Th1, Th2, or Th17 inflammation) (e.g., inflammation associated with psoriasis or atopic dermatitis or psoriatic arthritis), either alone or in combination with other therapeutics).
  • inflammation e.g., Th1, Th2, or Th17 inflammation
  • the therapeutic compositions comprise both EVs and whole bacteria (for example, live bacteria, killed bacteria, attenuated bacteria). In some embodiments, the therapeutic compositions comprise EVs in the absence of bacteria (for example, at least about 85%, at least about 90%, at least about 95%, or at least about 99% free of bacteria). In some embodiments, the therapeutic compositions comprise EVs and/or bacteria from one or more (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) of the bacteria from a taxonomic group. In some embodiments, the therapeutic compositions comprise EVs and/or bacteria from one or more of the bacteria strains or species. In some embodiments, the therapeutic compositions comprise EVs and/or bacteria from one of the bacteria from a taxonomic group.
  • the therapeutic compositions comprise EVs and/or bacteria from one of the bacteria strains or species.
  • provided are therapeutic compositions for administration to a subject e.g., human subject.
  • the therapeutic compositions are combined with additional active and/or inactive materials in order to produce a final product, which may be in single dosage unit or in a multi-dose format.
  • the therapeutic composition is combined with an adjuvant such as an immuno-adjuvant (e.g., a STING agonist, a TLR agonist, or a NOD agonist).
  • an adjuvant such as an immuno-adjuvant (e.g., a STING agonist, a TLR agonist, or a NOD agonist).
  • the therapeutic composition comprises at least one carbohydrate.
  • the therapeutic composition comprises at least one lipid.
  • the lipid comprises at least one fatty acid selected from lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1), margaric acid (17:0), heptadecenoic acid (17:1), stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2), linolenic acid (18:3), octadecatetraenoic acid (18:4), arachidic acid (20:0), eicosenoic acid (20:1), eicosadienoic acid (20:2), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5) (EPA), docosanoic acid (22:0), docosenoic acid (22:1), docosapentaenoic acid (22:5), docosahexaenoic acid (22:6) (DHA), and t
  • the therapeutic composition comprises at least one supplemental mineral or mineral source.
  • supplemental mineral or mineral source examples include, without limitation: chloride, sodium, calcium, iron, chromium, copper, iodine, zinc, magnesium, manganese, molybdenum, phosphorus, potassium, and selenium. Suitable forms of any of the foregoing minerals include soluble mineral salts, slightly soluble mineral salts, insoluble mineral salts, chelated minerals, mineral complexes, non-reactive minerals such as carbonyl minerals, and reduced minerals, and combinations thereof.
  • the therapeutic composition comprises at least one supplemental vitamin.
  • the at least one vitamin can be fat-soluble or water-soluble vitamins.
  • Suitable vitamins include but are not limited to vitamin C, vitamin A, vitamin E, vitamin B12, vitamin K, riboflavin, niacin, vitamin D, vitamin B6, folic acid, pyridoxine, thiamine, pantothenic acid, and biotin.
  • Suitable forms of any of the foregoing are salts of the vitamin, derivatives of the vitamin, compounds having the same or similar activity of the vitamin, and metabolites of the vitamin.
  • the therapeutic composition comprises an excipient.
  • Non-limiting examples of suitable excipients include a buffering agent, a preservative, a stabilizer, a binder, a compaction agent, a lubricant, a dispersion enhancer, a disintegration agent, a flavoring agent, a sweetener, and a coloring agent.
  • the excipient is a buffering agent.
  • suitable buffering agents include sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate.
  • the excipient comprises a preservative.
  • the therapeutic composition comprises a binder as an excipient.
  • suitable binders include starches, pregelatinized starches, gelatin, polyvinylpyrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, and combinations thereof.
  • the therapeutic composition comprises a lubricant as an excipient.
  • suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil.
  • the therapeutic composition comprises a dispersion enhancer as an excipient.
  • Non-limiting examples of suitable dispersants include starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.
  • the therapeutic composition comprises a disintegrant as an excipient.
  • the disintegrant is a non-effervescent disintegrant.
  • Non-limiting examples of suitable non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro- crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth.
  • the disintegrant is an effervescent disintegrant.
  • suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.
  • the therapeutic composition is (or is added to) a food product (e.g., a food or beverage) such as a health food or beverage, a food or beverage for infants, a food or beverage for pregnant women, athletes, senior citizens or other specified group, a functional food, a beverage, a food or beverage for specified health use, a dietary supplement, a food or beverage for patients, or an animal feed.
  • a food product e.g., a food or beverage
  • a food or beverage such as a health food or beverage, a food or beverage for infants, a food or beverage for pregnant women, athletes, senior citizens or other specified group, a functional food, a beverage, a food or beverage for specified health use, a dietary supplement, a food or beverage for patients, or an animal feed.
  • the foods and beverages include various beverages such as juices, refreshing beverages, tea beverages, drink preparations, jelly beverages, and functional beverages; alcoholic beverages such as beers; carbohydrate- containing foods such as rice food products, noodles, breads, and pastas; paste products such as fish hams, sausages, paste products of seafood; retort pouch products such as curries, food dressed with a thick starchy sauces, and Chinese soups; soups; dairy products such as milk, dairy beverages, ice creams, cheeses, and yogurts; fermented products such as fermented soybean pastes, yogurts, fermented beverages, and pickles; bean products; various confectionery products, including biscuits, cookies, and the like, candies, chewing gums, gummies, cold desserts including jellies, cream caramels, and frozen desserts; instant foods such as instant soups and instant soy-bean soups; microwavable foods; and the like.
  • beverages such as juices, refreshing beverages, tea beverages, drink preparations, jelly beverages, and functional beverages
  • the examples also include health foods and beverages prepared in the forms of powders, granules, tablets, capsules, liquids, pastes, and jellies.
  • the therapeutic composition is (or is added to) a food product for animals, including humans.
  • the animals, other than humans, are not particularly limited, and the composition can be used for various livestock, poultry, pets, experimental animals, and the like.
  • Specific examples of the animals include pigs, cattle, horses, sheep, goats, chickens, wild ducks, ostriches, domestic ducks, dogs, cats, rabbits, hamsters, mice, rats, monkeys, and the like, but the animals are not limited thereto.
  • Dose forms comprising Prevotella histicola EVs are also provided herein, e.g., for use in methods to treat or prevent inflammation (e.g., Th1, Th2, or Th17 inflammation) (e.g., inflammation associated with psoriasis or atopic dermatitis or psoriatic arthritis) in a subject (e.g., a human subject).
  • inflammation e.g., Th1, Th2, or Th17 inflammation
  • a subject e.g., a human subject
  • Dose forms comprising Prevotella histicola EVs are also provided herein, e.g., for use in methods to treat or prevent disease (for example, an immune disorder (e.g., an autoimmune disease, an inflammatory disease, an allergy), a dysbiosis, or a metabolic disease).
  • a therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs can be formulated as a solid dose form, e.g., for oral administration.
  • the therapeutic composition (e.g., pharmaceutical composition) comprising Prevotella histicola EVs is prepared as a dried form (such as a powder) (e.g., for resuspension or for use in a solid dose form (such as a capsule)) or as a solid dose form, such as a tablet, a mini- tablet, a capsule, or a powder (or other dried form) or a combination of these forms (e.g., mini- tablets comprised in a capsule)).
  • the dried form can comprise lyophilized EVs.
  • the Prevotella histicola EVs are gamma irradiated.
  • a therapeutic composition comprising a dried form of EVs is formulated as a solid dosage form (also referred to as “solid dose form”), for example, for oral administration.
  • the solid dosage form comprises one or more excipients, for example, pharmaceutically acceptable excipients, in addition to the dried form.
  • the dried form in the solid dosage form contains isolated Prevotella histicola EVs.
  • the Prevotella histicola EVs in the solid dosage form are gamma irradiated.
  • the solid dosage form comprises a tablet, a minitablet, a capsule, or a powder (or other dried form); or a combination of these forms (for example, minitablets comprised in a capsule).
  • the solid dosage form described herein can be, e.g., a capsule.
  • the solid dosage form described herein can be, e.g., a tablet or a minitablet. Further, a plurality of minitablets can be in (e.g., loaded into) a capsule.
  • the solid dosage form comprises a capsule.
  • the capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule.
  • the capsule is a size 0 capsule.
  • the size of the capsule refers to the size of the tablet prior to application of an enteric coating.
  • the capsule can comprise hydroxyl propyl methyl cellulose (HPMC) or gelatin.
  • HPMC hydroxyl propyl methyl cellulose
  • the capsule is an HPMC capsule.
  • the capsule is banded after loading (and prior to enterically coating the capsule).
  • the capsule is banded with an HPMC-based banding solution.
  • the solid dosage form comprises a tablet (> 4 mm) (e.g., 5 mm-17 mm).
  • the tablet is a 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, or 18 mm tablet.
  • the size refers to the diameter of the tablet, as is known in the art.
  • the size of the tablet refers to the size of the tablet prior to application of an enteric coating.
  • the solid dosage form comprises a minitablet.
  • the minitablet can be in the size range of 1 mm-4 mm range.
  • the minitablet can be a 1 mm minitablet, 1.5 mm minitablet, 2 mm minitablet, 3 mm minitablet, or 4 mm minitablet.
  • the size refers to the diameter of the minitablet, as is known in the art.
  • the size of the minitablet refers to the size of the minitablet prior to application of an enteric coating.
  • the minitablets can be in a capsule.
  • the capsule can be a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule.
  • the capsule that contains the minitablets can comprise hydroxyl propyl methyl cellulose (HPMC) or gelatin.
  • the minitablets can be inside a capsule: the number of minitablets inside a capsule will depend on the size of the capsule and the size of the minitablets. As an example, a size 0 capsule can contain 31-35 (an average of 33) minitablets that are 3 mm minitablets.
  • the capsule is banded after loading. In some embodiments, the capsule is banded with an HPMC-based banding solution.
  • a therapeutic composition comprising a solution and/or dried form (e.g., that comprises EVs, e.g., and a bulking agent) can be formulated as a suspension (e.g., a dried form such as a powder can be reconstituted; a solution can be diluted), e.g., for oral administration or for injection. Administration by injection includes intravenous (IV), intramuscular (IM), and subcutaneous (SC) administration.
  • EVs can be in a buffer, e.g., a pharmaceutically acceptable buffer, e.g., saline or PBS.
  • the suspension can comprise one or more excipients, e.g., pharmaceutically acceptable excipients.
  • the suspension can comprise, e.g., sucrose or glucose.
  • the EVs in the solution or powder e.g., that comprises EVs and a bulking agent
  • the EVs in the suspension can be gamma irradiated.
  • the solid dosage form can be a tablet. Tablets that can be used in the methods provided herein include those described in PCT/US22/13716 (published as WO2022164806) and PCT/US22/18842 (published as WO2022187578).
  • the tablets comprise about 10% to about 70% therapeutic agent (e.g., EVs or a dried form (such as a powder) comprising Prevotella histicola EVs); about 20% to about 73% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone (e.g., PVPP); about 1% magnesium stearate; and about 1% colloidal silica (e.g., Aerosil 200). See also the examples provided herein.
  • a therapeutic agent e.g., EVs or a dried form (such as a powder) comprising Prevotella histicola EVs
  • silicified microcrystalline cellulose e.g., HD90
  • crospovidone e.g., PVPP
  • magnesium stearate e.g., Aerosil 200
  • colloidal silica e.g., Aerosil 200
  • the capsules comprise (i) a therapeutic agent (e.g., EVs or a powder comprising EVs) having a total therapeutic agent mass that is about 10% to about 90% of the total mass of the capsule; (ii) a diluent (e.g., mannitol) having a total mass that is about 7% to about 88% of the total mass of the capsule; (iii) a lubricant (e.g., magnesium stearate) having a total mass that is about 1.5% of the total mass of the capsule; and (iv) a glidant (e.g., colloidal silicon dioxide) having a total mass that is about 1% of the total mass of the capsule.
  • a therapeutic agent e.g., EVs or a powder comprising EVs
  • a diluent e.g., mannitol
  • a lubricant e.g., magnesium stearate
  • a glidant e.g.
  • the capsules comprise (i) a therapeutic agent (e.g., EVs or a powder comprising EVs) having a total therapeutic agent mass that is about 50% to about 85% of the total mass of the capsule; (ii) a diluent (e.g., mannitol) having a total mass that is about 12% to about 50% of the total mass of the capsule; (iii) a lubricant (e.g., magnesium stearate) having a total mass that is about 1% or about 1.5% of the total mass of the capsule; and (iv) a glidant (e.g., colloidal silicon dioxide) having a total mass that is about 0.5% or about 1% of the total mass of the capsule.
  • a therapeutic agent e.g., EVs or a powder comprising EVs
  • a diluent e.g., mannitol
  • a lubricant e.g., magnesium stearate
  • the capsules comprise (i) a therapeutic agent (e.g., EVs or a powder comprising EVs) having a total therapeutic agent mass that is about 70% of the total mass of the capsule; (ii) a diluent (e.g., mannitol) having a total mass that is about 29% of the total mass of the capsule; (iii) a lubricant (e.g., magnesium stearate) having a total mass that is about 1.5% of the total mass of the capsule; and (iv) a glidant (e.g., colloidal silicon dioxide) having a total mass that is about 1% of the total mass of the capsule.
  • a therapeutic agent e.g., EVs or a powder comprising EVs
  • a diluent e.g., mannitol
  • a lubricant e.g., magnesium stearate
  • a glidant e.g., colloidal silicon dioxide
  • the capsules comprise (i) a therapeutic agent (e.g., EVs or a powder comprising EVs) having a total therapeutic agent mass that is about 85% of the total mass of the capsule; (ii) a diluent (e.g., mannitol) having a total mass that is about 12% of the total mass of the capsule; (iii) a lubricant (e.g., magnesium stearate) having a total mass that is about 1.5% of the total mass of the capsule; and (iv) a glidant (e.g., colloidal silicon dioxide) having a total mass that is about 1% of the total mass of the capsule.
  • a therapeutic agent e.g., EVs or a powder comprising EVs
  • a diluent e.g., mannitol
  • a lubricant e.g., magnesium stearate
  • a glidant e.g., colloidal silicon dioxide
  • the capsules comprise (i) a therapeutic agent (e.g., EVs or a powder comprising EVs) having a total therapeutic agent mass that is about 50% of the total mass of the capsule; (ii) a diluent (e.g., mannitol) having a total mass that is about 50% of the total mass of the capsule; (iii) a lubricant (e.g., magnesium stearate) having a total mass that is about 1% of the total mass of the capsule; and (iv) a glidant (e.g., colloidal silicon dioxide) having a total mass that is about 0.5% of the total mass of the capsule.
  • a therapeutic agent e.g., EVs or a powder comprising EVs
  • a diluent e.g., mannitol
  • a lubricant e.g., magnesium stearate
  • a glidant e.g., colloidal silicon dioxide
  • the capsules comprise (i) a therapeutic agent (e.g., EVs or a powder comprising EVs) having a total therapeutic agent mass that is about 1% to about 10% (e.g, about 6.5%) of the total mass of the capsule; (ii) a diluent (e.g., mannitol) having a total mass that is about 80% to about 99% (e.g., about 91%) of the total mass of the capsule; (iii) a lubricant (e.g., magnesium stearate) having a total mass that is about 0.1% to about 5% (e.g., about 1.5%) of the total mass of the capsule; and (iv) a glidant (e.g., colloidal silicon dioxide) having a total mass that is about 0.1% to about 5% (e.g., about 1%) of the total mass of the capsule.
  • a therapeutic agent e.g., EVs or a powder comprising EVs
  • the capsules comprise lyophilised powder of Prevotella histicola smEVs, mannitol, colloidal silicon dioxide, magnesium stearate, hydroxypropyl methylcellulose, methacrylic acid-ethyl acrylate copolymer, talc, triethyl citrate, titanium dioxide, and iron oxide.
  • the capsules consist essentially of lyophilised powder of Prevotella histicola smEVs, mannitol, colloidal silicon dioxide, magnesium stearate, hydroxypropyl methylcellulose, methacrylic acid-ethyl acrylate copolymer, talc, triethyl citrate, titanium dioxide, and iron oxide.
  • the percent of mass of a solid dosage form is on a percent weight:weight basis (% w:w).
  • a solid dosage form (e.g., capsule, tablet or minitablet) described herein can be enterically coated, e.g., with one enteric coating layer or with two layers of enteric coating, e.g., an inner enteric coating and an outer enteric coating.
  • the inner enteric coating and outer enteric coating are not identical (e.g., the inner enteric coating and outer enteric coating do not contain the same components in the same amounts).
  • the enteric coating allows for release of the therapeutic agent (such as Prevotella histicola EVs, dried forms, and/or solid dosage forms thereof), e.g., in the small intestine.
  • EUDRAGIT is the brand name for a diverse range of polymethacrylate-based copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters or their derivatives.
  • Examples of other materials that can be used in the enteric coating include cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), fatty acids, waxes, shellac (esters of aleurtic acid), plastics, plant fibers, zein, Aqua-Zein® (an aqueous zein formulation containing no alcohol), amylose starch, starch derivatives, dextrins, methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), methyl methacrylate-methacrylic acid copolymers, and/or sodium alginate.
  • CAP cellulose acetate phthalate
  • CAT cellulose acetate trimellitate
  • PVAP poly(vinyl acetate phthalate)
  • the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) can include a methacrylic acid ethyl acrylate (MAE) copolymer (1:1).
  • the one enteric coating can include methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P).
  • the one enteric coating can include a Eudragit copolymer, e.g., a Eudragit L (e.g., Eudragit L 100-55; Eudragit L 30 D-55), a Eudragit S, a Eudragit RL, a Eudragit RS, a Eudragit E, or a Eudragit FS (e.g., Eudragit FS 30 D).
  • a Eudragit copolymer e.g., a Eudragit L (e.g., Eudragit L 100-55; Eudragit L 30 D-55), a Eudragit S, a Eudragit RL, a Eudragit RS, a Eudragit E, or a Eudragit FS (e.g., Eudragit FS 30 D).
  • the one enteric coating can include Eudragit L 30 D-55.
  • enteric coating examples include those described in, e.g., U.S.6312728; U.S.6623759; U.S.4775536; U.S.5047258; U.S.5292522; U.S.6555124; U.S.6638534; U.S. 2006/0210631; U.S.2008/200482; U.S.2005/0271778; U.S.2004/0028737; WO 2005/044240.
  • methacrylic acid copolymers include: poly(methacrylic acid, methyl methacrylate) 1:1 sold, for example, under the Eudragit L100 trade name; poly(methacrylic acid, ethyl acrylate) 1:1 sold, for example, under the Eudragit L100-55 trade name; partially-neutralized poly(methacrylic acid, ethyl acrylate) 1:1 sold, for example, under the Kollicoat MAE-100P trade name; and poly(methacrylic acid, methyl methacrylate) 1:2 sold, for example, under the Eudragit S100 trade name.
  • methacrylic acid copolymers include: poly(methacrylic acid, methyl methacrylate) 1:1 sold, for example, under the Eudragit L100 trade name; poly(methacrylic acid, ethyl acrylate) 1:1 sold, for example, under the Eudragit L100-55 trade name; partially-neutralized poly(methacrylic acid, ethyl acrylate) 1:1 sold,
  • the solid dosage form comprises a sub-coat, e.g., under the enteric coating (e.g., one enteric coating).
  • Coating level The coating level (also referred to herein as thickness) of the enteric coating on a solid dosage form influences the site of release of the Prevotella histicola EVs from the solid dosage form after oral administration.
  • a coating level of enteric coating on the solid dosage form is designed to protect the Prevotella histicola EVs from release in the stomach (that is, the enteric coating maintains gastric integrity).
  • the coating level of the enteric coat influences the time to release of the Prevotella histicola EVs from the solid dosage form, e.g., the time to release after gastric emptying.
  • a coating level of enteric coating is designed to release the Prevotella histicola EVs from the solid dosage form in the small intestine, such as in the jejunum or the ileum. Release of the Prevotella histicola EVs can be determined by scintigraphy studies.
  • the solid dosage form releases the Prevotella histicola EVs contained therein in the small intestine.
  • the solid dosage form releases the Prevotella histicola EVs contained therein beyond the duodenum, for example, downstream of bile duct juncture. In some embodiments, the solid dosage form releases the Prevotella histicola EVs contained therein in the jejunum. In some embodiments, the solid dosage form releases the Prevotella histicola EVs contained therein in the ileum.
  • the enteric coating is at a coating level of between about 5 to about 31 mg per solid dose form (e.g., about 5 to about 31 mg total weight gain on the solid dose form) (e.g., per capsule (e.g., size 0 capsule) or per tablet (e.g., 17 mm tablet)) (e.g., or an equivalent coating level for the given sized solid dose form).
  • a size 0 capsule has a coating level of between about 5 to about 31 mg per capsule
  • a smaller capsule will have a coating level that is proportionate to about 5 to about 31 mg for its size.
  • the enteric coating is at a coating level of about 5 mg; about 9 mg; about 14 mg; about 19 mg; about 25 mg; or about 31 mg per solid dose form (e.g., per capsule (e.g., size 0 capsule) or per tablet (e.g., 17 mm tablet)) (e.g., or an equivalent coating level for the given sized solid dose form).
  • a size 0 capsule has a coating level of about 5 mg
  • a smaller capsule will have a coating level that is proportionate to about 5 mg for its size.
  • the enteric coating is at a coating level of between about 1 mg/cm 2 to about 6 mg/cm 2 per solid dose form (e.g., per capsule (e.g., between about 5 mg to about 31 mg per size 0 capsule)).
  • the enteric coating is at a coating level of about 1 mg/cm 2 (e.g., about 5 mg per size 0 capsule); about 1.7 mg/cm 2 (e.g., about 9 mg per size 0 capsule); about 2.7 mg/cm 2 (e.g., about 14 mg per size 0 capsule); about 3.7 mg/cm 2 (e.g., about 19 mg per size 0 capsule); about 4.8 mg/cm 2 (e.g., about 25 mg per size 0 capsule); or about 6 mg/cm 2 (e.g., about 31 mg per size 0 capsule) per solid dose form (such as a capsule).
  • a coating level of about 1 mg/cm 2 (e.g., about 5 mg per size 0 capsule); about 1.7 mg/cm 2 (e.g., about 9 mg per size 0 capsule); about 2.7 mg/cm 2 (e.g., about 14 mg per size 0 capsule); about 3.7 mg/cm 2 (e.g., about 19 mg per size
  • the enteric coating is at a coating level of about 1 mg/cm 2 per solid dose form (such as a capsule). In some embodiments, the enteric coating is at a coating level of about 1.7 mg/cm 2 per solid dose form (such as a capsule). In some embodiments, the enteric coating is at a coating level of about 2.7 mg/cm 2 total weight gain (e.g., a polymer weight gain of about 1.7 mg/cm 2 ) per solid dose form (such as a capsule). In some embodiments, the enteric coating is at a coating level of about 3.7 mg/cm 2 per solid dose form (such as a capsule).
  • the enteric coating is at a coating level of about 4.8 mg/cm 2 per solid dose form (such as a capsule). In some embodiments, the enteric coating is at a coating level of about 6 mg/cm 2 per solid dose form (such as a capsule).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 1 x 10 12 to about 1 x 10 15 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 1 x 10 12 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 2 x 10 12 to about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 3 x 10 12 to about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 2 x 10 13 to about 2 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 5 x 10 13 to about 5 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 1 x 10 13 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 1 x 10 11 to about 1 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 4 x 10 11 to about 4 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 1 x 10 11 to about 1 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 4 x 10 11 to about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein). In some embodiments, the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 1.6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein). In some embodiments, the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein). In some embodiments, the therapeutic composition comprises EVs from Prevotella histicola bacteria at a dose of about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein). [393] In some embodiments, the therapeutic compositions are prepared as solid dosage forms.
  • solid dosage forms comprising the Prevotella histicola EVs.
  • the solid dosage form comprises an enteric coating.
  • each tablet comprises Prevotella histicola EVs at a dose of about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the solid dosage form is a tablet, e.g., an enteric coated tablet.
  • each tablet comprises Prevotella histicola EVs at a dose of about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein). In some embodiments, each tablet comprises Prevotella histicola EVs at a dose of about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • each tablet comprises Prevotella histicola EVs at a dose of about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • the solid dosage form is a capsule e.g., an enteric coated capsule.
  • each capsule comprises Prevotella histicola EVs at a dose of about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • each capsule comprises Prevotella histicola EVs at a dose of about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein). In some embodiments, each capsule comprises Prevotella histicola EVs at a dose of about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • each capsule comprises Prevotella histicola EVs at a dose of about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein).
  • about 1 x 10 12 to about 1 x 10 15 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola EVs are administered to the subject daily, e.g., in a solid dosage form.
  • about 1 x 10 12 to about 1 x 10 14 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • about 2 x 10 12 to about 2 x 10 13 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola EVs are administered to the subject daily, e.g., in a solid dosage form.
  • about 3 x 10 12 to about 2 x 10 13 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • about 2 x 10 13 to about 2 x 10 14 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola EVs are administered to the subject daily, e.g., in a solid dosage form.
  • about 5 x 10 13 to about 5 x 10 14 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • about 1 x 10 13 to about 1 x 10 14 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola EVs are administered to the subject daily, e.g., in a solid dosage form.
  • about 1 x 10 11 to about 1 x 10 13 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • about 4 x 10 11 to about 4 x 10 13 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola EVs are administered to the subject daily, e.g., in one or more solid dosage forms.
  • about 1 x 10 11 to about 1 x 10 12 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola EVs are administered to the subject daily, e.g., in one or more solid dosage forms.
  • about 4 x 10 11 to about 4 x 10 12 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola EVs are administered to the subject daily, e.g., in one or more solid dosage forms.
  • about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of Prevotella histicola EVs are administered to the subject daily, e.g., in one or more solid dosage forms.
  • about 1.6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of Prevotella histicola EVs are administered to the subject daily, e.g., in one or more solid dosage forms.
  • about 4 x 10 12 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • about 2 x 10 13 particles e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein
  • Prevotella histicola EVs are administered to the subject daily, e.g., in a solid dosage form.
  • about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of Prevotella histicola EVs are administered to the subject daily, e.g., in a solid dosage form.
  • about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of Prevotella histicola EVs are administered to the subject daily, e.g., in a solid dosage form.
  • the therapeutic composition comprises about 1 x 10 12 to about 1 x 10 15 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 1 x 10 12 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 2 x 10 12 to about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 3 x 10 12 to about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 2 x 10 13 to about 2 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 5 x 10 13 to about 5 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 1 x 10 13 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 1 x 10 11 to about 1 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 4 x 10 11 to about 4 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 1 x 10 11 to about 1 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 4 x 10 11 to about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 1.6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition comprises about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • the therapeutic composition is provided as a solid dosage form (also referred to as a solid dose form).
  • solid dosage forms comprising the Prevotella EVs.
  • the solid dosage form comprises an enteric coating.
  • the enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1) such as Kollicoat MAE 100P.
  • the enteric coating comprises Eudragit L 30 D-55.
  • the solid dosage form comprises about 1 x 10 12 to about 1 x 10 15 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 1 x 10 12 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 2 x 10 12 to about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 3 x 10 12 to about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 2 x 10 13 to about 2 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 5 x 10 13 to about 5 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 1 x 10 13 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 1 x 10 11 to about 1 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 4 x 10 11 to about 4 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 1 x 10 11 to about 1 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 4 x 10 11 to about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 1.6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form is an enteric coated solid dosage form.
  • the enteric coating comprises a polymethacrylate-based copolymer.
  • the enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1). In some embodiments, the enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1) such as Kollicoat MAE 100P. In some embodiments, the enteric coating comprises Eudragit L 30 D-55. [399] In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 solid dosage forms are administered, e.g., once or twice daily to a subject. In some embodiments, 1 solid dosage form is administered, e.g., once or twice daily to a subject.
  • the Prevotella EVs in the solid dosage form are in a dried form.
  • the Prevotella EVs in the solid dosage form are lyophilized.
  • the Prevotella EVs in the solid dosage form are spray dried.
  • the dried form comprises Prevotella EVs and mannitol.
  • the dried form comprises Prevotella EVs and trehalose.
  • the dried form comprises Prevotella EVs, mannitol, and trehalose. In some embodiments, the dried form consists essentially of Prevotella EVs, mannitol, and trehalose.
  • the solid dosage form comprises about 1 x 10 12 to about 1 x 10 15 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 1 x 10 12 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 2 x 10 12 to about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 3 x 10 12 to about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 2 x 10 13 to about 2 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 5 x 10 13 to about 5 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 1 x 10 13 to about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 1 x 10 11 to about 1 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 4 x 10 11 to about 4 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 1 x 10 11 to about 1 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 4 x 10 11 to about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • NTA nanoparticle tracking analysis
  • eTPN Equivalent total particle number
  • the solid dosage form comprises about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 1.6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 2 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • the solid dosage form comprises about 1 x 10 14 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329 (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
  • each solid dosage form comprises about 4 x 10 11 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 1 solid dosage form e.g., comprising about 4 x 10 11 particles
  • 2 solid dosage forms e.g., each comprising about 4 x 10 11 particles
  • 3 solid dosage forms e.g., each comprising about 4 x 10 11 particles
  • 4 solid dosage forms e.g., each comprising about 4 x 10 11 particles
  • 5 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 6 solid dosage forms e.g., each comprising about 4 x 10 11 particles
  • 8 solid dosage forms e.g., each comprising about 4 x 10 11 particles
  • 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • each solid dosage form comprises about 4 x 10 12 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 1 solid dosage form e.g., comprising about 4 x 10 12 particles
  • 2 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 3 solid dosage forms e.g., each comprising about 4 x 10 12 particles
  • 4 solid dosage forms e.g., each comprising about 4 x 10 12 particles
  • 5 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 6 solid dosage forms e.g., each comprising about 4 x 10 12 particles
  • 8 solid dosage forms e.g., each comprising about 4 x 10 12 particles
  • 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • each solid dosage form comprises about 6 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 1 solid dosage form e.g., comprising about 6 x 10 13 particles
  • 2 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 3 solid dosage forms e.g., each comprising about 6 x 10 13 particles
  • 4 solid dosage forms e.g., each comprising about 6 x 10 13 particles
  • 5 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 6 solid dosage forms e.g., each comprising about 6 x 10 13 particles
  • 8 solid dosage forms e.g., each comprising about 6 x 10 13 particles
  • 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • each solid dosage form comprises about 8 x 10 13 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis) or by eTPN (equivalent total particle number), as described herein) of EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 1 solid dosage form e.g., comprising about 8 x 10 13 particles
  • 2 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 3 solid dosage forms e.g., each comprising about 8 x 10 13 particles
  • 4 solid dosage forms e.g., each comprising about 8 x 10 13 particles
  • 5 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 6 solid dosage forms are administered, e.g., once or twice daily to a subject.
  • 8 solid dosage forms e.g., each comprising about 8 x 10 13
  • 10 solid dosage forms e.g., each comprising about 8 x 10 13 particles
  • Gamma-irradiation Powders (e.g., of EVs from Prevotella histicola bacteria) can be gamma-irradiated at 17.5 kGy radiation unit at ambient temperature.
  • Frozen biomasses e.g., of EVs from Prevotella histicola bacteria
  • the therapeutic compositions allow, e.g., for oral administration of a therapeutic agent (e.g., pharmaceutical agent) contained therein.
  • the therapeutic compositions can be used in the treatment and/or prevention of inflammation (e.g., Th1, Th2, or Th17 inflammation) (e.g., inflammation associated with psoriasis or atopic dermatitis or psoriatic arthritis).
  • the therapeutic compositions (such as the solid dosage forms) described herein can be used in the treatment and/or prevention of disease (for example, an immune disorder (e.g., an autoimmune disease, an inflammatory disease, an allergy), a dysbiosis, or a metabolic disease).
  • disease for example, an immune disorder (e.g., an autoimmune disease, an inflammatory disease, an allergy), a dysbiosis, or a metabolic disease).
  • the therapeutic compositions (such as the solid dosage forms) described herein can be used either alone or in combination with an additional therapeutic.
  • the therapeutic compositions (such as the solid dosage forms) described herein can be used in the treatment and/or prevention of inflammation, autoimmunity, a metabolic condition, or a dysbiosis.
  • the therapeutic compositions (such as the solid dosage forms) described herein can be used in the treatment and/or prevention of bacterial septic shock, cytokine storm and/or viral infection (such as a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection).
  • the therapeutic compositions (such as the solid dosage forms) described herein can be used in the treatment and/or prevention of an inflammatory disease.
  • the therapeutic compositions (such as the solid dosage forms) described herein can be used in the treatment and/or prevention of psoriasis.
  • the therapeutic compositions (such as the solid dosage forms) described herein can be used in the treatment and/or prevention of atopic dermatitis.
  • the therapeutic compositions (such as the solid dosage forms) described herein can be used in the treatment and/or prevention of psoriatic arthritis.
  • the therapeutic compositions (such as the solid dosage forms) described herein can be used in the treatment and/or prevention of an autoimmune disease.
  • the therapeutic compositions (such as the solid dosage forms) described herein can be used in the treatment and/or prevention of a metabolic disease.
  • the therapeutic compositions (such as the solid dosage forms) described herein can be used in the treatment and/or prevention of a dysbiosis.
  • the therapeutic compositions (such as the solid dosage forms) described herein can be used to decrease inflammatory cytokine expression (e.g., decreased TNF ⁇ expression levels).
  • the therapeutic compositions (such as the solid dosage forms) described herein can be used in the treatment and/or prevention of bacterial septic shock.
  • the therapeutic compositions (such as the solid dosage forms) described herein can be used in the treatment and/or prevention of a viral infection.
  • compositions such as the solid dosage forms (e.g., for oral administration) (e.g., for pharmaceutical use) comprising a theraeptuic agent (e.g., pharmaceutical agent) (e.g., a therapeutically effective amount thereof), wherein the theraeptuic agent (e.g., pharmaceutical agent) comprises Prevotella histicola EVs, and wherein the solid dosage form further comprises the disclosed components are described herein.
  • the methods and administered therapeutic composition (such as a solid dosage form) described herein allow, e.g., for oral administration of a therapetuic agent (e.g., pharmaceutical agent) contained therein.
  • the therapeutic composition (such as a solid dosage form) can be administered to a subject is a fed or fasting state.
  • the therapeutic composition (such as a solid dosage form) can be administered, e.g., on an empty stomach (e.g., one hour before eating or two hours after eating).
  • the therapeutic composition (such as a solid dosage form) can be administered one hour before eating.
  • the therapeutic composition (such as a solid dosage form) can be administered two hours after eating.
  • the therapeutic composition (such as a solid dosage form) can be administered one hour before drinking (e.g., drinking an acidic drink).
  • the therapeutic composition (such as a solid dosage form) can be administered one hour after drinking (e.g., drinking an acidic drink).
  • a therapeutic composition for use in the treatment and/or prevention of inflammation (e.g., Th1, Th2, or Th17 inflammation) (e.g., inflammation associated with psoriasis or atopic dermatitis or psoriatic arthritis) is provided herein.
  • inflammation e.g., Th1, Th2, or Th17 inflammation
  • a therapeutic composition for use in the treatment and/or prevention of disease (for example, an immune disorder (e.g., an autoimmune disease, an inflammatory disease, an allergy), a dysbiosis, or a metabolic disease) is provided herein.
  • a therapeutic composition for use in the treatment and/or prevention of inflammation, autoimmunity, a metabolic condition, or a dysbiosis is provided herein.
  • a therapeutic composition for use in the treatment and/or prevention of bacterial septic shock, cytokine storm and/or viral infection (such as a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection) is provided herein.
  • a therapeutic composition for the preparation of a medicament for the treatment and/or prevention of inflammation (e.g., Th1, Th2, or Th17 inflammation) (e.g., inflammation associated with psoriasis or atopic dermatitis or psoriatic arthritis) is provided herein.
  • inflammation e.g., Th1, Th2, or Th17 inflammation
  • a therapeutic composition for the preparation of a medicament for the treatment and/or prevention of disease (for example, an immune disorder (e.g., an autoimmune disease, an inflammatory disease, an allergy), a dysbiosis, or a metabolic disease) is provided herein.
  • a therapeutic composition for the preparation of a medicament for the treatment and/or prevention of inflammation, autoimmunity, a metabolic condition, or a dysbiosis is provided herein.
  • a therapeutic composition for the preparation of a medicament for the treatment and/or prevention of bacterial septic shock, cytokine storm and/or viral infection (such as a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection) is provided herein.
  • a therapeutic composition for the preparation of a medicament for decreasing inflammatory cytokine expression (e.g., decreased TNF ⁇ (also referred to as TNF or TNF-a or TNF-alpha) expression levels) is provided herein.
  • Additional Therapeutic [435]
  • the methods provided herein include the administration to a subject of a therapeutic composition described herein either alone or in combination with an additional therapeutic.
  • the additional therapeutic is an immunosuppressant or a steroid.
  • the additional therapeutic is a topical treatment.
  • the topical treatment comprises a topical corticosteroid (TCS), a topical calcineurin inhibitor (TCI) (Katoh, 2019), a topical Janus Kinase (JAK) or a Phosphodiesterase 4 (PDE) inhibitor (Bieber, 2021).
  • TCS topical corticosteroid
  • TCI topical calcineurin inhibitor
  • JAK topical Janus Kinase
  • PDE Phosphodiesterase 4
  • the methods provided herein include use of an emollient cream, gel or ointment as an additional therapeutic.
  • a bland additive-free, sodium lauryl sulfate (SLS)-free, and fragrance-free emollient cream, gel or ointment is used.
  • the emollient cream, gel or ointment is used daily (e.g., twice daily) (or more, as needed) for at least 14 consecutive days immediately prior use of the Prevotella histicola EVs. In some embodiments, the emollient cream, gel or ointment is used daily (e.g., twice daily) (or more, as needed) while the Prevotella histicola EVs are used.
  • the emollient cream, gel or ointment is used daily (e.g., twice daily) (or more, as needed) for at least 14 consecutive days immediately prior use of the Prevotella histicola EVs and is used daily (e.g., twice daily) (or more, as needed) while the Prevotella histicola EVs are used.
  • the Prevotella histicola EVs are administered to the subject before the additional therapeutic is administered (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours before or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days before).
  • the Prevotella histicola EVs are administered to the subject after the additional therapeutic is administered (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours after or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days after).
  • the Prevotella histicola EVs and the additional therapeutic are administered to the subject simultaneously or nearly simultaneously (e.g., administrations occur within an hour of each other).
  • the subject is administered an antibiotic before the Prevotella histicola EVs are administered to the subject (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours before or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days before).
  • an antibiotic e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours before or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days before.
  • the subject is administered an antibiotic after the Prevotella histicola EVs are administered to the subject (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours before or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days after).
  • the Prevotella histicola EVs and the antibiotic are administered to the subject simultaneously or nearly simultaneously (e.g., administrations occur within an hour of each other).
  • antibiotics can be selected based on their bactericidal or bacteriostatic properties.
  • Bactericidal antibiotics include mechanisms of action that disrupt the cell wall (e.g., ⁇ -lactams), the cell membrane (e.g., daptomycin), or bacterial DNA (e.g., fluoroquinolones).
  • Bacteriostatic agents inhibit bacterial replication and include sulfonamides, tetracyclines, and macrolides, and act by inhibiting protein synthesis.
  • drugs can be bactericidal in certain organisms and bacteriostatic in others, knowing the target organism allows one skilled in the art to select an antibiotic with the appropriate properties.
  • bacteriostatic antibiotics inhibit the activity of bactericidal antibiotics.
  • bactericidal and bacteriostatic antibiotics are not combined.
  • Antibiotics include, but are not limited to aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidonones, penicillins, polypeptide antibiotics, quinolones, fluoroquinolone, sulfonamides, tetracyclines, and anti-mycobacterial compounds, and combinations thereof.
  • Aminoglycosides include, but are not limited to Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, and Spectinomycin.
  • Aminoglycosides are effective, e.g., against Gram-negative bacteria, such as Escherichia coli, Klebsiella, Pseudomonas aeruginosa, and Francisella tularensis, and against certain aerobic bacteria but less effective against obligate/facultative anaerobes. Aminoglycosides are believed to bind to the bacterial 30S or 50S ribosomal subunit thereby inhibiting bacterial protein synthesis.
  • Ansamycins include, but are not limited to, Geldanamycin, Herbimycin, Rifamycin, and Streptovaricin. Geldanamycin and Herbimycin are believed to inhibit or alter the function of Heat Shock Protein 90.
  • Carbacephems include, but are not limited to, Loracarbef. Carbacephems are believed to inhibit bacterial cell wall synthesis.
  • Carbapenems include, but are not limited to, Ertapenem, Doripenem, Imipenem/Cilastatin, and Meropenem. Carbapenems are bactericidal for both Gram-positive and Gram-negative bacteria as broad-spectrum antibiotics.
  • Cephalosporins include, but are not limited to, Cefadroxil, Cefazolin, Cefalotin, Cefalothin, Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline fosamil, and Ceftobiprole.
  • Cephalosporins are effective, e.g., against Gram-negative bacteria and against Gram-positive bacteria, including Pseudomonas, certain Cephalosporins are effective against methicillin- resistant Staphylococcus aureus (MRSA). Cephalosporins are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.
  • Glycopeptides include, but are not limited to, Teicoplanin, Vancomycin, and Telavancin. Glycopeptides are effective, e.g., against aerobic and anaerobic Gram-positive bacteria including MRSA and Clostridium difficile.
  • Lincosamides include, but are not limited to, Clindamycin and Lincomycin. Lincosamides are effective, e.g., against anaerobic bacteria, as well as Staphylococcus and Streptococcus. Lincosamides are believed to bind to the bacterial 50S ribosomal subunit thereby inhibiting bacterial protein synthesis.
  • Lipopeptides include, but are not limited to, Daptomycin. Lipopeptides are effective, e.g., against Gram-positive bacteria.
  • Macrolides include, but are not limited to, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, and Spiramycin. Macrolides are effective, e.g., against Streptococcus and Mycoplasma. Macrolides are believed to bind to the bacterial or 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.
  • Monobactams include, but are not limited to, Aztreonam. Monobactams are effective, e.g., against Gram-negative bacteria.
  • Nitrofurans include, but are not limited to, Furazolidone and Nitrofurantoin.
  • Oxazolidonones include, but are not limited to, Linezolid, Posizolid, Radezolid, and Torezolid. Oxazolidonones are believed to be protein synthesis inhibitors.
  • Penicillins include, but are not limited to, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin and Ticarcillin.
  • Penicillins are effective, e.g., against Gram-positive bacteria, facultative anaerobes, e.g., Streptococcus, Borrelia, and Treponema. Penicillins are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.
  • Penicillin combinations include, but are not limited to, amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, and ticarcillin/clavulanate.
  • Polypeptide antibiotics include, but are not limited to, Bacitracin, Colistin, and Polymyxin B and E. Polypeptide antibiotics are effective, e.g., against Gram-negative bacteria. Certain polypeptide antibiotics are believed to inhibit isoprenyl pyrophosphate involved in synthesis of the peptidoglycan layer of bacterial cell walls, while others destabilize the bacterial outer membrane by displacing bacterial counter-ions.
  • Quinolones and Fluoroquinolone include, but are not limited to, Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, and Temafloxacin.
  • Quinolones/Fluoroquinolone are effective, e.g., against Streptococcus and Neisseria.
  • Sulfonamides include, but are not limited to, Mafenide, Sulfacetamide, Sulfadiazine, Silver sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole (Co-trimoxazole), and Sulfonamidochrysoidine.
  • Tetracyclines include, but are not limited to, Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, and Tetracycline. Tetracyclines are effective, e.g., against Gram-negative bacteria. Tetracyclines are believed to bind to the bacterial 30S ribosomal subunit thereby inhibiting bacterial protein synthesis.
  • Anti-mycobacterial compounds include, but are not limited to, Clofazimine, Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide, Rifampicin, Rifabutin, Rifapentine, and Streptomycin.
  • Suitable antibiotics also include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin, tigecycline, tinidazole, trimethoprim amoxicillin/clavulanate, ampicillin/sulbactam, amphomycin ristocetin, azithromycin, bacitracin, buforin II, carbomycin, cecropin Pl, clarithromycin, erythromycins, furazolidone, fusidic acid, Na fusidate, gramicidin, imipenem, indolicidin, josamycin, magainan II, metronidazole, nitroimidazoles, mikamycin, mutacin B-Ny266, mutacin B-JHl 140, mutacin J-T8, nisin, nisin A, novobiocin, oleand
  • the additional therapeutic is an immunosuppressive agent, a DMARD, a pain-control drug, a steroid, a non-steroidal anti-inflammatory drug (NSAID), or a cytokine antagonist, and combinations thereof.
  • a DMARD a pain-control drug
  • a steroid a steroid
  • NSAID non-steroidal anti-inflammatory drug
  • cytokine antagonist a cytokine antagonist
  • Representative agents include, but are not limited to, cyclosporin, retinoids, corticosteroids, propionic acid derivative, acetic acid derivative, enolic acid derivatives, fenamic acid derivatives, Cox-2 inhibitors, lumiracoxib, ibuprophen, cholin magnesium salicylate, fenoprofen, salsalate, difunisal, tolmetin, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac, ketorolac, nabumetone, naproxen, valdecoxib, etoricoxib, MK0966; rofecoxib, acetominophen, Celecoxib, Diclofenac, tramadol, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, mefanamic acid, meclofenamic acid
  • the additional therapeutic is apremilast, etanercept, infliximab, adalimumab, ustekinumab, dupilumab, or secukinumab.
  • the additional therapeutic is a PDE4 inhibitor. In some embodiments, the additional therapeutic is apremilast.
  • the additional therapeutic is a JAK1 inhibitor. In some embodiments, the additional therapeutic is upadacitinib. In some embodiments, the additional therapeutic is abrocitinib.
  • the additional therapeutic is a tumor necrosis factor alpha (TNFa) antagonist.
  • the additional therapeutic is an antibody that targets TNFa. In some embodiments, the additional therapeutic is a TNF alpha receptor antagonist. [465] In some embodiments, the additional therapeutic is an interleukin 17 (IL-17) antagonist. In some embodiments, the additional therapeutic is an antibody that targets IL-17. [466] In some embodiments, the additional therapeutic is an interleukin 23 (IL-23) antagonist. In some embodiments, the additional therapeutic is an antibody that targets IL-23. In some embodiments, the additional therapeutic is risankizumab. [467] In some embodiments, the additional therapeutic is an interleukin 4 (IL-4) antagonist. [468] In some embodiments, the additional therapeutic is an interleukin 13 (IL-13) antagonist.
  • the additional therapeutic targets IL-4 and IL-13. In some embodiments, the additional therapeutic is an antibody that targets IL-4 and IL-13. In some embodiments, the additional therapeutic is dupilumab. [470] In some embodiments, the additional therapeutic is an agent used to treat psoriatic arthritis. [471] In some embodiments, the additional therapeutic is an agent used to treat psoriasis.
  • the additional therapeutic is an anti- interleukin 8 (IL-8) monoclonal antibody; adalimumab-afzb; adalimumab; olopatadine hydrochloride; etanercept ; itolizumab; amcinonide; infliximab-axxq; infliximab; betamethasone valerate; bimekizumab; tacalcitol; halobetasol propionate; certolizumab pegol; clobetasol propionate; secukinumab; adalimumab-adbm; methylprednisolone; betamethasone dipropionate / salicylic acid; calcipotriene; halobetasol propionate / tazarotene; netakimab; mometasone furoate; calcipotriol hydrate; betamethasone di
  • the additional therapeutic is roflumilast; bimekizumab; deucravacitinib; tapinarof; spesolimab; ustekinumab; imsidolimab; pegcantratinib; sonelokimab; cedirogant; tepilamide fumarate; izokibep; aminopterin; bermekimab; BI 730357; BMX-010; JTE-451; orticumab; hypericin; vunakizumab; SNA-125; AUR-101; AST-005; AZD-0284; CC- 90006; DMT310; ESK-001; GLPG3667; GSK2831781; GSK2982772; LY3316531; LY3462817; ME3183; NKTR-358; PBI-100; S011806; SB414; SFA002; brepocitini
  • the additional therapeutic is an agent used to treat atopic dermatitis.
  • the additional therapeutic is tralokinumab; methylprednisolone aceponate; atopiclair; bilastine; abrocitinib; clocortolone pivalate; delgocitinib; methylprednisolone; desonide gel; dupilumab; pimecrolimus; crisaborole; hydrocortisone-17- butyrate; difamilast; baricitinib; hypericin; vunakizumab; SNA-125; AUR-101; AST-005; AZD- 0284; CC-90006; DMT310; ESK-001; GLPG3667; GSK2831781; GSK2982772; LY3316531; LY3462817; ME3183; NKTR-358; PBI-100; S011806; SB
  • the additional therapeutic is baricitinib; lebrikizumab; nemolizumab; tapinarof; tradipitant; roflumilast; gusacitinib; CBP-201; DS107G; telazorlimab; niclosamide; B-244; AMG 451; ATI-1777; etrasimod; difamilast; amlitelimab; bermekimab; spesolimab; BMS-986166; BMX-010; branebrutinib; cendakimab; FB825; FMX114; LEO- 152020; LNK01001; LY3375880; MBM-02; difelikefalin; brepocitinib; Q301; SAR444727; SB011; SCD-044; AMTX-100; ARQ-252; LUT014; MSB-0221; SNA-125; RPT193
  • the additional therapeutic is an immunosuppressive agent.
  • immunosuppressive agents include, but are not limited to, corticosteroids, mesalazine, mesalamine, sulfasalazine, sulfasalazine derivatives, immunosuppressive drugs, cyclosporin A, mercaptopurine, azathiopurine, prednisone, methotrexate, antihistamines, glucocorticoids, epinephrine, theophylline, cromolyn sodium, anti-leukotrienes, anti-cholinergic drugs for rhinitis, TLR antagonists, inflammasome inhibitors, anti-cholinergic decongestants, mast-cell stabilizers, monoclonal anti-IgE antibodies, vaccines (e.g., vaccines used for vaccination where the amount of an allergen is gradually increased), cytokine inhibitors, such as anti-IL-6 antibodies, TNF inhibitor
  • the additional therapeutic is an oral or injectable corticosteroid, methotrexate, azathioprine, cyclosporine, mycophenolate mofetil, a JAK inhibitor, tacrolimus, and/or leukotriene inhibitor.
  • the additional therapeutic is a topical corticosteroid, a topical calcineurin inhibitor (e.g., tacrolimus or pimecrolimus), or a topical PDE-4 inhibitor (e.g., crisaborole).
  • Administration [480] In some embodiments, the therapeutic composition is administered orally. In some embodiments, the administration to the subject once daily. In some embodiments, the administration to the subject twice daily.
  • the therapeutic composition is administered in 2 or more doses (e.g., 3 or more, 4 or more or 5 or more doses).
  • the administration to the subject of the two or more doses are separated by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days.
  • the therapeutic composition is administered once daily.
  • the therapeutic composition is administered once daily for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks. In some embodiments, the therapeutic composition is administered once daily for 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks. [482] In some embodiments, the therapeutic composition is administered twice daily. In some embodiments, the therapeutic composition is administered twice daily for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks. In some embodiments, the therapeutic composition is administered twice daily for 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks. [483] In some embodiments, the therapeutic composition is formulated as a tablet.
  • the therapeutic composition is formulated as a capsule. In some embodiments, the therapeutic composition comprises an enteric coating or micro encapsulation.
  • the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal (e.g., a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee). [485] In some aspects, provided are therapeutic compositions for administration to subjects.
  • the therapeutic compositions are combined with additional active and/or inactive materials in order to produce a final product, which may be in single dosage unit or in a multi-dose format.
  • the therapeutic composition is combined with an adjuvant such as an immuno-adjuvant (e.g., STING agonists, TLR agonists, NOD agonists).
  • an adjuvant such as an immuno-adjuvant (e.g., STING agonists, TLR agonists, NOD agonists).
  • the therapeutic composition is administered in conjunction with the administration of an additional therapeutic.
  • the therapeutic composition comprises Prevotella EVs co-formulated with the additional therapeutic.
  • the therapeutic composition is co-administered with the additional therapeutic.
  • the additional therapeutic is administered to the subject before administration of the therapeutic composition (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes before, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours before, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days before).
  • the therapeutic composition e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes before, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours before, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days before.
  • the additional therapeutic is administered to the subject after administration of the therapeutic composition (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes after, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours after, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after).
  • the same mode of delivery are used to deliver both the therapeutic composition and the additional therapeutic.
  • different modes of delivery are used to administer the therapeutic composition and the additional therapeutic.
  • the therapeutic composition is administered orally while the additional therapeutic is administered via injection (e.g., an intravenous, and/or intramuscular injection).
  • the therapeutic compositions and dosage forms (e.g., solid dosage forms) described herein can be administered in conjunction with any other conventional treatment. These treatments may be applied as necessary and/or as indicated and may occur before, concurrent with or after administration of the therapeutic compositions anddosage forms described herein.
  • the dosage regimen of an additional therapeutic can be any of a variety of methods and amounts, and can be determined by one skilled in the art according to known clinical factors.
  • dosages for any one patient can depend on many factors, including the subject's species, size, body surface area, age, sex, immunocompetence, and general health, the particular microorganism to be administered, duration and route of administration, the kind and stage of the disease, and other compounds such as drugs being administered concurrently.
  • levels can be affected by the infectivity of the microorganism, and the nature of the microorganism, as can be determined by one skilled in the art.
  • appropriate minimum dosage levels of microorganisms can be levels sufficient for the microorganism to survive, grow and replicate.
  • the dose of the of an additional therapeutic described herein may be appropriately set or adjusted in accordance with the dosage form, the route of administration, the degree or stage of a target disease, and the like.
  • the dose administered to a subject is sufficient to prevent disease (e.g., autoimmune disease, inflammatory disease, metabolic disease), or treat disease, e.g., delay its onset, ameliorate one or more symptom of the disease, lessen the severity of the disease (or a symptom thereof), or slow or stop its progression.
  • disease e.g., autoimmune disease, inflammatory disease, metabolic disease
  • treat disease e.g., delay its onset, ameliorate one or more symptom of the disease, lessen the severity of the disease (or a symptom thereof), or slow or stop its progression.
  • dosage will depend upon a variety of factors including the strength of the particular compound employed, as well as the age, species, condition, and body weight of the subject.
  • the size of the dose will also be determined by the route, timing, and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound and the desired physiological effect.
  • the dosages of an additional therapeutic used in accordance with the methods disclosed herein vary depending on the active agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
  • Separate administrations of an additional therapeutic can include any number of two or more administrations, including two, three, four, five or six administrations.
  • the methods provided herein include methods of providing to the subject one or more administrations of an additional therapeutic, where the number of administrations can be determined by monitoring the subject, and, based on the results of the monitoring, determining whether or not to provide one or more additional administrations. Deciding on whether or not to provide one or more additional administrations can be based on a variety of monitoring results.
  • the time period between administrations can be any of a variety of time periods.
  • the time period between administrations can be a function of any of a variety of factors, including monitoring steps, as described in relation to the number of administrations, the time period for a subject to mount an immune response and/or the time period for a subject to clear the bacteria from normal tissue.
  • the time period can be a function of the time period for a subject to mount an immune response; for example, the time period can be more than the time period for a subject to mount an immune response, such as more than about one week, more than about ten days, more than about two weeks, or more than about a month; in another example, the time period can be less than the time period for a subject to mount an immune response, such as less than about one week, less than about ten days, less than about two weeks, or less than about a month.
  • the time period can be a function of the time period for a subject to clear the bacteria from normal tissue; for example, the time period can be more than the time period for a subject to clear the bacteria from normal tissue, such as more than about a day, more than about two days, more than about three days, more than about five days, or more than about a week.
  • the delivery of an additional therapeutic in combination with the therapeutic composition described herein reduces the adverse effects and/or improves the efficacy of the additional therapeutic.
  • the effective dose of an additional therapeutic described herein is the amount that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, with the least toxicity to the patient.
  • the effective dosage level can be identified using the methods described herein and will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions administered, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • an effective dose of an additional therapy (such as an additional therapeutic) will be the amount which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the toxicity of an additional therapy is the level of adverse effects experienced by the subject during and following treatment.
  • Adverse events associated with additional therapy toxicity include, but are not limited to, abdominal pain, acid indigestion, acid reflux, allergic reactions, alopecia, anaphylaxis, anemia, anxiety, lack of appetite, arthralgias, asthenia, ataxia, azotemia, loss of balance, bone pain, bleeding, blood clots, low blood pressure, elevated blood pressure, difficulty breathing, bronchitis, bruising, low white blood cell count, low red blood cell count, low platelet count, cardiotoxicity, cystitis, hemorrhagic cystitis, arrhythmias, heart valve disease, cardiomyopathy, coronary artery disease, cataracts, central neurotoxicity, cognitive impairment, confusion, conjunctivitis, constipation, coughing, cramping, cystitis, deep vein thrombosis, dehydration, depression, diarrhea, dizziness, dry mouth, dry skin, dyspepsia, dyspnea, edema, electrolyte imbalance, esophagitis, fatigue
  • the methods and compositions described herein relate to the treatment or prevention of a disease or disorder associated a pathological immune response, such as an autoimmune disease, an allergic reaction and/or an inflammatory disease.
  • the disease or disorder is an inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis).
  • the disease or disorder is psoriasis (e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis).
  • the disease or disorder is atopic dermatitis (e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis).
  • the disease or disorder is psoriatic arthritis (e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis).
  • a “subject in need thereof” includes any subject that has a disease or disorder associated with a pathological immune response such as one that includes inflammation (psoriasis (e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis) or atopic dermatitis (e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis)) or psoriatic arthritis (e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis), as well as any subject with an increased likelihood of acquiring a such a disease or disorder.
  • psoriasis e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis
  • atopic dermatitis e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis
  • compositions described herein can be used, for example, as a therapeutic composition for preventing or treating (reducing, partially or completely, the adverse effects of) an autoimmune disease, such as chronic inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, muckle-wells syndrome, rheumatoid arthritis, multiple sclerosis, or Hashimoto's disease; an allergic disease, such as a food allergy, pollenosis, or asthma; an infectious disease, such as an infection with Clostridium difficile; an inflammatory disease such as a TNF-mediated inflammatory disease (e.g., an inflammatory disease of the gastrointestinal tract, such as pouchitis, a cardiovascular inflammatory condition, such as atherosclerosis, or an inflammatory lung disease, such as chronic obstructive pulmonary disease); a therapeutic composition for suppressing rejection in organ transplantation or other situations in which tissue rejection might occur; a supplement, food, or beverage for improving immune functions; or a autoimmune disease, such
  • the methods and compositions provided herein are useful for the treatment of inflammation.
  • the methods and compositions provided herein are useful for the treatment of Th1 inflammation.
  • the methods and compositions provided herein are useful for the treatment of Th2 inflammation.
  • the methods and compositions provided herein are useful for the treatment of Th17 inflammation.
  • the inflammation of any tissue and organs of the body including musculoskeletal inflammation, vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, and other inflammation, as discussed below.
  • Immune disorders of the musculoskeletal system include, but are not limited, to those conditions affecting skeletal joints, including joints of the hand, wrist, elbow, shoulder, jaw, spine, neck, hip, knew, ankle, and foot, and conditions affecting tissues connecting muscles to bones such as tendons.
  • immune disorders which may be treated with the methods and compositions described herein include, but are not limited to, arthritis (including, for example, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis), tendonitis, synovitis, tenosynovitis, bursitis, fibrositis (fibromyalgia), epicondylitis, myositis, and osteitis (including, for example, Paget's disease, osteitis pubis, and osteitis fibrosa cystic).
  • arthritis including, for example, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis
  • tendonitis synovitis, ten
  • Ocular immune disorders refer to an immune disorder that affects any structure of the eye, including the eye lids.
  • ocular immune disorders which may be treated with the methods and compositions described herein include, but are not limited to, blepharitis, blepharochalasis, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis.
  • Examples of nervous system immune disorders which may be treated with the methods and compositions described herein include, but are not limited to, encephalitis, Guillain-Barre syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis and schizophrenia.
  • Examples of inflammation of the vasculature or lymphatic system which may be treated with the methods and compositions described herein include, but are not limited to, arthrosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.
  • Examples of digestive system immune disorders which may be treated with the methods and compositions described herein include, but are not limited to, cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease, ileitis, and proctitis.
  • Inflammatory bowel diseases include, for example, certain art-recognized forms of a group of related conditions.
  • Crohn's disease regional bowel disease, e.g., inactive and active forms
  • ulcerative colitis e.g., inactive and active forms
  • the inflammatory bowel disease encompasses irritable bowel syndrome, microscopic colitis, lymphocytic- plasmocytic enteritis, coeliac disease, collagenous colitis, lymphocytic colitis and eosinophilic enterocolitis.
  • Other less common forms of IBD include indeterminate colitis, pseudomembranous colitis (necrotizing colitis), ischemic inflammatory bowel disease, Behcet’s disease, sarcoidosis, scleroderma, IBD-associated dysplasia, dysplasia associated masses or lesions, and primary sclerosing cholangitis.
  • reproductive system immune disorders which may be treated with the methods and compositions described herein include, but are not limited to, cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, tubo- ovarian abscess, urethritis, vaginitis, vulvitis, and vulvodynia.
  • the methods and compositions described herein may be used to treat conditions (such as autoimmune conditions) having an inflammatory component.
  • Such conditions include, but are not limited to, acute disseminated alopecia universalise, Behcet's disease, Chagas' disease, chronic fatigue syndrome, dysautonomia, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, diabetes mellitus type 1, giant cell arteritis, Goodpasture's syndrome, Grave's disease, Guillain-Barre syndrome, Hashimoto's disease, Henoch-Schonlein purpura, Kawasaki's disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, Muckle-Wells syndrome, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome, optic neuritis, Ord’s thyroiditis, pemphi
  • T-cell mediated hypersensitivity diseases having an inflammatory component.
  • Such conditions include, but are not limited to, contact hypersensitivity, contact dermatitis (including that due to poison ivy), uticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis, house dust mite allergy) and gluten-sensitive enteropathy (Celiac disease).
  • immune disorders which may be treated with the methods and compositions include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, ulceris, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, pneumonitis, prostatitis, pyelonephritis, and stomatitis, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts, and heart valve xenografts, serum sickness, and graft vs
  • transplant rejection
  • Exemplary treatments include treatment of transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosis, psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease, and inflammation accompanying infectious conditions (e.g., sepsis).
  • rheumatoid arthritis rheumatoid arthritis
  • psoriatic arthritis multiple sclerosis
  • Type 1 diabetes asthma
  • asthma inflammatory bowel disease
  • systemic lupus erythematosis systemic lupus erythematosis
  • psoriasis psoriatic arthritis
  • chronic obstructive pulmonary disease e.g., sepsis
  • a therapeutic composition comprising Prevotella histicola EVs, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) for use in treating psoriasis is described herein.
  • the psoriasis comprises mild to moderate psoriasis.
  • the psoriasis comprises mild, moderate, or severe psoriasis.
  • a therapeutic composition for the preparation of a medicament for treating psoriasis e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis
  • psoriasis e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis
  • a therapeutic composition for the preparation of a medicament for treating psoriasis e.g., mild to moderate psoriasis, or mild, moderate, or severe psoriasis
  • the therapeutic composition comprises Prevotella histicola EVs, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) is described herein.
  • therapeutic compositions for use of treating psoriatic arthritis are disclosed.
  • a therapeutic composition comprising Prevotella histicola EVs, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) for use in treating psoriatic arthritis is described herein.
  • the psoriatic arthritis comprises mild to moderate psoriatic arthritis. In some embodiments, the psoriatic arthritis comprises mild, moderate, or severe psoriatic arthritis.
  • a therapeutic composition for the preparation of a medicament for treating psoriatic arthritis e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis
  • use of a therapeutic composition for the preparation of a medicament for treating psoriatic arthritis e.g., mild to moderate psoriatic arthritis, or mild, moderate, or severe psoriatic arthritis
  • the therapeutic composition comprises Prevotella histicola EVs, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) is described herein.
  • therapeutic compositions for use of treating atopic dermatitis are disclosed.
  • a therapeutic composition comprising Prevotella histicola EVs, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) for use in treating atopic dermatitis is described herein.
  • the atopic dermatitis comprises mild to moderate atopic dermatitis.
  • the atopic dermatitis comprises mild, moderate, or severe atopic dermatitis.
  • a therapeutic composition for the preparation of a medicament for treating atopic dermatitis e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis.
  • a therapeutic composition for the preparation of a medicament for treating atopic dermatitis wherein the therapeutic composition comprises Prevotella histicola EVs, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) is described herein.
  • atopic dermatitis e.g., mild to moderate atopic dermatitis, or mild, moderate, or severe atopic dermatitis
  • the therapeutic composition comprises Prevotella histicola EVs, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) is described herein.
  • the Prevotella histicola EVs are from a strain comprising at least 99.9% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella histicola EVs are from the Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
  • the therapeutic composition is administered orally. In some embodiments, the therapeutic composition is formulated as a tablet. In some embodiments, the therapeutic composition is formulated as a capsule. [515] In some embodiments, the therapeutic composition is administered once daily.
  • the therapeutic composition is administered once daily for 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks. In some embodiments, the therapeutic composition is administered once daily for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks. In some embodiments, the psoriasis is mild to moderate psoriasis. In some embodiments, the atopic dermatitis is mild, moderate, or severe atopic dermatitis. [516] In some embodiments, the therapeutic composition is administered twice daily. In some embodiments, the therapeutic composition is administered twice daily for 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the therapeutic composition is administered twice daily for at least 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 weeks.
  • the psoriasis is mild to moderate psoriasis.
  • the atopic dermatitis is mild, moderate, or severe atopic dermatitis.
  • the methods and compositions described herein relate to the treatment or prevention of a metabolic disease or disorder a, such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, fatty liver, non- alcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, ketoacidosis, hypoglycemia, thrombotic disorders, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), Nonalcoholic Steatohepatitis (NASH) or a related disease.
  • a metabolic disease or disorder a such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, fatty liver, non- alcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, ketoacidosis, hypoglycemia, thrombotic disorders, dyslipidemia, non-alcoholic
  • the related disease is cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, or edema.
  • the methods and therapeutic compositions described herein relate to the treatment of Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH).
  • NAFLD Nonalcoholic Fatty Liver Disease
  • NASH Nonalcoholic Steatohepatitis
  • the methods and compositions described herein can be used to treat any subject in need thereof.
  • a “subject in need thereof” includes any subject that has a metabolic disease or disorder, as well as any subject with an increased likelihood of acquiring a such a disease or disorder.
  • compositions described herein can be used, for example, for preventing or treating (reducing, partially or completely, the adverse effects of) a metabolic disease, such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, fatty liver, non-alcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, ketoacidosis, hypoglycemia, thrombotic disorders, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), Nonalcoholic Steatohepatitis (NASH), or a related disease.
  • a metabolic disease such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, fatty liver, non-alcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, ketoacidosis, hypoglycemia, thrombotic disorders, dyslipidemia
  • the related disease is cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, or edema.
  • Other Diseases and Disorders [520]
  • the methods and compositions described herein relate to the treatment of liver diseases.
  • Such diseases include, but are not limited to, Alagille Syndrome, Alcohol-Related Liver Disease, Alpha-1 Antitrypsin Deficiency, Autoimmune Hepatitis, Benign Liver Tumors, Biliary Atresia, Cirrhosis, Galactosemia, Gilbert Syndrome, Hemochromatosis, Hepatitis A, Hepatitis B, Hepatitis C, Hepatic Encephalopathy, Intrahepatic Cholestasis of Pregnancy (ICP), Lysosomal Acid Lipase Deficiency (LAL-D), Liver Cysts, Liver Cancer, Newborn Jaundice, Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC), Reye Syndrome, Type I Glycogen Storage Disease, and Wilson Disease.
  • ICP Pregnancy
  • LAL-D Lysosomal Acid Lipase Deficiency
  • PBC Primary Biliary Cholangitis
  • PSC Primary S
  • the methods and compositions described herein may be used to treat neurodegenerative and neurological diseases.
  • the neurodegenerative and/or neurological disease is Parkinson’s disease, Alzheimer’s disease, prion disease, Huntington’s disease, motor neuron diseases (MND), spinocerebellar ataxia, spinal muscular atrophy, dystonia, idiopathicintracranial hypertension, epilepsy, nervous system disease, central nervous system disease, movement disorders, multiple sclerosis, encephalopathy, peripheral neuropathy or post- operative cognitive dysfunction.
  • gut microbiota also called the “gut microbiota”
  • gut microbiota can have a significant impact on an individual’s health through microbial activity and influence (local and/or distal) on immune and other cells of the host
  • a healthy host-gut microbiome homeostasis is sometimes referred to as a “eubiosis” or “normobiosis,” whereas a detrimental change in the host microbiome composition and/or its diversity can lead to an unhealthy imbalance in the microbiome, or a “dysbiosis” (Hooks and O’Malley. Dysbiosis and its discontents. American Society for Microbiology. Oct 2017. Vol.8. Issue 5. mBio 8:e01492-17. doi.org/10.1128/mBio.01492-17).
  • Dysbiosis, and associated local or distal host inflammatory or immune effects may occur where microbiome homeostasis is lost or diminished, resulting in: increased susceptibility to pathogens; altered host bacterial metabolic activity; induction of host proinflammatory activity and/or reduction of host anti-inflammatory activity.
  • Such effects are mediated in part by interactions between host immune cells (e.g., T cells, dendritic cells, mast cells, NK cells, intestinal epithelial lymphocytes (IEC), macrophages and phagocytes) and cytokines, and other substances released by such cells and other host cells.
  • host immune cells e.g., T cells, dendritic cells, mast cells, NK cells, intestinal epithelial lymphocytes (IEC), macrophages and phagocytes
  • a dysbiosis may occur within the gastrointestinal tract (a “gastrointestinal dysbiosis” or “gut dysbiosis”) or may occur outside the lumen of the gastrointestinal tract (a “distal dysbiosis”).
  • Gastrointestinal dysbiosis is often associated with a reduction in integrity of the intestinal epithelial barrier, reduced tight junction integrity and increased intestinal permeability.
  • Citi, S. Intestinal Barriers protect against disease, Science 359:1098-99 (2016); Srinivasan et al., TEER measurement techniques for in vitro barrier model systems. J. Lab. Autom. 20:107-126 (2015).
  • a gastrointestinal dysbiosis can have physiological and immune effects within and outside the gastrointestinal tract.
  • dysbiosis has been associated with a wide variety of diseases and conditions including: infection, cancer, autoimmune disorders (e.g., systemic lupus erythematosus (SLE)) or inflammatory disorders (e.g., functional gastrointestinal disorders such as inflammatory bowel disease (IBD), ulcerative colitis, and Crohn’s disease), neuroinflammatory diseases (e.g., multiple sclerosis), transplant disorders (e.g., graft-versus-host disease), fatty liver disease, type I diabetes, rheumatoid arthritis, Sjögren’s syndrome, celiac disease, cystic fibrosis, chronic obstructive pulmonary disorder (COPD), and other diseases and conditions associated with immune dysfunction.
  • autoimmune disorders e.g., systemic lupus erythematosus (SLE)
  • inflammatory disorders e.g., functional gastrointestinal disorders such as inflammatory bowel disease (IBD), ulcerative colitis, and Crohn’s disease
  • neuroinflammatory diseases e.g
  • Exemplary therapeutic compositions disclosed herein can treat a dysbiosis and its effects by modifying the immune activity present at the site of dysbiosis.
  • compositions can modify a dysbiosis via effects on host immune cells, resulting in, e.g., an increase in secretion of anti-inflammatory cytokines and/or a decrease in secretion of pro- inflammatory cytokines, reducing inflammation in the subject recipient or via changes in metabolite production.
  • exemplary therapeutic compositions disclosed herein that are useful for treatment of disorders associated with a dysbiosis contain one or more types of immunomodulatory EVs (e.g., anti-inflammatory EVs).
  • immunomodulatory EVs e.g., anti-inflammatory EVs
  • compositions disclosed herein that are useful for treatment of disorders associated with a dysbiosis contain a population of immunomodulatory EVs of a single bacterial species (e.g., a single strain) (e.g., anti-inflammatory EVs). Such compositions are capable of affecting the recipient host’s immune function, in the gastrointestinal tract, and /or a systemic effect at distal sites outside the subject’s gastrointestinal tract.
  • therapeutic compositions containing an isolated population of immunomodulatory EVs e.g., anti-inflammatory Evs
  • the dysbiosis may be a gastrointestinal tract dysbiosis or a distal dysbiosis.
  • therapeutic compositions provided herein can treat a gastrointestinal dysbiosis and one or more of its effects on host immune cells, resulting in an increase in secretion of anti-inflammatory cytokines and/or a decrease in secretion of pro- inflammatory cytokines, reducing inflammation in the subject recipient.
  • the therapeutic compositions can treat a gastrointestinal dysbiosis and one or more of its effects by modulating the recipient immune response via cellular and cytokine modulation to reduce gut permeability by increasing the integrity of the intestinal epithelial barrier.
  • the therapeutic compositions can treat a distal dysbiosis and one or more of its effects by modulating the recipient immune response at the site of dysbiosis via modulation of host immune cells.
  • Other exemplary therapeutic compositions are useful for treatment of disorders associated with a dysbiosis, which compositions contain one or more types of EVs capable of altering the relative proportions of host immune cell subpopulations, e.g., subpopulations of T cells, immune lymphoid cells, dendritic cells, NK cells and other immune cells, or the function thereof, in the recipient.
  • compositions are useful for treatment of disorders associated with a dysbiosis, which compositions contain a population of immunomodulatory bacteria of a single bacterial species e.g., a single strain) capable of altering the relative proportions of immune cell subpopulations, e.g., T cell subpopulations, immune lymphoid cells, NK cells and other immune cells, or the function thereof, in the recipient subject.
  • a population of immunomodulatory bacteria of a single bacterial species e.g., a single strain
  • immune cell subpopulations e.g., T cell subpopulations, immune lymphoid cells, NK cells and other immune cells, or the function thereof, in the recipient subject.
  • the therapeutic composition can contain one or more types of immunomodulatory EVs or a population of immunomodulatory EVs of a single bacterial species (e.g., a single strain).
  • a single bacterial species e.g., a single strain.
  • methods of treating a distal dysbiosis and one or more of its effects by orally administering to a subject in need thereof a therapeutic composition which alters the subject’s immune response outside the gastrointestinal tract.
  • the therapeutic composition can contain one or more types of immunomodulatory EVs or a population of immunomodulatory EVs of a single bacterial species (e.g., a single strain).
  • therapeutic compositions useful for treatment of disorders associated with a dysbiosis stimulate secretion of one or more anti-inflammatory cytokines by host immune cells.
  • Anti-inflammatory cytokines include, but are not limited to, IL-10, IL-13, IL- 9, IL-4, IL-5, TGF ⁇ , and combinations thereof.
  • therapeutic compositions useful for treatment of disorders associated with a dysbiosis that decrease (e.g., inhibit) secretion of one or more pro-inflammatory cytokines by host immune cells.
  • Pro- inflammatory cytokines include, but are not limited to, IFN ⁇ , IL-12p70, IL-1 ⁇ , IL-6, IL-8, MCP1, MIP1 ⁇ , MIP1 ⁇ , TNF ⁇ , and combinations thereof. Other exemplary cytokines are known in the art and are described herein.
  • the provided herein is a method of treating or preventing a disorder associated with a dysbiosis in a subject in need thereof, comprising administering (e.g., orally administering) to the subject a therapeutic composition in the form of a medical food comprising EVs an amount sufficient to alter the microbiome at a site of the dysbiosis, such that the disorder associated with the dysbiosis is treated.
  • a therapeutic composition provided herein in the form of a medical food may be used to prevent or delay the onset of a dysbiosis in a subject at risk for developing a dysbiosis.
  • Infection [540] Inflammation can be a protective response to harmful stimuli, such as invading pathogens, damaged cells, toxic compounds, or cancerous cells. However, excessive inflammatory responses to such stimuli can result in serious adverse effects, including tissue damage and even death.
  • IL-8 interleukin-8
  • IL-6 interleukin-6
  • IL-1 beta interleukin-1 beta
  • TNF ⁇ tumor necrosis factor alpha
  • release of inflammatory cytokines has been associated with disease severity resulting from infection by a number of viruses, including infection by coronaviruses (e.g., SARS-CoV-2, the virus that causes Coronavirus Disease 2019 (COVID-19)), influenza viruses, and respiratory syncytial viruses.
  • coronaviruses e.g., SARS-CoV-2, the virus that causes Coronavirus Disease 2019 (COVID-19)
  • influenza viruses e.g., influenza viruses, and respiratory syncytial viruses.
  • the methods and compositions described herein relate to the treatment or prevention of bacterial septic shock, cytokine storm and/or viral infection.
  • the methods and compositions described herein relate to the treatment or prevention of a viral infection such as a respiratory viral infection, such as a coronavirus infection (e.g., a MERS (Middle East Respiratory Syndrome) infection, a severe acute respiratory syndrome (SARS) infection, such as a SARS-CoV-2 infection), an influenza infection, and/or a respiratory syncytial virus infection.
  • a respiratory viral infection such as a coronavirus infection (e.g., a MERS (Middle East Respiratory Syndrome) infection, a severe acute respiratory syndrome (SARS) infection, such as a SARS-CoV-2 infection), an influenza infection, and/or a respiratory syncytial virus infection.
  • a respiratory viral infection such as a coronavirus infection (e.g., a MERS (Middle East Respiratory Syndrome) infection,
  • the methods and therapeutic compositions (such as solid dosage forms) described herein provided herein are for the treatment of a coronavirus infection (e.g., a MERS infection, a severe acute respiratory syndrome (SARS) infection, such as a SARS-CoV-2 infection).
  • a coronavirus infection e.g., a MERS infection, a severe acute respiratory syndrome (SARS) infection, such as a SARS-CoV-2 infection.
  • SARS severe acute respiratory syndrome
  • methods and therapeutic compositions (such as solid dosage forms) for treating COVID-19 are provided herein.
  • the methods and compositions described herein relate to the treatment or prevention of a viral infection.
  • the infection is a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection.
  • the viral infection is a SARS-CoV-2 infection.
  • an additional therapy is administered to the subject.
  • the additional therapy comprises an antiviral medication.
  • the additional therapy comprises an antiviral medication such as ribavirin, neuraminidase inhibitor, protease inhibitor, recombinant interferons, antibodies, oseltamivir, zanamivir, peramivir or baloxavir marboxil.
  • the additional therapy comprises hydroxychloroquine and/or chloroquine.
  • the additional therapy comprises remdesivir.
  • the additional therapy comprises plasma from a subject who has recovered from infection by the same virus that is infecting the subject (e.g., plasma from a subject who has recovered from SARS-CoV-2 infection).
  • the additional therapy comprises an anti-inflammatory agent such as NSAIDs or anti-inflammatory steroids.
  • the additional therapy comprises dexamethasone.
  • the additional therapy comprises an antibody specific for IL-6 and/or the IL-6 receptor.
  • the additional therapy comprises tocilizumab (Actemra®).
  • the additional therapy comprises sarilumab (Kevzara®).
  • the additional therapy can comprise an anti-viral therapy.
  • the anti-viral therapy can comprise a nucleotide analog, such as remdesivir, galidesivir or clevudine; a viral RNA polymerase inhibitor such as favipiravir or galidesivir; a protease inhibitor such as ritonavir, darunavir, or danoprevir; an inhibitor of viral membrane fusion such as umifenovir; and/or anti-SARS-CoV-2 plasma.
  • the additional therapy can comprise an anti-inflammatory therapy.
  • the anti-inflammatory therapy can comprise a corticosteroid; sirolimus; anakinra; filamod; or an antibody.
  • the antibody can comprise a GMSF inhibitor, such as lenzilumab or gimsilumab; an anti-IL1beta inhibitor such as canakinumab; an IL-6 inhibitor such as tocilizumab or siltuximab; an IL-6R inhibitor such as sarilumab; and/or a CCR5 antagonist such as leronlimab.
  • the additional therapy can comprise a JAK inhibitor such as baricitinib, ruxolitinib, tofacitinib, and/or pacritinib.
  • the additional therapy can comprise a TLR7 agonist such as imiquimod or reisquimod.
  • the additional therapy can comprise a cell based therapy.
  • the cell based therapy can comprise Remestemcel- L; bone marrow stem cell therapy, such as MultiStem or Bm-Allo-MSC; mesenchymal stromal cells; and/or adipose derived mesenchymal stem cells such as AstroStem.
  • the additional therapy can comprise an ACE receptor inhibitor.
  • the additional therapy can comprise a regulator of the Sigma 1 and/or Sigma 2 receptor. EXEMPLARY EMBODIMENTS [553] 1.
  • a method of treating a condition in a subject comprising orally administering to the subject a dose of about 1 x 10 11 particles to about 1 x 10 15 particles of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria.
  • the condition comprises psoriasis, optionally wherein the psoriasis is mild, moderate, or severe psoriasis.
  • the condition comprises atopic dermatitis, optionally wherein the atopic dermatitis is mild, moderate, or severe atopic dermatitis.
  • the condition comprises psoriatic arthritis, optionally wherein the psoriatic arthritis is mild, moderate, or severe psoriatic arthritis.
  • the condition comprises an inflammatory disease.
  • the inflammatory disease is a Th1, Th2, or Th17 inflammatory disease.
  • the condition comprises an immune disorder.
  • the condition comprises an autoimmune disease.
  • the condition comprises a metabolic disease.
  • the condition comprises a dysbiosis. [563] 11.
  • the condition comprises bacterial septic shock, cytokine storm, and/or a viral infection.
  • the dose comprises about 4 x 10 12 cells to about 1 x 10 14 particles.
  • the dose comprises about 4 x 10 11 particles.
  • the dose comprises about 4 x 10 11 particles.
  • the dose comprises about 4 x 10 12 particles.
  • the dose comprises about 2 x 10 13 particles. [569] 17.
  • the method of embodiment 12, wherein the dose comprises about 8 x 10 13 particles. [570] 18. The method of embodiment 12, wherein the dose comprises about 1 x 10 14 particles. [571] 19. The method of any one of embodiments 1 to 18, wherein the dose is administered to the subject once a day. [572] 20. The method of any one of embodiments 1 to 18, wherein the dose is administered to the subject twice a day. [573] 21. The method of any one of embodiments 1 to 20, wherein the dose is formulated in one or more solid dosage forms. [574] 22. The method of embodiment 21, wherein the solid dosage form comprises about 4 x 10 11 particles per solid dosage form. [575] 23.
  • the solid dosage form comprises about 4 x 10 12 particles per solid dosage form.
  • 24 The method of embodiment 21, wherein the solid dosage form comprises about 6 x 10 13 particles per solid dosage form.
  • 25 The method of embodiment 21, wherein the solid dosage form comprises about 8 x 10 13 particles per solid dosage form.
  • 26 The method of any one of embodiments 21 to 25, wherein one solid dosage form is administered to the subject once a day.
  • 27 The method of any one of embodiments 21 to 25, wherein two solid dosage forms are administered to the subject once a day.
  • 28 The method of any one of embodiments 21 to 25, wherein three solid dosage forms are administered to the subject once a day. [581] 29.
  • a method of treating inflammation in a human subject comprising orally administering to the human subject a dose of about 1 x 10 11 particles to about 1 x 10 15 particles of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is administered to the human subject for at least 8 weeks, wherein the dose is formulated in one or more solid dosage forms.
  • the dose is administered in combination with an additional therapeutic.
  • the dose comprises about 1x 10 11 particles to about 1 x 10 14 particles.
  • the dose comprises about 4 x 10 12 particles to about 1 x 10 14 particles. [598] 46.
  • the method of embodiment 43, wherein the dose comprises about 4 x 10 11 particles. [599] 47.
  • the method of embodiment 43, wherein the dose comprises about 4 x 10 12 particles.
  • the dose comprises about 2 x 10 13 particles.
  • the dose comprises about 8 x 10 13 particles.
  • the dose comprises about 1 x 10 14 particles. [603] 51.
  • the method of any one of embodiments 43 to 50, wherein the solid dosage form is enteric coated. [604] 52.
  • any one of embodiments 43 to 61, wherein the inflammation comprises Th1 inflammation.
  • the inflammation comprises Th2 inflammation.
  • the inflammation comprises Th17 inflammation.
  • the inflammation comprises psoriasis, optionally wherein the psoriasis is mild, moderate, or severe psoriasis.
  • 66 The method of any one of embodiments 43 to 61, wherein the inflammation comprises psoriasis, optionally wherein the psoriasis is mild, moderate, or severe psoriasis.
  • any one of embodiments 43 to 61, wherein the inflammation comprises psoriatic arthritis, optionally wherein the psoriatic arthritis is mild, moderate, or severe psoriatic arthritis.
  • the inflammation comprises atopic dermatitis, optionally wherein the atopic dermatitis is mild, moderate, or severe atopic dermatitis.
  • the dose of particles is determined by eTPN (equivalent total particle number).
  • a capsule comprising (i) a therapeutic agent (e.g., EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, or a powder comprising the EVs) having a total therapeutic agent mass that is about 70% of the total mass of the capsule; (ii) a diluent (e.g., mannitol) having a total mass that is about 29% of the total mass of the capsule; (iii) a lubricant (e.g., magnesium stearate) having a total mass that is about 1.5% of the total mass of the capsule; and (iv) a glidant (e.g., colloidal silicon dioxide) having a total mass that is about 1% of the total mass of the capsule; optionally wherein the capsule comprises about 4 x 10 12 particles of the EVs (e.g., wherein particle count is determined by eTPN (equivalent total particle number)).
  • a therapeutic agent e.
  • a capsule comprising (i) a therapeutic agent (e.g., EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, or a powder comprising the EVs) having a total therapeutic agent mass that is about 6.5% of the total mass of the capsule; (ii) a diluent (e.g., mannitol) having a total mass that is about 91% of the total mass of the capsule; (iii) a lubricant (e.g., magnesium stearate) having a total mass that is about 1.5% of the total mass of the capsule; and (iv) a glidant (e.g., colloidal silicon dioxide) having a total mass that is about 1% of the total mass of the capsule; optionally wherein the capsule comprises about 4 x 10 12 particles of the EVs (e.g., wherein particle count is determined by eTPN (equivalent total particle number)).
  • a therapeutic agent e
  • a capsule comprising (i) a therapeutic agent (e.g., EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, or a powder comprising the EVs) having a total therapeutic agent mass that is about 85% of the total mass of the capsule; (ii) a diluent (e.g., mannitol) having a total mass that is about 12% of the total mass of the capsule; (iii) a lubricant (e.g., magnesium stearate) having a total mass that is about 1.5% of the total mass of the capsule; and (iv) a glidant (e.g., colloidal silicon dioxide) having a total mass that is about 1% of the total mass of the capsule; optionally wherein the capsule comprises about 6 x 10 13 particles of the EVs (e.g., wherein particle count is determined by eTPN (equivalent total particle number)).
  • a therapeutic agent e
  • a capsule comprising (i) a therapeutic agent (e.g., EVs from Prevotella histicola bacteria, e.g., Prevotella Strain B 50329, or a powder comprising the EVs) having a total therapeutic agent mass that is about 50% of the total mass of the capsule; (ii) a diluent (e.g., mannitol) having a total mass that is about 50% of the total mass of the capsule; (iii) a lubricant (e.g., magnesium stearate) having a total mass that is about 1% of the total mass of the capsule; and (iv) a glidant (e.g., colloidal silicon dioxide) having a total mass that is about 0.5% of the total mass of the capsule; optionally wherein the capsule comprises about 8 x 10 13 particles of the EVs (e.g., wherein particle count is determined by eTPN (equivalent total particle number)).
  • a therapeutic agent e.g
  • a solid dosage form comprising about 4 x 10 11 particles to about 8 x 10 13 particles of EVs from Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria (e.g., wherein particle count is determined by eTPN (equivalent total particle number)); wherein the solid dosage form is enteric coated and the enteric coating is at a coating level of between about 1 mg/cm 2 to about 6 mg/cm 2 per solid dosage form.
  • 77 The solid dosage form of embodiment 76, wherein the dose comprises about 4 x 10 11 particles.
  • the dose comprises about 4 x 10 12 particles.
  • the solid dosage form of embodiment 76, wherein the dose comprises about 6 x 10 13 particles.
  • the solid dosage form of embodiment 76, wherein the dose comprises about 8 x 10 13 particles.
  • the solid dosage form of any one of embodiments 76 to 80, wherein the enteric coating is at a coating level of about 2.7 mg/ cm 2 total weight gain (a polymer weight gain of about 1.7 mg/cm 2 ) per solid dosage form.
  • the solid dosage form comprises a capsule.
  • Drug substance was prepared by lyophilization using excipient formula 7a (20% Trehalose, 80% Mannitol). See also WO2022132738 and WO2022164806.
  • HS DS high strength drug substance.
  • LS DS low strength drug substance.
  • LS DS was prepared by diluting HS DS 10x (using lyophilization excipients) before lyophilization.
  • Drug substance was (i) mixed with water; (ii) dried on a fluid bed dryer; (iii) milled; (iv) blended with the drug product excipients provided in Table 2; and (v) filled into capsules. [643] The capsules were size 0. [644] Capsules of the recipes in Table 3a for the three indicated doses (by eTPN) were prepared: Table 3a: Composition of capsules a Composed of hydroxypropyl methylcellulose, titanium dioxide, and iron oxide. b Adjusted based on the potency of drug substance to ensure targeted strength.
  • the Prevotella histicola smEVs in Table 3a were from strain Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
  • Drug substance (powder) was prepared by lyophilization using excipient formula 7a (20% Trehalose, 80% Mannitol). See also WO2022132738 and WO2022164806.
  • To prepare the pharmaceutical composition capsules wet granulation (using water) was performed on the drug substance (pharmaceutical agent) containing the smEVs.
  • the capsules were size 0.
  • Capsules of the recipes in Table 3b for the indicated dose (by eTPN) were prepared: Table 3b: Composition of capsules a Composed of hydroxypropyl methylcellulose, titanium dioxide, and iron oxide. b Adjusted based on the potency of drug substance to ensure targeted strength.
  • the Prevotella histicola smEVs in Table 3b were from strain Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
  • Drug substance (powder) was prepared by lyophilization using excipient formula 7a (20% Trehalose, 80% Mannitol). See also WO2022132738 and WO2022164806.
  • the Prevotella histicola smEVs in Table 3c are from strain Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
  • Drug substance (powder) is prepared by lyophilization using excipient formula 7a (20% Trehalose, 80% Mannitol). The drug substance is prepared by diluting the 3.9 x 10 12 eTPN drug substance from Table 3a 10x (using lyophilization excipients) before lyophilization.
  • Drug substance is (i) mixed with water; (ii) dried on a fluid bed dryer; (iii) milled; (iv) blended with the drug product excipients provided in Table 3c; and (v) filled into capsules.
  • the capsules are size 0.
  • Example 2 Preparation of a Tablet Containing Prevotella histicola EVs
  • Tablets of the recipes in Table 4 were prepared: Table 4: Composition of active tablets (400mg) [660] The Prevotella histicola smEVs in Table 4 were from strain Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
  • Drug substance (powder) was prepared by lyophilization using excipient formula 7a (20% Trehalose, 80% Mannitol).
  • HS DS high strength drug substance.
  • LS DS low strength drug substance.
  • LS DS was prepared by diluting HS DS 10x (using lyophilization excipients) before lyophilization.
  • To prepare the pharmaceutical composition tablets wet granulation was performed on the drug substance (pharmaceutical agent) containing the smEVs. Drug substance was (i) mixed with water; (ii) dried on a fluid bed dryer; (iii) milled; (iv) then blended with the drug product excipients provided in Table 4.
  • the percent of mass is on a percent weight:weight basis (% w:w).
  • the tablets were 5.5 mm x 15.8 mm.
  • Tablets of the recipes in Table 5 were prepared.
  • Table 5: Composition of active tablet [666] The Prevotella histicola smEVs in Table 5 were smEVs of Prevotella Strain B 50329 (NRRL accession number B 50329).
  • the percent of mass is on a percent weight:weight basis (% w:w).
  • Example 3 Preparation of Enteric Coated Capsules Equipment List
  • Table 7 Equipment list for the manufacturing of Prevotella Strain B 50329 (NRRL accession number B 50329) EV enteric coated capsules.
  • Manufacturing Procedure The workflow of the manufacturing process is 1- blending; 2- capsule filling; 3- capsule banding; 4- capsule coating.
  • 1.1 Powder blending procedure and capsule filling 1.1.1.
  • Blending Procedure The blending process is summarized as follows: 1. Pass the powder through 35 mesh screen. 2. Pass silicon dioxide and mannitol through 20 mesh screen. 3. Blend sieved powder, silicon dioxide and mannitol at 250 RPM for 15 min. 4. Add magnesium stearate and mix for 3 min. 1.1.2.
  • Capsule Filling The capsule filling process is summarized as follows: 1. Set up the Profilel 300 with size 0 HPMC (Hypromellose) Vcaps plus Swedish orange capsules. 2. Use the powder tray and powder spreader to fill the powder into the capsules. Powder in the capsule was tamped 3 times to minimize the weight variations. 3. Final capsule fill weight is ⁇ 300 mg per capsule. 4. Repeat the process to get a required number of capsules. 1.2. Capsule banding 1.2.1. Preparation of the Banding Solution The composition of the banding solution is listed in Table 8. Table 8: Composition of the banding solution. The preparation procedure of the banding solution is specified as follows: 1. Slowly add the hypromellose powder into 70% alcohol. 2.
  • the banding process is summarized as follows: 1. Turn on the banding machine. 2. Set up the following parameter: Wheel speed of 80, a chain speed of 20, and an application thickness of 0.5 mm. 3. Add the filled capsules into the capsule trays. 4. Add the banding solution into the solution tray. 5. Load the capsule trays, turn on the wheel and run the capsule tray through the banding area. 6. Check the completeness of the banding before the next capsule tray. 7. Air dry the banded capsules by leaving the capsules in trays for 20 minutes. 1.3.
  • composition of the enteric coating solution is listed in Table 9.
  • Table 9 Composition of the coating solution.
  • the following steps elaborate the process to prepare the coating solution. 1. Add talc and triethyl citrate into water for injection while mixing. Homogenize it at 6000 rpm for 5 min using high shear mixer. 2. Slowly add the above suspension into Eudragit L30D-55 suspension while mixing. 3. Mix for 30 min and pass through 60 mesh screen prior to use. 1.3.1. Capsule Coating The following steps elaborate the coating process: 1. Weigh out 20 uncoated capsules and calculate the average capsule weight. 2. Load the uncoated capsules, warm up the pan coater and calibrate the spray rate. 3.
  • a coating level of about 1 mg/cm 2 is about 5 mg per size 0 capsule; of about 1.7 mg/cm 2 is about 9 mg per size 0 capsule; of about 2.7 mg/cm 2 is about 14 mg per size 0 capsule; of about 3.7 mg/cm 2 is about 19 mg per size 0 capsule; of about 4.8 mg/cm 2 is about 25 mg per size 0 capsule; and of about 6 mg/cm 2 is about 31 mg per size 0 capsule.
  • Example 4 Equivalent Total Particle Number Calculation Purpose [674] This method describes the quantification of equivalent Total Particle Number (eTPN) of secreted microbial extracellular vesicles (smEVs) by using a total lipid content method by fluorescent dye FM4-64.
  • Lipophilic FM4-64 dye is non-fluorescent in aqueous media; when inserted into the lipid membrane layer of an EV it becomes intensely fluorescent at Ex/Em 515/640 nm.
  • the relative fluorescent unit (RFU) readouts of the test samples are plotted against a trendline of TPN/mg DS for a calibration curve. Since TPN per mg DS is well characterized, the RFU is plotted against the TPN to determine the particle count of the sample.
  • Step 1 Measure 50 mg of pilot batch control and transfer to a 1.5 mL microcentrifuge tube. Add 500 ⁇ L PBS. Vortex on high for at least 10 seconds until no clumps observed. . 7.3.2.2.
  • Step 2. Take 100 ⁇ L of the suspension from step 1 and add to 900 ⁇ L PBS. Vortex on high for at least 10 seconds. This is the 1:100 dilution. . 7.3.2.3.
  • Step 3 Take 200 ⁇ L of the 1:100 dilution and add in 800 ⁇ L PBS. Vortex on high for at least 10 seconds. This is the 1:500 dilution.
  • Drug Substance sample preparation o 7.4.1. Dilute DS test samples: . Strength A/B: 1:100 to 1:500 . Strength C: 1:10,000 . Weigh ⁇ 50 mg sample and dilute in 450 ⁇ L PBS. This is the 1:10 dilution. . Add 100 ⁇ L of 1:10 dilution into 900 ⁇ L PBS. This is the 1:100 dilution. . Add 200 ⁇ L of 1:100 dilution into 800 ⁇ L PBS. This is the 1:500 dilution. o 7.4.2. Each DS test sample should be tested in 3 independent preparations, starting with 3 DS aliquots. Each preparation is also tested in 3 replicates.
  • Example 5 Prevotella histicola Strain B smEVs Preclinical Studies [678] A pharmaceutical composition of secreted microbial extracellular vesicles (smEVs) produced by a strain of Prevotella histicola isolated from the duodenum of a human donor has been prepared. The Prevotella histicola smEVs are from Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
  • the pharmaceutical composition is an orally delivered, gut- restricted investigational medicine which acts on immune cells in the small intestine leading to resolution of systemic inflammation. Preclinical and clinical results demonstrate that this is a potent mechanism of systemic inflammatory control which may enable the development of a new class of oral products which are effective, safe, and manufactured affordably at large scale.
  • the composition contains non-live biopharmaceutical smEVs that cannot colonize the gut or modify the background microbiome. These smEVs are non-live and non-replicating.
  • [680] Almost all prokaryotic and eukaryotic cells shed extracellular vesicles. These smEVs are lipid nanoparticles of average diameter roughly 100 nm.
  • the strain of Prevotella histicola of this pharmaceutical composition produces smEVs that share molecular content with the parent bacterium in a particle that is roughly 1/1000 th the volume. Whilst remaining gut-restricted after oral delivery, this small size confers two significant advantages; firstly, a much greater ability to diffuse, which is essential to reaching their cellular targets in the gut wall; and secondly, the ability to fill capsules at higher strength which is predicted to lead to improved efficacy.
  • the pharmaceutical composition contains a lyophilized powder in an enterically-coated capsule.
  • Prevotella smEVs In vitro studies of the Prevotella smEVs in human and mouse cellular assays and in vivo models support its use in the treatment of immunoinflammatory diseases, including psoriasis and atopic dermatitis.
  • the Prevotella smEVs increase secretion of anti-inflammatory cytokines from human immune cells, such as interleukin (IL)-10, while inducing minimal production of pro- inflammatory cytokines such as tumour necrosis factor (TNF) and interferon gamma (IFN ⁇ ).
  • IL interleukin
  • IFN ⁇ interferon gamma
  • DTH delayed-type hypersensitivity
  • IMQ imiquimod
  • the Prevotella smEVs are orally delivered and not systemically absorbed, confirming that interactions of the Prevotella smEVs with host cells in the epithelial lining of the small intestine can affect the immune response in distal peripheral sites.
  • the combination of in vitro, in vivo, and ex vivo data demonstrate that the Prevotella smEVs resolve systemic inflammation across T-helper (Th)1 and Th17 pathways, but do not broadly impair either innate or adaptive immune responses.
  • Anti-viral responses such as cluster of differentiation (CD)4 and CD8 T cell production of IFN ⁇ , innate anti-viral production of IFN ⁇ and IFN ⁇ , and the generation of effector T cell populations are all preserved after treatment with the Prevotella smEVs.
  • the Prevotella smEVs are expected to attenuate peripheral inflammation without leading to immunosuppression of host anti-viral responses.
  • the studies planned with pharmaceutical compositions of the Prevotella smEVs include Phase 1/2 study will be conducted including healthy volunteers dosed for 10 days, followed by participants with mild and moderate psoriasis dosed for 16 weeks.
  • Background The studies planned with pharmaceutical compositions of the Prevotella smEVs include Phase 1/2 study will be conducted including healthy volunteers dosed for 10 days, followed by participants with mild and moderate psoriasis dosed for 16 weeks.
  • the pharmaceutical composition contains smEVs of a single strain of Prevotella histicola, originally isolated from the duodenal mucosa of a human donor.
  • Prevotella histicola is a naturally occurring species of human commensal non-motile, Gram-negative bacteria found within the gastrointestinal (GI) tract and oral cavity.
  • GI gastrointestinal
  • the pharmaceutical composition of Prevotella smEVs is manufactured by anaerobic fermentation, followed by concentration, lyophilization, and encapsulation in a capsule with an enteric coating which protects the active ingredient from the low pH in the stomach. Neither the Prevotella smEVs, nor its parent microbe are genetically modified.
  • the Prevotella smEVs are non-live, they do not colonize the gut and have no detectable systemic exposure following oral dosing. In non-clinical studies, the therapeutic effects are dose-dependent.
  • the Prevotella smEVs exhibit potent anti-inflammatory effects in two preclinical animal models, namely DTH- and IMQ-induced skin inflammation, supporting attenuation of both Th1 and Th17 inflammatory pathways. These results, together with a biodistribution study, show gut- restricted distribution and systemic pharmacodynamic effects of the Prevotella smEVs, linking intestinal immune modulation to systemic immunity. [689] Structure.
  • the parent microbe is a strain of Prevotella histicola which is an obligately anaerobic, non-motile, gram-negative polymorphic bacterium. It is a naturally occurring human commensal microbe, found primarily within the GI tract and oral cavities. Prevotella histicola cells are long filamentous rods 0.7 ⁇ 3-10 ⁇ m in size during exponential growth phase, and short oval rods 0.5 to 0.7 ⁇ 1-3 ⁇ m during stationary phase and on Brucella agar plates. [690] The pharmaceutical composition contains the Prevotella smEVs, which are naturally secreted membrane vesicles by Prevotella histicola.
  • the smEVs mainly consist of a lipid bilayer containing proteins, glycans and lipo-peptides, largely derived from the surface of the parent microbe.
  • the smEVs are approximately 50-200 nm in diameter.
  • the drug substance (DS) (pharmaceutical agent) of the pharmaceutical composition is the freeze-dried preparation of smEVs, extracted from culture of a cloned, non-genetically modified strain of Prevotella histicola.
  • DS drug substance
  • Formulation Formulation.
  • the drug product (DP) (pharmaceutical composition) formulation is a blend of freeze-dried powder of smEVs of Prevotella histicola (drug substance; DS) and excipients (mannitol, colloidal silicon dioxide, and magnesium stearate). Two active DP strengths with matching placebo are manufactured to support the clinical studies.
  • the pharmaceutical composition finished product is manufactured as an enteric-coated capsule, designed to protect the smEVs from stomach pH degradation and designed to release at pH ⁇ 5.5, which is the approximate pH in the small intestine.
  • References. [695] Mangalam A, Shahi SK, Luckey D, Karau M, Marietta E, Luo N, et al.
  • the Prevotella smEVs have been found to stimulate secretion of anti-inflammatory cytokines such as IL-10 from human macrophages and dendritic cells (DCs), whilst not inducing significant levels of proinflammatory cytokines and chemokines such as TNF and IFN . ⁇ (or IFNg or IFN-gamma).
  • cytokines such as IL-10 from human macrophages and dendritic cells (DCs)
  • DCs dendritic cells
  • APC antigen presenting cells
  • CD cluster of differentiation
  • CEF Cytomegalovirus, Epstein Bar virus and Flu viruses
  • DC dendritic cell
  • DTH delayed-type hypersensitivity
  • ELISA enzyme-linked immunosorbent assay
  • GI gastrointestinal
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • IFN ⁇ interferon alpha
  • IFN ⁇ interferon beta
  • IFN ⁇ interferon gamma
  • IL interleukin
  • IMQ imiquimod
  • KLH keyhole limpet haemocyanin
  • LPS lipopolysaccharide
  • MLN mesenteric lymph node
  • PBMC peripheral blood mononuclear cells
  • PMA phorbol myristate acetate
  • Th T-helper cell type
  • TLR toll-like receptor
  • TNF tumour necrosis factor [703]
  • Prevotella smEVs are restricted to the gut, there are a limited number of immune cells types with which they can interact as they pass through the GI tract.
  • the immune cells that are most likely to directly encounter Prevotella smEVs are located in the lamina intestinal epithelial cell layer, and are in the myeloid lineage, including DCs and macrophages.
  • a series of in vitro studies were undertaken to examine the effects of the interaction of Prevotella smEVs on human immune cells derived from healthy volunteer peripheral blood. The effect of Prevotella smEVs also evaluated on human DC-mediated activation of CD8+ T cells, a major producer of the pro- inflammatory cytokine IFN ⁇ .
  • Prevotella smEVs dose-response of Prevotella smEVs on the induction of IL-10 from primary purified peripheral blood monocytes, dendritic cells, and macrophages from human donors.
  • Prevotella smEVs stimulate the production of the anti-inflammatory cytokine IL-10 from purified human peripheral blood mononuclear cells (PBMCs) and DCs from three individual donors in a dose- dependent manner.
  • PBMCs peripheral blood mononuclear cells
  • Isolated human PBMCs, DCs, and macrophages from whole blood were cultured with a range of doses from 1 x 10 4 to 5 x 10 6 particles of Prevotella smEVs as described above. After 24 hours, supernatants were collected and IL-10 was measured by multiplexed enzyme-linked immunosorbent assay (ELISA) (MSD). A dose-response relationship was observed between increasing smEV particle numbers and production of IL-10 from PBMCs, macrophages and DCs.
  • ELISA enzyme-linked immunosorbent assay
  • Macrophages are one of the major human cell types to produce and secrete the pro- inflammatory cytokines in response to various stimuli e.g., exposure to microbial products.
  • an in vitro assay with primary human myeloid cells skewed towards a pro-inflammatory phenotype was carried out. Briefly, primary human CD14+ PBMCs were purified from three healthy donors by Ficoll-Paque gradient centrifugation in combination with magnetic cell separation.
  • CD14+ cells were differentiated to a mature antigen presenting cell (APC) phenotype for 7 days with granulocyte-macrophage colony-stimulating factor (GM-CSF).
  • APC antigen presenting cell
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • the cells were skewed to an inflammatory phenotype with a cocktail of lipopolysaccharide (LPS) + IFN ⁇ , and subsequently treated with varying doses (1 x 10 10 , 1 x 10 7 and 1 x 10 3 particles/well) of Prevotella smEVs. After 24 hours, cell supernatants were collected and the pro- and anti-inflammatory cytokines were measured using multiplex ELISAs (MSD).
  • MSD multiplex ELISAs
  • Prevotella smEVs do not enhance the production of the pro- inflammatory cytokines IFN ⁇ and TNF, nor do they inhibit the production of the anti- inflammatory cytokine IL-10.
  • Prevotella smEVs induce a dose-dependent release of anti-inflammatory cytokine IL-10 from the differentiated macrophage cell line via the toll-like receptor (TLR)1/TLR2 heterodimer.
  • TLR toll-like receptor
  • Macrophages are one of the major human cell types that produce and secrete the anti- inflammatory cytokines to resolve the inflammation following initial exposure to microbial products.
  • Prevotella smEVs To determine whether exposure to Prevotella smEVs might induce anti-inflammatory cytokines, an in vitro assay with primary human monocytic cell line, U937, was utilized. U937 cells were first differentiated with phorbol myristate acetate (PMA, 200nM) to a macrophage phenotype. Varying doses (1 x 10 9 to 1 x 10 3 particles/well) of Prevotella smEVs were added to these cells and cell supernatants were collected after 24 hours. The anti-inflammatory cytokine IL-10 was measured using ELISA (MSD). The data demonstrate that Prevotella smEVs induced a dose dependent production of the anti-inflammatory cytokine IL-10.
  • PMA phorbol myristate acetate
  • Prevotella smEVs The EC50 of Prevotella smEVs was established at ⁇ 4.3 x 10 8 particles. Preincubation with neutralizing antibodies to TLR1 and TLR2 but not an isotype matched control antibody or a TRL6 antibody blocked the maximal levels of IL-10 released and shifted the dose response curve to the right. These data indicate that Prevotella smEVs signal predominantly via the TLR1/TLR2 but not the TLR2/TLR6 heterodimer in this macrophage cell line to induce the release of IL-10. [710] In vivo Murine Disease Models. [711] Two models of immuno-inflammatory disease have been used to generate efficacy and safety information on Prevotella smEVs with the potential to treat skin inflammation.
  • the DTH model is a mechanistic skin inflammation model that measures Ag-specific T cell mediated inflammation in the ear. DTH has been used to generate efficacy and safety information on Prevotella smEVs with the potential to treat Th1-mediated inflammation. In addition, Prevotella smEVs have been evaluated in the IMQ-induced model of Th17-mediated skin inflammation, a model of psoriasis based on common immune mechanisms.
  • mice were immunized by subcutaneous injection with KLH emulsified with Complete Freund’s Adjuvant (CFA). Eight days after sensitization, the previously sensitized mice were challenged by intradermal ear injection with KLH or a buffer control. The DTH response was evaluated 24 hours post-challenge, which represents the peak of disease in this model.
  • CFA Complete Freund’s Adjuvant
  • mice were dosed for 3 days daily by oral gavage starting Day 5 post-sensitization with vehicle, reconstituted Prevotella smEVs at 4 doses over 7 logs (2 x 10 9 , 2 x 10 7 2 x 10 5 and 2 x 10 3 particles), or a positive control (Dexamethasone, 1mg/kg).
  • mice were dosed based on the lipid content of Prevotella smEVs that are equivalent to particle counts ranging from 2 x 10 9 to 2 x 10 3 particles.
  • E max maximal effect
  • KLH DTH 3.0 Prevotella smEVs in Adoptive Transfer DTH.
  • the inflammation resolution of peripheral tissues after oral dosing with Prevotella smEVs suggested that a circulating immune cell population conferred efficacy. It was hypothesized that CD4+ T cells could be the cell population responsible for resolving inflammation in the periphery.
  • recipient C57BL/6 mice were shaved on their dorsal side and immunized with four 50 ⁇ L dorsal subcutaneous injections of KLH (1 mg/mL in PBS) emulsified in CFA (mixed at a ratio of 1:1).
  • donor mice from vehicle and Prevotella smEVs treated groups were euthanized, spleens and lymph nodes (inguinal, axillary, brachial) were excised, and CD4+ T cells were isolated from each group by negative magnetic selection from a pooled homogenized single cell suspension of the tissues.
  • CD4+ T cells Isolated CD4+ T cells were then washed with PBS, counted, and resuspended at 1 x 10 8 cells/mL.
  • CD4+ T cells (1 x 10 7 cells/mouse) were then transferred into recipient mice by intraperitoneal injection. On Day 12, the left ears of recipient mice were measured for baseline thickness and challenged with a 10 ⁇ L intradermal injection of 1 mg/mL KLH. On Day 13, 24 hours after challenge, the left ears of recipient mice were measured for thickness and the difference in thickness was calculated.
  • Results The change in ear thickness of mice treated with CD4+ T cells from Prevotella smEV-dosed donor mice was significantly reduced compared to recipient mice receiving CD4+ T cells from PBS-treated donor mice.
  • KLH DTH 4.0 Prevotella smEVs are well-tolerated in 30-day DTH. A 30-day murine DTH study with KLH was carried out to test the anti-inflammatory properties of Prevotella smEVs over an extended period of dosing. Mice were subcutaneously immunized with an emulsion of 50 ⁇ L KLH in CFA on Day 0, and then received a KLH booster on Day 7.
  • mice received two intradermal antigen challenges with 10 ⁇ g KLH in the ear on Days 15 and 29. Changes in ear swelling thickness vs. baseline were measured using a caliper 24 hours after each ear challenge on Day 16 and Day 30.
  • Two treatment groups were included in the study: Vehicle and Prevotella smEVs (2 x 10 9 particles). Mice were dosed orally Monday to Friday from Days 1 to 30. A group of age-matched na ⁇ ve mice that did not receive immunization, challenge, or treatment was also included in the study for comparison. A third group of animals treated with 1 mg/kg Dexamethasone (every other day, total of 13 doses) were used as a positive control arm. Health observations and body weight were recorded daily.
  • ALT alanine transaminase
  • AST aspartate transaminase
  • ALP alkaline phosphatase
  • GTT gamma-glutamyltransferase
  • Tbil total bilirubin
  • Chol cholesterol
  • mice treated with Prevotella smEVs for up to 30 days there was no difference in spleen weights observed for mice treated with Prevotella smEVs for up to 30 days compared to mice treated with vehicle.
  • Liver weight was slightly higher in mice treated with Prevotella smEVs compared to mice treated with vehicle, but there was no significant difference compared to na ⁇ ve mice.
  • No notable changes in body weight were observed throughout the study. Some variability in weight was measured on Day 3, which was likely due to variability in stress responses at the beginning of the study. Body weights returned to normal thereafter. Daily health observations did not show any abnormalities in the health of the animals that were dosed with Prevotella smEVs for up to 30 days. [723] At study termination on Day 30, blood was collected from the animals and serum was obtained.
  • IMQ Imiquimod
  • This IMQ-induced psoriasis models human plaque-type psoriasis in which the IL-23/IL-17 cytokine axis plays a pivotal role.
  • Study parameters include in-life clinical evaluation of skin, measurement of ear thickness, and analysis of cytokine expression in the skin and immune organs.
  • Methods Mice were sensitized on the shaved back and ear with IMQ cream daily for 7 consecutive days. Mice were gavaged daily with Prevotella smEVs (2 x 10 11 or 2 x 10 10 particles per dose) or vehicle.
  • mice were also treated with dexamethasone (1 mg/kg intraperitoneally) or given an anti-IL-17 antibody (200 mg/mouse intraperitoneally on Days 2, 4, and 6).
  • the severity of inflammation of the back skin was evaluated using a lesion psoriasis severity scoring system. Mice were monitored and graded daily on the scale: 0 (no alteration), 1 (mild erythema), 2 (moderate to severe erythema and some plaques), 3 (marked erythema and plaques) and 4 (very marked erythema and plaques).
  • Prevotella smEV-treated mice showed visibly substantial reduction of erythema, scaling and thickening associated with IMQ-induced skin inflammation compared to vehicle- treated mice with the largest difference seen on Day 6 with the effect wearing off by Day 7.
  • the kinetics of Prevotella smEVs passage through the stomach, small intestine, and colon, following a single dose (6 x 10 11 particles) of Prevotella smEVs was determined.
  • dissemination from the intestine was examined by measuring fluorescence levels in MLNs, spleen, liver, heart, kidney, and lungs, at 10 minutes, 1 hour, 6 hours, 12 hours, and 24 hours post administration.
  • Prevotella smEVs were administered by oral gavage and measured at the same time points in order to establish a baseline for background fluorescence.
  • Oral administration of Prevotella smEVs led to a transient rise in the GI tract.
  • Prevotella smEVs were only detected in the intestine and stool for up to 12 hours post-treatment, demonstrating that EVs are unable to persist in the intestinal tract after a single dose.
  • Prevotella smEVs were not detected outside of the GI tract at any time point above background fluorescence as determined by the free dye control and more importantly the intravenous route.
  • Antiviral responses are activated rapidly after viral infection in order to control and prevent dissemination of the virus.
  • Virus infection results in two general types of immune response. The first is a rapid-onset innate immune response against the virus, which involves the synthesis of Type 1 interferons (IFNs) and the stimulation of natural killer (NK) cells. If the infection proceeds beyond the first few rounds of viral replication, the innate immune response will trigger the adaptive immune response.
  • the adaptive immune response itself has two components, the humoral response (the synthesis of virus-specific antibodies by B lymphocytes) and the cell-mediated response (the synthesis of specific CD8+ cytotoxic T lymphocytes that kill infected cells).
  • the pharmaceutical composition comprises bacterial smEVs produced and secreted by a single strain of human commensal Prevotella histicola. Preclinically, Prevotella smEVs are administered orally and are not systemically bioavailable.
  • Prevotella smEVs exert their anti- inflammatory effects on peripheral tissue through engagement of cells of the intestine, including intestinal epithelial cells and immune cells in the lamina basement.
  • Prevotella smEVs have been shown in preclinical mouse inflammation models to reduce Ag-specific T cell responses, without impacting: .
  • IFN- ⁇ production by murine T cells The generation of functional CD4+ Th1 cells in a mouse model of inflammation .
  • Prevotella smEVs resolve tissue inflammation in a KLH (DTH) model. Mice were immunized by subcutaneous injection with KLH emulsified with CFA.
  • mice were dosed for 15 days with vehicle (PBS) and Prevotella smEVs by oral gavage (2 x 10 10 particles/day) or dexamethasone (1 mg/kg) by intraperitoneal injection.
  • mice were challenged by intradermal ear injection with KLH. The DTH response was evaluated 24 hours post-challenge.
  • Results Fifteen days of dosing with Prevotella smEVs or dexamethasone significantly inhibited ear inflammation.
  • IFNs are cytokines that are secreted by host cells in response to virus infection and are the body's first line of antiviral defense. By inducing the expression of hundreds of IFN-stimulated genes, several of which have antiviral functions, IFNs block virus replication at many levels.
  • Type I or 'viral' IFNs include IFN- ⁇ , IFN- ⁇ , IFN- ⁇ and IFN- ⁇ ; type II IFN is IFN- ⁇ .
  • Most cell types can produce IFN- ⁇ and IFN- ⁇ , which are the best-characterized type I IFNs, whereas IFN- ⁇ is produced only by certain cells of the immune system, including NK cells, CD4+ Th1 cells and CD8+ cytotoxic T cells.
  • Drugs with broad immuno-suppressant activity such as corticosteroids, can inhibit the production of IFNs, which can lead to delayed viral clearance and adverse outcomes in various viral pneumonias.
  • Poly I:C is a molecule that mimics viral double-strained ribonucleic acid (RNA), and a potent ligand for TLR3, which induces interferon alpha (IFN ⁇ ) and interferon beta (IFN ⁇ ) from immune cells.
  • IFN ⁇ interferon alpha
  • IFN ⁇ interferon beta
  • Prevotella smEVs selectively inhibit tissue inflammation while preserving protective Type I and II IFN responses.
  • Mouse CD4 Th1 T cell responses are not reduced by Prevotella smEVs treatment in DTH.
  • CD4 T cells help B cells to produce antibodies and help CD8+ T cells to kill virus-infected cells.
  • One of the dominant cytokines produced by T cells is IFN- ⁇ , a key player in controlling viral infection.
  • IFN- ⁇ a key player in controlling viral infection.
  • One report has described a higher proportion of IFN- ⁇ -producing Th1-like cells in patients with moderate disease than in patients with severe disease.
  • CD4+ T cells specific for the SARS-CoV-2 spike protein have been identified in acute infection and have a Th1 cell cytokine profile (Weiskopf et al, 2020).
  • cytokines such as IFN- ⁇ and TNF
  • CD4 T cells were isolated from spleens and lymph nodes after a DTH response, and Th1 T cell numbers were determined by flow cytometry.
  • Th1 T cells which are defined by their expression of the transcription factor T- bet, were of a similar proportion (roughly 2%) of total CD4 T cells in mice treated with either vehicle or Prevotella smEVs.
  • CD8+ T cells In addition to CD4+ T cells and neutralizing antibodies, CD8+ T cells contribute to protective immune responses against SARS- CoV-2 in patients with COVID-19. In adaptive immunity, CD8+ T cells play an essential role in controlling viral infection by killing virus-infected cells and producing effector cytokines such as IFN- ⁇ . DCs that present viral antigens to CD8 T cells also produce cytokines such as IL-12, TNF, and IL-6, which then induce the differentiation and activation of IFN- ⁇ -producing CD8 T cells. [743] An in vitro assay with primary human DCs and autologous CD8+ T cells was carried out to measure the capacity of Prevotella smEVs to modulate both DCs and Ag-specific CD8+ T cell responses.
  • Prevotella smEVs Primary human DCs from the blood of 3 healthy human donors were differentiated in vitro for 7 days. To assess the immuno-modulatory properties of Prevotella smEVs, DCs were incubated with 3 doses of Prevotella smEVs for 24 hours. After 24 hours, Prevotella smEVs were removed from the DC culture and autologous human CD8+ T cells and CEF Class I peptide pool was added. The CEF peptide pool is composed of peptides from Cytomegalovirus, Epstein Bar virus, and Influenza virus, pathogens to which the majority of the human population has been exposed. Controls used were DCs only, DCs + T Cells only, and DCs + T cells + CEF peptide.
  • Anti-viral responses such as CD4 and CD8 T cell production of IFN- ⁇ , innate anti-viral production of IFN- ⁇ and IFN- ⁇ , and the generation of effector T cell populations are all preserved after treatment with Prevotella smEVs.
  • the data demonstrate that treatment with Prevotella smEVs results in resolution of peripheral inflammation without leading to immunosuppression of the host anti-viral response.
  • References. [748] Vukmanovic-Stejic M, Reed JR, Lacy KE, Rustin MH, Akbar AN. Mantoux Test as a model for a secondary immune response in humans.
  • Example 6 A Phase 1/2, Randomised, Placebo-Controlled Study of Prevotella histicola Strain B smEVs in Healthy Volunteers and Participants with Moderate Plaque Psoriasis
  • the Prevotella histicola smEVs are from Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
  • This study will evaluate Prevotella histicola smEVs in healthy volunteers followed by participants with moderate psoriasis to determine safety and tolerability and preliminary efficacy.
  • Objectives and Endpoints are:
  • Part A of the study will be conducted according to a randomised, placebo-controlled, participant-and investigator-blind, sponsor-open design. It will include up to 3 sequential, escalating multiple dose cohorts. Each cohort will comprise 12 healthy volunteers receiving Prevotella histicola smEVs or placebo in oral enteric coated capsule(s) once a day for up to 10 days according to a 2:1 randomisation (active: placebo). Prior to dose escalation, safety will be reviewed by a dose level review committee (DLRC). Dose escalation to the next cohort may proceed once safety data from at least 8 participants who have completed 10 days dosing in the current cohort has been reviewed.
  • DLRC dose level review committee
  • Part B of the study will be conducted according to a randomised, double-blind, placebo-controlled design in participants with moderate plaque psoriasis. Participants will be randomly assigned in a 1:1 ratio to Prevotella histicola smEVs or placebo administered orally as a single enteric coated capsule once a day for up to 16 weeks. No active psoriasis treatments may be used during the 16-week treatment period. Optional skin biopsies, half-body photographs and genotyping will be included in Part B.
  • Part A Planned daily doses of Prevotella histicola smEVs are 3.9 x 10 12 equivalent total particle number (eTPN) once daily (QD) (Cohort 1), 1.95 x 10 13 eTPN QD (Cohort 2) and 1.12 x 10 14 eTPN QD (Cohort 3).
  • the study treatment duration in Part A will be up to 52 days (screening period up to 28 days, treatment period of 10 days and a follow-up period up to 14 days).
  • Part B The planned dose of Prevotella histicola smEVs is up to 7.5 x 10 13 eTPN QD.
  • This dose may be adapted based on the final IMP formulation for the cohort and/or safety review of data from Part A but will be no higher than 7.5 x 10 13 eTPN QD and will not exceed dose levels studied in Part A.
  • the total study duration in Part B will be up to 24 weeks (screening period up to 28 days, treatment period of 16 weeks and a follow up period up to 28 days).
  • Psoriasis is a chronic immune-mediated inflammatory skin disease in which hyperactive T cells trigger excessive keratinocyte proliferation. This results in the formation of raised erythematous plaques with scaling. Psoriatic lesions can appear anywhere on the body but are most often seen on the knees, elbows, scalp, and lumbar area.
  • Critical events in the inflammatory process include activation of Langerhans cells and T cells, selective trafficking of activated T cells to the skin, and induction of an inflammatory cytokine and chemokine cascade in skin lesions.
  • Clinical data have validated the role of anti-TNF, anti-IL-17 and anti-IL-23 therapy in moderate to severe psoriasis (Griffiths, 2021).
  • therapy usually involves topical agents, with topical corticosteroids providing the greatest efficacy.
  • topical corticosteroids providing the greatest efficacy.
  • the oral phosphodiesterase type 4 inhibitor apremilast, has been approved for mild to moderate psoriasis.
  • Prevotella histicola smEVs will be evaluated in this Phase 1/2 study in healthy volunteers for a 10-day treatment period, and then in participants with moderate psoriasis for a 16-week treatment period.
  • Benefit/Risk Assessment [768] Risk Assessment. Non-live and non-replicating vaccines including for COVID-19 are permitted in participants treated with Prevotella histicola smEVs in Part B of the study.
  • vaccines should not be administered within 7 days after first dose of IMP.
  • the efficacy of the vaccines co-administered with Prevotella histicola smEVs has not been tested. [769]
  • the effects of Prevotella histicola smEVs on fertility or fetal development following clinical dosing are unknown. As such, Prevotella histicola smEVs should not be administered to pregnant or lactating females, or females of child-bearing potential (unless adhering to protocol-defined contraception requirements).
  • Prevotella histicola smEVs As this is the first study with Prevotella histicola smEVs as an isolated preparation of EVs, it is unknown whether Prevotella histicola smEVs will produce clinical efficacy in participants with psoriasis. However, the demonstrated pharmacological activity with Prevotella histicola smEVs in multiple in vitro and in vivo models relevant to psoriasis indicate significant potential for participants in this study to experience clinical benefit [773] Overall Benefit/Risk Conclusion. Prevotella histicola smEVs will initially be tested in healthy volunteers and, following independent safety review of this part of the study by the DMC, in patients with moderate psoriasis for a duration of 16 weeks.
  • Prevotella histicola smEVs will be well tolerated in humans, and appropriate to evaluate initially in healthy volunteers and for 16 weeks in patients with psoriasis. No specific AEs are expected.
  • the potential benefit/risk profile is assessed as favourable for evaluation of Prevotella histicola smEVs in healthy volunteers and patients with psoriasis.
  • Study Design [777] Overall Design. This is a randomised, placebo-controlled, Phase 1/2 study evaluating the safety, tolerability and clinical efficacy of a pharmaceutical composition of Prevotella histicola smEVs.
  • Part A of the study will be conducted according to a randomised, placebo-controlled, participant- and investigator-blind, sponsor-open design. It will include up to 3 sequential, escalating multiple dose cohorts.
  • Each cohort will comprise 12 healthy volunteers receiving Prevotella histicola smEVs or placebo in enteric coated capsule(s) once a day for up to 10 days according to a 2:1 randomisation (active: placebo).
  • Planned daily doses of Prevotella histicola smEVs are 3.9 x 10 12 eTPN QD (Cohort 1), 1.95 x 10 13 eTPN QD (Cohort 2) and 1.12 x 10 14 eTPN QD (Cohort 3).
  • Part A will include a screening period of up to 28 days, a treatment period of 10 days and a follow-up period to 14 days after the last dose of the pharmaceutical composition.
  • the treatment period will include ambulatory visits on Days 1, 2, 3, 4, 7 and 10. Dosing on these days will occur at the clinic. On Day 1, participants will be observed for a minimum of 4 hours after dosing prior to discharge. On Days 5, 6, 8 and 9, dosing, AE and concomitant medication review (via telephone) may be conducted at home at the discretion of the investigator. [779] Prior to dose escalation, safety will be reviewed by a DLRC. Dose escalation to the next cohort may proceed once safety data from at least 8 participants completing 10 days dosing in the current cohort has been reviewed.
  • Part B of the study will be conducted according to a randomised, double-blind, placebo-controlled design in participants with moderate plaque psoriasis. This part of the study will include a screening period of a minimum of 7 days up to 28 days, a treatment period of 16 weeks and a follow-up period to 28 days after the last dose of the pharmaceutical composition. After eligibility is confirmed, participants will be randomly assigned in a 1:1 ratio to Prevotella histicola smEVs or placebo administered as a single enteric coated capsule once a day for up to 16 weeks.
  • the planned dose of Prevotella histicola smEVs is up to 7.5 x 10 13 eTPN QD (this dose may be adapted prior to conduct of Part B depending on the final IMP formulation and/or emergent safety data in Part A but will not exceed 7.5 x 10 13 eTPN QD).
  • this dose may be adapted prior to conduct of Part B depending on the final IMP formulation and/or emergent safety data in Part A but will not exceed 7.5 x 10 13 eTPN QD).
  • Participants will attend for ambulatory visits at Days 1, 15, 29, 57, 85 and 113. No active psoriasis treatments may be used during the 16-week treatment period.
  • Optional skin biopsies and half-body photographs will be included in Part B.
  • Prevotella histicola is a human commensal bacterium, which naturally produces smEVs.
  • the Prevotella histicola smEVs are from a single strain of the parent bacterium, Prevotella histicola. In vitro studies of Prevotella histicola smEVs in human and murine cellular assays and in vivo models support their use in the treatment of immunoinflammatory diseases.
  • Dose escalation in healthy volunteers (Part A) will be conducted to evaluate safety and tolerability of multiple doses prior to progression to patients with psoriasis (Part B) at a dose no higher than that studied in Part A. Data from each healthy volunteer cohort will be reviewed before dose escalation, and cumulative safety data will be reviewed by the DMC before commencement of Part B.
  • the duration of dosing in Part A is considered sufficient to identify relevant AEs prior to the longer treatment period in Part B.
  • the primary and secondary endpoints selected for the study are precedented in Phase 1 and 2 studies in healthy volunteers and patients with psoriasis, respectively.
  • the 16-week treatment period in Part B is considered appropriate to establish the efficacy of Prevotella histicola smEVs in psoriasis on key endpoints such as PASI, PGA and PROs.
  • the inclusion of placebo in the study design is appropriate given the subjective component of evaluation for a number of the clinical endpoints, the moderate severity of disease, and the availability of alternative therapies [784] Justification for Dose.
  • Contraception A male participant with a female partner of child-bearing potential must meet the criteria for acceptable contraception during the study and for a period of 90 days after the last dose. All male participants must refrain from donating sperm during this period. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: i.Not a woman of child-bearing potential.
  • Participant has GI tract disease (e.g., short bowel syndrome, diarrhea-predominant irritable bowel syndrome, active inflammatory bowel disease) that could interfere with the GI delivery and transit time of Prevotella histicola smEVs.
  • Participant has an active infection (e.g., sepsis, pneumonia, abscess) or has had an infection requiring antibiotic treatment within 6 weeks prior to study intervention administration. When in doubt, the investigator should confer with the Medical Monitor. 3.
  • Participant has undergone major surgery within 3 months prior to screening or in whom major surgery is planned during study participation. 5.
  • Participant has received any investigational drug or experimental procedure within 90 days or 5 half-lives, whichever is longer, prior to randomisation.
  • Previous participation in a clinical study of Prevotella histicola microbe. History of drug abuse or current regular use of illicit drugs or a history of alcohol abuse within 1 year prior to screening. 11.
  • Male participant who intends to donate sperm during the course of this study and for a period of 90 days after the last dose.
  • the participant has donated more than 400 mL of blood or blood products within 90 days prior to baseline (Day -1) or plans to donate blood during the study. [795] All Participants in Part B Only 18. Plaque psoriasis limited to the scalp and/or hands and/or feet. 19. Psoriasis flare (significant worsening beyond typical disease) within 8 weeks prior to screening. 20.
  • systemic immunosuppressive therapy systemic medications that could affect psoriasis or its symptoms, or phototherapy within 28 days of randomisation.
  • systemic medications would include, but are not limited to: corticosteroids, methotrexate, apremilast, azathioprine, cyclosporine, mycophenolate mofetil, hydroxyurea, retinoids, fumaric acid derivatives, JAK inhibitors, and tacrolimus.
  • Other medications which may affect psoriasis include lithium, antimalarials, leflunomide, and gold. 22.
  • Topical medications not including unmedicated emollients
  • topical medications would include, but are not limited to: corticosteroids, topical vitamin D derivatives, retinoids, tazarotene, pimecrolimus, and tacrolimus.
  • Unmedicated emollients should be stopped at least 7 days prior to first administration of study drug. 23. Received any of the following: - Any cell-depleting agent, including rituximab, within 6 months prior to randomisation, or until lymphocyte cell counts return to normal, whichever is longer.
  • Screen failures are defined as participants who consent to take part in the clinical study but are not subsequently randomly assigned to study intervention/entered in the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants to meet the CONSORT publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any SAEs.
  • Prevotella histicola smEVs capsules will be manufactured in 3 strengths: 3.9 x 10 12 eTPN/capsule, 5.6 x 10 13 eTPN/capsule and 7.5 x 10 13 eTPN/capsule.
  • Prevotella histicola smEVs enteric-coated capsules contain lyophilised powder
  • Prevotella histicola smEVs as the API, mannitol, colloidal silicon dioxide, magnesium stearate, hydroxypropyl methylcellulose, methacrylic acid-ethyl acrylate copolymer, talc, triethyl citrate, titanium dioxide, and iron oxide.
  • the capsule is a size 0 capsule that is enteric coated with Eudragit L30D-55 at a coating level to a total weight gain of 14 mg/capsule (2.7 mg/cm 2 ) (a polymer weight gain of 1.7 mg/cm 2 ).
  • the matching placebo is identical in appearance but does not contain the API.
  • the enteric-coated placebo capsules are composed of microcrystalline cellulose, magnesium stearate, hydroxypropyl methylcellulose, methacrylic acid-ethyl acrylate copolymer, talc, triethyl citrate, titanium dioxide, and iron oxide.
  • Part A participants will be randomised 2:1 to receive capsules containing Prevotella histicola smEVs or matching placebo. Planned daily doses of Prevotella histicola smEVs in each cohort are shown below:
  • eTPN equivalent total particle number
  • QD once daily
  • Part B participants will be randomised 1:1 to receive 1 capsule QD of Prevotella histicola smEVs or matching placebo.
  • the planned dose of Prevotella histicola smEVs in Part B is up to 7.5 x 10 13 eTPN QD.
  • the dose in Part B may be adapted based on the final IMP formulation for Part B and/or safety review of data from Part A but will be no higher than 7.5 x 10 13 eTPN QD and will not exceed dose levels studied in Part A.
  • the IMP should be taken with approximately 100mL water at approximately the same time each day ( ⁇ 2 hours, whenever possible).
  • the dose should be taken at the clinic.
  • Part B after the initial dose on Day 1, all doses may be taken at home, including on clinic days.
  • Prevotella histicola smEV composition/placebo finished product is manufactured as an enteric-coated capsule, designed to protect the IMP from stomach pH degradation and designed to release at pH ⁇ 5.5, which is approximately the pH in the small intestine.
  • the capsules are packaged in blister wallets of 10 capsules. All capsules must be stored at 2-8°C.
  • Part B of the study will be conducted using a double-blind, placebo-controlled design, where the participant, investigator and sponsor are all blinded to the treatment allocation.
  • any unblinding will be handled within the IRT system.
  • Participants who are unblinded will be allowed to continue their participation in the study; however, any data collected after the unblinding occurred may be excluded from one or more of the defined data point sets.
  • eDiary Part B only
  • the primary purpose of the diary is to allow accurate daily capture of certain endpoints and to enhance participant compliance with the protocol.
  • eDiary All participants in Part B will be provided with an electronic diary (eDiary).
  • eDiary An electronic diary
  • a paper diary will be dispensed at the screening visit to record daily symptoms, itch and fatigue prior to the Day 1 visit.
  • the participants will then utilise an eDiary commencing upon completion of the Day 1 visit through to the Week 20 follow-up visit.
  • Part A Prescription drugs, vaccines or OTC drugs are not permitted during Part A of the study from 14 days prior to randomisation up to the follow-up visit, except for: ⁇ paracetamol (maximum of 4 grams/day in any 24-hour period). ⁇ hormonal contraceptives.
  • Other OTC or prescription medications may be permitted if approved by the Medical Monitor as not influencing GI transit/uptake or potential safety of participation.
  • Part B In Part B, the following concomitant medications are permitted throughout the study: ⁇ Concomitant medications for conditions other than psoriasis may continue throughout the study if not meeting any exclusion criteria and should continue without change in dosage or formulation whenever possible.
  • Non-replicating/non-live vaccines are permitted in Parts A and B if administered at least 14 days prior to randomisation.
  • non-replicating/non-live vaccines are not permitted up to the follow-up visit.
  • non-replicating/non-live vaccines are permitted throughout the study but should not be administered within 7 days after the first dose of IMP.
  • Live (attenuated) vaccinations are not permitted at any point during the study. This includes vaccines for measles, mumps, rubella, vaccinia, varicella, zoster (which contains the same virus as varicella vaccine but in much higher amount), yellow fever, rotavirus, and influenza (intranasal).
  • a study participant in Part B has a COVID-19 infection (diagnosed clinically or by laboratory tests), the participant may continue study treatment if the investigator considers that there is an individual positive benefit/risk.
  • Efficacy Assessments [845] Efficacy will only be evaluated in Part B of the study. The following efficacy measurements will be collected at the planned timepoints as provided in the SoA. [846] PGA. PGA to be performed by the investigator. Where possible, the same investigator should complete all clinical outcome assessments for the same participant at all visits.
  • the BSA is calculated by estimating the number of participant’s handprints of active psoriasis that are present where one handprint (including digits) represents 1% BSA.
  • the BSA provides another assessment of disease severity by looking at coverage of body surface.
  • the product of the PGA and the BSA involvement will also be recorded (Walsh, 2013).
  • PASI PASI to be performed by the investigator. Where possible, the same investigator should complete all clinical outcome assessments for the same participant at all visits.
  • the PASI score will be assessed as described by (Langley, 2004)
  • the PASI is a physician assessment that combines the assessment of the severity and area affected by psoriasis into a single score in the range 0 (no disease) to 72 (maximal disease).
  • the absolute PASI score in this study is used as part of inclusion criterion 11.
  • the PASI percentage response rates are efficacy endpoints (i.e., PASI-50, PASI-75, PASI-90, and PASI-100). For example, the percentage of participants who achieve a 75% or greater reduction in PASI score from baseline is represented by the PASI-75 value. Details of the PASI assessment will be provided in the relevant training material.
  • EQ-PSO EQ-PSO to be performed by the participant before any other assessments where possible.
  • EQ-PSO is a psoriasis-specific adaptation of the EQ-5D (Swinburn, 2013). It is a standardised measure of health status that can be used to provide a simple, generic measure of health outcome.
  • the EQ-5D comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, each of which is assessed by the respondent according to 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems.).
  • the EQ-PSO includes 2 additional, psoriasis-specific dimensions: skin irritation and self-confidence. [853] DLQI.
  • DLQI DLQI to be performed by the participant before any other assessments where possible. This is a validated patient reported outcomes instrument comprised of 10 questions to assess how a participant’s skin disease has affected their quality of life over the past week (Finlay, 1994).
  • the DLQI score ranges from 0 to 30, with higher scores indicating greater impairment of quality of life.
  • a DLQI score of 0 or 1 is considered as having no effect on a patient’s quality of life, and a 4-point change from baseline is considered the minimal clinically important difference threshold (Basra, 2015).
  • PP-NRS PP-NRS (worst itch) to be asked daily from the screening visit to the Week 16 visit via a participant diary.
  • the PP-NRS is a scale from 0 (“no itch”) to 10 (“worse imaginable itch”) for participants to rate their worst itch that they have experienced over the previous 24 hours (Phan, 2012).
  • the PP-NRS will be completed via a daily questionnaire. A ⁇ 2-4 point change from baseline is considered the minimally clinically important difference threshold (Yosipovitch, 2019).
  • PSD Participants will record symptoms daily using a 16-item PSD, from the screening visit to the Week 16 visit (Strober, 2013).
  • the PSD addresses key symptoms (severity and bother) and functional impacts that are most relevant to patients with chronic plaque psoriasis.
  • Symptom items assess the severity and bother of psoriasis-related itching, stinging, burning, pain and scaling.
  • Impact items assess the embarrassment and avoidance of activities with other people.
  • Symptom severity, bother, and impact items use a 0 to 10 numerical rating scale, with higher scores indicating more severe symptoms, bother, or impact.
  • Photographs Digital close-up photographs to be taken for all participants of up to 6 specific body areas (i.e., limbs, trunk and back) with target lesion representative of the participant’s condition. The same close-up sites photographed at Day 1 should be followed throughout the study for each participant.
  • Photographs may be used to understand visual correspondence of individual patient level scores with change in skin disease on photographs.
  • Physical Examinations A complete physical examination will include, at a minimum, assessments of the general appearance, cardiovascular, respiratory, GI, musculoskeletal, central nervous system, lymph nodes and skin. Height and weight (measured with the participant wearing indoor daytime clothing with no shoes) will also be measured and recorded at the timepoints detailed in the SoA.
  • a brief physical examination will include, at a minimum, assessments of the general appearance, cardiovascular, respiratory, GI and skin at the timepoints detailed in the SoA.
  • ⁇ Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest in a supine position in a quiet setting without distractions (e.g., television, mobile phones).
  • ⁇ Blood pressure measurements should include 3 consecutive readings recorded at intervals of at least 1 minute. The average of the 3 readings will be recorded on the eCRF.
  • Electrocardiograms ⁇ 12-lead ECGs will be obtained as outlined in the SoA. Heart rate, PR, RR, QRS, QT should be recorded by the ECG machine.
  • QTcF calculated by the ECG machine or in the EDC database, should be recorded in the source documentation.
  • ECG abnormalities and investigator assessment of clinical significance should be noted in the source documents and recorded on the eCRF.
  • ⁇ ECG recordings should be preceded by at least 5 minutes of rest in a supine position in a quiet setting without distractions (e.g., television, mobile phones).
  • samples may be used for further research by the sponsor to contribute to the understanding of psoriasis or other diseases, the development of related or new treatments, or research methods.
  • Blood Cytokine Analysis Blood samples from all participants will be analysed to assess the responsiveness of the innate and adaptive immune system. Ex vivo stimulation by LPS or anti-CD3/anti-CD28 will be performed on the blood and analysed for levels of cytokines and chemokines, including IL-2, IL-1 ⁇ , IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IFN ⁇ , TNF ⁇ .
  • cytokines and chemokines including IL-2, IL-1 ⁇ , IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IFN ⁇ , TNF ⁇ .
  • Immunoglobulins A, G and M are antibodies produced by the immune system and Prevotella histicola smEV-specific IgA, IgG and IgM proteins were detected in peripheral blood of animals administered with Prevotella histicola smEVs. It is being measured in participants to see if Prevotella histicola smEV-specific IgA, IgG and IgM are detected after they are administrated Prevotella histicola smEVs.
  • cytokines and other inflammatory proteins may be measured to assess the anti-inflammatory and disease-modifying effects of Prevotella histicola smEVs.
  • hsCRP inflammatory protein markers
  • Circulating Immune Cells Transcription Analysis RNA will be collected from whole blood samples to quantify inflammation markers in immune cells to assess the effect of Prevotella histicola smEVs. These samples may be analysed subject to the clinical data in the study. The genes to be analysed may include those related to host immune response, as well as those related to the disease pathology.
  • Skin Tissue Transcription Analysis Part B).
  • the SAPs will be finalised prior to database lock of the relevant part and will include a more technical and detailed description of the statistical analyses described in this section. This section is a summary of the planned statistical analyses of the most important endpoints including primary and key secondary endpoints.
  • This section is a summary of the planned statistical analyses of the most important endpoints including primary and key secondary endpoints.
  • Statistical Hypothesis There is no formal hypothesis testing in Part A of the study.
  • RRE is the response rate for PASI-50 at Week 16 in the Prevotella histicola smEVs treatment group.
  • RR P is the response rate for PASI-50 at Week 16 in the placebo treatment group.
  • Safety set The SS will consist of all participants who received any IMP. All analyses using the SS will group participants according to treatment received.
  • EDPS1 Consists of all data collected at a scheduled timepoint. Data collected after the use of a prohibited medication or missing due to withdrawal from the study for reasons considered related to study medication (lack of efficacy, requirement for alternative psoriasis treatment or drug-related AE) will be replaced as follows: ⁇ Continuous endpoints: value will be imputed as missing (after a prohibited concomitant medication) or remain as missing if due to withdrawal from the study for reasons considered related to study medication.
  • EDPS2 Consists of all data collected at a scheduled timepoint which were not collected after the use of a prohibited medication. Missing data for participants who did not use a prohibited medication will not be imputed regardless of reason for missingness. Data collected after the use of a prohibited medication will also be imputed as non-response.
  • EDPS3 Is a subset of EDPS2.
  • SDPS1 Consists of all observed data collected at a scheduled visit
  • SDPS2 Consists of all observed data collected, including data from scheduled and unscheduled visits.
  • the FAS with EDPS1 will be used to estimate the primary estimand and all secondary and exploratory estimands.
  • the FAS with EDPS2 and EDPS3 will be used to estimate supplementary estimands for the primary and key secondary endpoints.
  • the SS and SDPS1 will be used to present safety data assigned to a specific study visit.
  • the SS and SDPS2 will be used to present all other safety data, including AEs.
  • Estimands and Intercurrent Events [905] Part A Estimands
  • Part A Estimands [906] Primary Safety Estimands [907] For Part A, the primary objective of the study is to determine the safety and tolerability of each dose of Prevotella histicola smEVs in healthy volunteers. All Part A estimands will use the SS.
  • a treatment policy approach will be used for all intercurrent events, with all available data from participants being included regardless of treatment discontinuation, treatment compliance, or any deviations from the study protocol.
  • SDPS1 will be used to estimate safety endpoints which are collected at scheduled visits.
  • SDPS2 will be used to estimate safety endpoints which are assessed at any time in the study.
  • Safety Endpoint Details [911] Exploratory Biomarker and PK Estimands [912] The exploratory estimands relating to the microbiome composition, blood RNA expression, Prevotella histicola smEV systemic levels in blood and other biomarkers will be addressed fully in a separate data analysis plan. This data is not expected to be included in the CSR.
  • the primary estimand and the supplemental estimands for the primary objective will consider the effect of Prevotella histicola smEVs compared to placebo on the percentage of participants achieving PASI-50 at Week 16. While the main analysis timepoint of interest is at Week 16, other timepoints with PASI data will also be evaluated and considered supplementary to the Week 16 results and to further inform on the response-time relationships.
  • the population summary measure of interest will be the odds ratio between the Prevotella histicola smEV treatment group and placebo group. The FAS will be used.
  • the intercurrent event strategy used is the same as that for the primary estimand
  • a treatment policy estimand will be used with data analysed as collected.
  • the main analysis timepoint of interest is at Week 16, but all timepoints with data collected for the relevant endpoint will also be evaluated and considered supplementary to the Week 16 results and to further inform on the response-time relationships.
  • the same intercurrent event strategy used for the Week 16 estimands will also be applied to other post-baseline timepoints for the relevant endpoint.
  • Body mass index, gender, race, and region will also be considered and included in the model if found to be significant (p ⁇ 0.05).
  • the actual and predicted proportions of PASI-50 responders will be presented together with the odds ratio, with 95% CI and associated p-value, for the Prevotella histicola smEV group compared to the placebo group.
  • the percentage of participants with PASI-50 response for each treatment group at each scheduled visit will be presented in a vertical bar chart. The odds ratios with associated 95% CI will also be plotted.
  • LS mean (with 95% CI) estimates will be plotted by treatment group against visit.
  • LS mean treatment differences (with 95% CI) between the Prevotella histicola smEV group and the placebo group will also be plotted against visit.
  • Waterfall plots will also be produced for each endpoint at the Week 16 visit.
  • graphical summaries showing the weekly mean ( ⁇ SE) item scores will be plotted. Study weeks will be defined by 7-day blocks starting from Day 2 with Week 1 comprised of the average of Days 2-8, Week 2 comprised of the average of Days 9-15 etc.
  • the samples may be analysed as part of a multi-study assessment of genetic factors involved in the response to Prevotella histicola smEVs or study interventions of this class to understand study disease or related conditions. .
  • the results of genetic analyses will be reported separately to the CSR.
  • the sponsor or its agents will store the DNA samples in a secure storage space with adequate measures to protect confidentiality. .
  • the samples will be stored for a maximum of 10 years and will be destroyed if not used within this time.
  • the Prevotella histicola smEVs are from Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
  • Cohort 1 3.9 x 10 12 equivalent total particle number (eTPN) Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with atopic dermatitis for 16 or 24 weeks.
  • Cohort 2 1.95 x 10 13 eTPN Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with atopic dermatitis for 16 or 24 weeks.
  • Cohort 3 1.12 x 10 14 eTPN Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with atopic dermatitis for 16 or 24 weeks.
  • Cohort 4 7.5 x 10 13 eTPN Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with atopic dermatitis for 16 or 24 weeks.
  • Cohort 5 3.9 x 10 11 equivalent total particle number (eTPN) Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with atopic dermatitis for 16 or 24 weeks.
  • Prevotella histicola smEVs enteric-coated capsules contain lyophilised powder Prevotella histicola smEVs as the API, mannitol, colloidal silicon dioxide, magnesium stearate, hydroxypropyl methylcellulose, methacrylic acid-ethyl acrylate copolymer, talc, triethyl citrate, titanium dioxide, and iron oxide.
  • the capsule is a size 0 capsule that is enteric coated with Eudragit L30D-55 at a coating level to a total weight gain of 14 mg/capsule (2.7 mg/cm 2 ) (a polymer weight gain of 1.7 mg/cm 2 ).
  • EASI Eczema Area and Severity Index
  • EASI score ranges from 0 – 72.
  • EASI, 2017 EASI-50 and EASI-75 responses are defined as at least 50% and 75% decrease from baseline EASI score respectively.
  • SCORAD The SCORing Atopic Dermatitis (SCORAD) is a clinical tool which is also used to assess the extent and severity of eczema, to assess treatment effects (ETFAD, 1993). As well as an investigator-rated area and disease intensity score, there is a subjective symptoms component which takes into account itch and sleeplessness using a visual analogue scale. The SCORAD score ranges from 0 – 103. [988] BSA.
  • the Body Surface Area is a measure of the extent of atopic dermatitis at a given time. It is calculated by estimating the number of participant’s handprints of active atopic dermatitis are present; where one handprint (including digits) represents 1% body surface area.
  • IGA The Validated Investigator Global Assessment scale for Atopic Dermatitis (vIGA-AD) will be used to describe the overall appearance of lesions, at a given time-point (Simpson, 2020). There is a standardized grading system. In indeterminate cases, extent will be used to differentiate between scores – but otherwise extent is not used in the scoring system. The IGA score ranges from 0 (Clear) to 4 (Severe).
  • IGA x BSA The product of the IGA and BSA provides a simple but useful measure of the extent and severity of eczema that is commonly used in the clinical trial setting.
  • DLQI questionnaire This is a validated patient reported outcomes instrument which asks 10 questions to assess how a participant’s skin disease has affected their quality of life over the past week (Finlay, 1994). The DLQI score ranges from 0 to 30.
  • POEM questionnaire The Patient-Orientated Eczema Measure (POEM) includes 7 questions about the participant’s atopic dermatitis. Each of the 7 questions is scored from 0 to 4, giving a POEM score range from 0 to 28.
  • Pruritus NRS questionnaire The Patient-Orientated Eczema Measure (POEM) includes 7 questions about the participant’s atopic dermatitis. Each of the 7 questions is scored from 0 to 4, giving a POEM score range from 0 to 28.
  • Pruritus-NRS The Pruritus Numerical Rating Scale (Pruritus-NRS) is a 10-point scale for participants to rate both their average and worst itch that they have experienced over the previous 24 hours.
  • Example 8 Prevotella histicola Strain B smEVs Treatment for Psoriatic Arthritis
  • Prevotella histicola Strain B smEVs are used for the treatment of psoriatic arthritis (PsA), e.g., at the doses and dosing regimens provided herein.
  • PsA psoriatic arthritis
  • the Prevotella histicola smEVs are from Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
  • Cohort 1 3.9 x 10 12 equivalent total particle number (eTPN) Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with psoriatic arthritis for 16 or 24 weeks.
  • Cohort 2 1.95 x 10 13 eTPN Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with psoriatic arthritis for 16 or 24 weeks.
  • Cohort 3 1.12 x 10 14 eTPN Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with psoriatic arthritis for 16 or 24 weeks.
  • Cohort 4 7.5 x 10 13 eTPN Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with psoriatic arthritis for 16 or 24 weeks.
  • Cohort 5 3.9 x 10 11 equivalent total particle number (eTPN) Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with psoriatic arthritis for 16 or 24 weeks.
  • Prevotella histicola smEVs enteric-coated capsules contain lyophilised powder Prevotella histicola smEVs as the API, mannitol, colloidal silicon dioxide, magnesium stearate, hydroxypropyl methylcellulose, methacrylic acid-ethyl acrylate copolymer, talc, triethyl citrate, titanium dioxide, and iron oxide.
  • the capsule is a size 0 capsule that is enteric coated with Eudragit L30D-55 at a coating level to a total weight gain of 14 mg/capsule (2.7 mg/cm 2 ) (a polymer weight gain of 1.7 mg/cm 2 ).
  • Endpoints [1002] The effects of Prevotella histicola Strain B smEVs on psoriatic arthritis can be evaluated by one or more of the following criteria e.g., at week 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 and/or 2 or 4 weeks after treatment: [1003] Percentage of patients with an ACR20, ACR50, and/or ACR70 response: The ACR (American College of Rheumatology) is a standard criteria originally developed to measure the effectiveness of various arthritis medications or treatments in clinical trials for rheumatoid arthritis but is also widely used in PsA The ACR measures improvement in tender joint count (TJC) or swollen joint count (SJC), and improvement in at least 3 of the following 5 parameters: Patient Global Assessment (PtGA), Physician's Global Assessment of Disease Activity (PhGA), physical function (using HAQ-DI), visual analog pain scale, and acute phase reactant (using ESR or CRP).
  • PtGA Patient Global Assessment
  • ACR 20/50/70 response is achieved if ⁇ 20% / ⁇ 50% / ⁇ 70% improvement in tender joint count (TJC) or swollen joint count (SJC) as well as a ⁇ 20% / ⁇ 50% / ⁇ 70% improvement in ⁇ 3 of the other 5 parameters.
  • PsARC Modified Psoriatic Arthritis Response Criteria
  • Dactylitis severity score Changes from baseline in Dactylitis Severity Score at 4, 8, 12, and/or 16 weeks.
  • the total score is calculated as the sum of the individual digits dactylitis scores, ranging from a minimum 0 to a maximum of 60, with higher scores corresponding to worse severities.
  • the CDAI score ranges from 0-76 where lower scores indicate less disease activity.
  • DAS28 Disease Activity Score (DAS): Changes in DAS28 (utilizing hsCRP) from baseline.
  • the DAS28 is a measure of disease activity in PsA based on Swollen and Tender Joint Counts (out of a total of 28), hsCRP and the Patient's Global Assessment of Disease Activity
  • a DAS28 score higher than 51 indicates high disease activity
  • a DAS28 score of 3.2 to 5.1 indicates moderate disease activity
  • a DAS28 score of 2.6 to 3.2 indicates low disease activity
  • a DAS28 score less than 2.6 indicates clinical remission.
  • Maastricht Ankylosing Spondylitis Enthesis Score (MASES): The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Achilles tendon left/right.
  • the MASES ranging from 0 to 13, is the number of painful entheses out of 13 entheses. See also L Heuft-Dorenbosch et al., Ann. Rheum. Dis.62: 127-132 (2003).
  • Psoriasis Area and Severity Index Psoriasis Area and Severity Index (PASI), Nail Psoriasis Severity Index (NAPSI), Modified Nail Psoriasis Severity Index (mNAPSI), Mander/Newcastle Enthesitis Index (MEI), Leeds Enthesitis Index (LEI), Spondyloarthritis Research Consortium of Canada (SPARCC), Maastricht Ankylosing Spondylitis Enthesis Score (MASES), Leeds Dactylitis Index (LDI), Patient Global for Psoriatic Arthritis, Dermatology Life Quality Index (DLQI), Psoriatic Arthritis Quality of Life (PsAQOL), Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT ⁇ F), Psoriatic Arthritis Response Criteria (PsARC), Psoriatic Arthritis Response Criteria (PsARC), Psoriatic Arthritis Response Criteria (PsARC), Psoriatic Arthritis
  • Example 9 A Phase 1/2, Randomised, Placebo-Controlled Study of Prevotella histicola Strain B smEVs in Healthy Volunteers and Participants with Moderate Plaque Psoriasis [1011]
  • the Prevotella histicola smEVs are from Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
  • Prevotella histicola smEVs are used for the treatment of psoriasis (such as mild to moderate psoriasis), e.g., at the doses and dosing regimens provided herein.
  • the Prevotella histicola smEVs are from Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
  • Cohort 1 3.9 x 10 12 equivalent total particle number (eTPN) Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with psoriasis for 16 or 24 weeks.
  • Cohort 2 1.95 x 10 13 eTPN Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with psoriasis for 16 or 24 weeks.
  • Cohort 3 1.12 x 10 14 eTPN Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with psoriasis for 16 or 24 weeks.
  • Cohort 4 7.5 x 10 13 eTPN Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with psoriasis for 16 or 24 weeks.
  • Cohort 5 3.9 x 10 11 equivalent total particle number (eTPN) Prevotella Strain B smEVs or matching placebo administered as capsules, once daily to subjects with psoriasis for 16 or 24 weeks.
  • Prevotella histicola smEVs enteric-coated capsules contain lyophilised powder Prevotella histicola smEVs as the API, mannitol, colloidal silicon dioxide, magnesium stearate, hydroxypropyl methylcellulose, methacrylic acid-ethyl acrylate copolymer, talc, triethyl citrate, titanium dioxide, and iron oxide.
  • the capsule is a size 0 capsule that is enteric coated with Eudragit L30D-55 at a coating level to a total weight gain of 14 mg/capsule (2.7 mg/cm 2 ) (a polymer weight gain of 1.7 mg/cm 2 ).
  • Endpoints [1022] The effects of Prevotella histicola Strain B smEVs on psoriasis are evaluated by one or more criteria e.g., at week 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or 56 and/or 2 or 4 weeks after treatment. The endpoints are one or more of the criteria provided in Example 6. Incorporation by Reference [1023] All publications patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. Equivalents [1024] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

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Abstract

L'invention concerne des procédés et des compositions associés à des vésicules extracellulaires de Prevotella histicola utiles en tant qu'agents thérapeutiques, par exemple, pour le traitement d'une maladie inflammatoire.
PCT/US2023/024590 2022-06-07 2023-06-06 Compositions et méthodes de traitement d'une inflammation à l'aide de vésicules extracellulaires de prevotella histicola Ceased WO2023239728A1 (fr)

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Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4775536A (en) 1986-02-24 1988-10-04 Bristol-Myers Company Enteric coated tablet and process for making
US5047258A (en) 1989-07-14 1991-09-10 Sterling Drug Inc. Aqueous spray-coating process
US5292522A (en) 1989-06-20 1994-03-08 Rohm Gmbh Aqueous film coating agent for solid medicaments
US6312728B1 (en) 1998-07-07 2001-11-06 Cascade Development, Inc. Sustained release pharmaceutical preparation
US6555124B1 (en) 1996-08-01 2003-04-29 Basf Aktiengesellschaft Use of (meth)acrylic acid copolymers to increase the permeability of mucous membranes
US6623759B2 (en) 1996-06-28 2003-09-23 Astrazeneca Ab Stable drug form for oral administration with benzimidazole derivatives as active ingredient and process for the preparation thereof
US6638534B1 (en) 1998-07-28 2003-10-28 Tanabe Seiyaku Co., Ltd. Preparation capable of releasing drug at target site in intestine
US20040028737A1 (en) 2002-08-12 2004-02-12 Kopran Research Laboratories Limited Enteric coated stable oral pharmaceutical composition of acid unstable drug and process for preparing the same
WO2005044240A2 (fr) 2003-10-31 2005-05-19 Dexcel, Ltd. Formulation stable contenant du lansoprazole
US20050271778A1 (en) 2002-12-20 2005-12-08 Roehm Gmbh & Co., Kg Method for producing coated pharmaceuticals and food supplements with concentration gradients in the coating thereof
US20060210631A1 (en) 2005-03-21 2006-09-21 Patel Ashish A Multi-particulate, modified-release composition
US20080200482A1 (en) 2005-07-12 2008-08-21 Evonik Roehm Gmbh Use of a Partially Neutralized, Anionic (Meth)Acrylate Copolymer as a Coating for the Production of a Medicament Releasing Active Substance at Reduced Ph Values
US9233074B2 (en) 2013-03-01 2016-01-12 Bpsi Holdings, Llc Delayed release film coatings containing calcium silicate and substrates coated therewith
WO2019051381A1 (fr) * 2017-09-08 2019-03-14 Evelo Biosciences, Inc. Vésicules extracellulaires provenant de prevotella
WO2020172492A2 (fr) * 2019-02-22 2020-08-27 Evelo Biosciences, Inc. Préparations de membrane bactérienne
WO2020252149A1 (fr) * 2019-06-11 2020-12-17 Evelo Biosciences, Inc. Vésicules extracellulaires microbiennes traitées
WO2020257390A1 (fr) * 2019-06-21 2020-12-24 Evelo Biosciences, Inc. Compositions et procédés de traitement d'une affection médiée par th2 à l'aide de prevotella
WO2022061094A1 (fr) 2020-09-18 2022-03-24 Evelo Biosciences, Inc. Formes galéniques solides de bactéries
WO2022132738A1 (fr) 2020-12-14 2022-06-23 Evelo Biosciences, Inc. Préparations de vésicules extracellulaires
WO2022164806A1 (fr) 2021-01-26 2022-08-04 Evelo Biosciences, Inc. Préparations de vésicules extracellulaires de prevotella
WO2022187578A1 (fr) 2021-03-05 2022-09-09 Evelo Biosciences, Inc. Formes posologiques solides

Patent Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4775536A (en) 1986-02-24 1988-10-04 Bristol-Myers Company Enteric coated tablet and process for making
US5292522A (en) 1989-06-20 1994-03-08 Rohm Gmbh Aqueous film coating agent for solid medicaments
US5047258A (en) 1989-07-14 1991-09-10 Sterling Drug Inc. Aqueous spray-coating process
US6623759B2 (en) 1996-06-28 2003-09-23 Astrazeneca Ab Stable drug form for oral administration with benzimidazole derivatives as active ingredient and process for the preparation thereof
US6555124B1 (en) 1996-08-01 2003-04-29 Basf Aktiengesellschaft Use of (meth)acrylic acid copolymers to increase the permeability of mucous membranes
US6312728B1 (en) 1998-07-07 2001-11-06 Cascade Development, Inc. Sustained release pharmaceutical preparation
US6638534B1 (en) 1998-07-28 2003-10-28 Tanabe Seiyaku Co., Ltd. Preparation capable of releasing drug at target site in intestine
US20040028737A1 (en) 2002-08-12 2004-02-12 Kopran Research Laboratories Limited Enteric coated stable oral pharmaceutical composition of acid unstable drug and process for preparing the same
US20050271778A1 (en) 2002-12-20 2005-12-08 Roehm Gmbh & Co., Kg Method for producing coated pharmaceuticals and food supplements with concentration gradients in the coating thereof
WO2005044240A2 (fr) 2003-10-31 2005-05-19 Dexcel, Ltd. Formulation stable contenant du lansoprazole
US20060210631A1 (en) 2005-03-21 2006-09-21 Patel Ashish A Multi-particulate, modified-release composition
US20080200482A1 (en) 2005-07-12 2008-08-21 Evonik Roehm Gmbh Use of a Partially Neutralized, Anionic (Meth)Acrylate Copolymer as a Coating for the Production of a Medicament Releasing Active Substance at Reduced Ph Values
US9233074B2 (en) 2013-03-01 2016-01-12 Bpsi Holdings, Llc Delayed release film coatings containing calcium silicate and substrates coated therewith
WO2019051381A1 (fr) * 2017-09-08 2019-03-14 Evelo Biosciences, Inc. Vésicules extracellulaires provenant de prevotella
WO2020172492A2 (fr) * 2019-02-22 2020-08-27 Evelo Biosciences, Inc. Préparations de membrane bactérienne
WO2020252149A1 (fr) * 2019-06-11 2020-12-17 Evelo Biosciences, Inc. Vésicules extracellulaires microbiennes traitées
WO2020257390A1 (fr) * 2019-06-21 2020-12-24 Evelo Biosciences, Inc. Compositions et procédés de traitement d'une affection médiée par th2 à l'aide de prevotella
WO2022061094A1 (fr) 2020-09-18 2022-03-24 Evelo Biosciences, Inc. Formes galéniques solides de bactéries
WO2022132738A1 (fr) 2020-12-14 2022-06-23 Evelo Biosciences, Inc. Préparations de vésicules extracellulaires
WO2022164806A1 (fr) 2021-01-26 2022-08-04 Evelo Biosciences, Inc. Préparations de vésicules extracellulaires de prevotella
WO2022187578A1 (fr) 2021-03-05 2022-09-09 Evelo Biosciences, Inc. Formes posologiques solides

Non-Patent Citations (39)

* Cited by examiner, † Cited by third party
Title
"FDA Guidance for Industry", July 2009, US DEPARTMENT OF HEALTH AND HUMAN SERVICES, article "Drug-induced liver injury: premarketing clinical evaluation"
ACHTMAN MWAGNER M: "Microbial diversity and the genetic nature of microbial species", NAT. REV. MICROBIOL., vol. 6, no. 431-440, 2008, pages 431 - 440, XP037115178, DOI: 10.1038/nrmicro1872
ATSCHUL, S. F. ET AL., J MOLEC BIOL, vol. 215, 1990, pages 403
BASRA MKSALEK MSCAMILLERI LSTURKEY RFINLAY AY: "Determining the minimal clinically important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further data", DERMATOLOGY, vol. 230, no. 1, 2015, pages 27 - 33
CARDING ET AL.: "Dysbiosis of the Gut Microbiota in Disease", MICROB. ECOL. HEALTH DIS, vol. 26, 2015, pages 26191
CARILLO ET AL., SIAM J APPLIED MATH, vol. 48, 1988, pages 1073
CITI, S: "Intestinal Barriers protect against disease", SCIENCE, vol. 359, 2018, pages 1098 - 99
CLAESSON M JWANG QO'SULLIVAN OGREENE-DINIZ RCOLE J RROS RPO'TOOLE P W: "Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions", NUCLEIC ACIDS RES, vol. 38, no. 8, 2010, pages e200, XP055250083, DOI: 10.1093/nar/gkq873
DEVEREUX, J. ET AL., NUCLEIC ACIDS RESEARCH, vol. 12, no. I, 1984, pages 387
FELDMAN SRKRUEGER GG: "Psoriasis assessment tools in clinical trials", ANN RHEUM DIS, vol. 64, 2005, pages ii65 - 8
FINLAY AYKHAN GK: "Dermatology Life Quality Index (DLQI)-a simple practical measure for routine clinical use", CLIN EXP DERMATOL, vol. 19, no. 3, 1994, pages 210 - 6
G. NORHEIM ET AL., PLOS ONE., vol. 10, no. 9, 2015, pages e0134353
GLADMAN ET AL., J RHEUMATOLOGY, vol. 34, 2007, pages 1159 - 1166
GRIFFITHS CEMARMSTRONG AWGUDJONSSON JEBARKER JNWN, PSORIASIS. LANCET, vol. 397, 2021, pages 1301 - 15
HOOKSO'MALLEY: "mBio", vol. 8, October 2017, AMERICAN SOCIETY FOR MICROBIOLOGY, article "Dysbiosis and its discontents", pages: e01492 - 17
ITANO ANDREA ET AL: "Orally-administered EDP1815, a single strain of Prevotella histicola, has potent systemic anti-inflammatory effects in Type 1, Type 2, and Type 3 inflammatory models", 31 December 2020 (2020-12-31), XP055922007, Retrieved from the Internet <URL:https://evelobio.com/wp-content/uploads/2020/12/Evelo-EADV-2020-Poster.pdf> [retrieved on 20220517] *
JEPPESEN ET AL., CELL, vol. 177, 2019, pages 428
KONSTANTINIDIS K TRAMETTE ATIEDJE J M.: "The bacterial species definition in the genomic era", PHILOS TRANS R SOC LOND B BIOL SCI, vol. 361, 2006, pages 1929 - 1940
L HEUFT-DORENBOSCH ET AL., ANN. RHEUM. DIS., vol. 62, 2003, pages 127 - 132
LANGLEY RGELLIS CN: "Evaluating psoriasis with Psoriasis Area and Severity Index, Psoriasis Global Assessment, and Lattice System Physician's Global Assessment", J AM ACAD DERMATOL, vol. 51, no. 4, 2004, pages 563 - 9, XP004590820, DOI: 10.1016/j.jaad.2004.04.012
LEVY ET AL.: "Dysbiosis and the Immune System", NATURE REVIEWS IMMUNOLOGY, vol. 17, April 2017 (2017-04-01), pages 219, XP055953368, DOI: 10.1038/nri.2017.7
LYNCH ET AL.: "The Human Microbiome in Health and Disease", N. ENGL. J. MED, vol. 375, 2016, pages 2369 - 79
MANGALAM ASHAHI SKLUCKEY DKARAU MMARIETTA ELUO N ET AL.: "Human gut-derived commensal bacteria suppress CNS inflammatory and demyelinating disease", CELL REP., vol. 20, no. 6, 2017, pages 1269 - 1277, XP055741471, DOI: 10.1016/j.celrep.2017.07.031
MARIETTA EVMURRAY JALUCKEY DHJERALDO PRLAMBA APATEL R ET AL.: "Human gut-derived Prevotella histicola suppresses inflammatory arthritis in humanized mice", ARTHRITIS RHEUMATOL., vol. 68, no. 12, 2016, pages 2878 - 2888, XP055665204, DOI: 10.1002/art.39785
MEASE, ARTHRITIS CARE & RESEARCH, vol. 63, 2011, pages S64 - S85
PEARSON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 85, 1988, pages 2444
PHAN NQBLOME CFRITZ FGERSS JREICH AEBATA T ET AL.: "Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus", ACTA DERM VENEREOL., vol. 92, no. 5, 2012, pages 502 - 7
S. BIN PARK ET AL., PLOS ONE, vol. 6, no. 3, 2011, pages 17629
SANDRINI ET AL., BIO-PROTOCOL, vol. 4, no. 21, 2014, pages e1287
SRINIVASAN ET AL.: "TEER measurement techniques for in vitro barrier model systems", J. LAB. AUTOM., vol. 20, 2015, pages 107 - 126, XP055560328, DOI: 10.1177/2211068214561025
STROBER BENYIRADY JMALLYA UGGUETTNER APAPAVASSILIS CGOTTLIEB AB ET AL.: "Item-level psychometric properties for a new patient-reported psoriasis symptom diary", VALUE HEALTH, vol. 16, no. 6, 2013, pages 1014 - 22, XP028716559, DOI: 10.1016/j.jval.2013.07.002
SWINBURN PLLOYD ABOYE KSEDSON-HEREDIA EBOWMAN LJANSSEN B: "Development of a disease-specific version of the EQ-5D-5L for use in patients suffering from psoriasis: lessons learned from a feasibility study in the UK", VALUE HEALTH, vol. 16, no. 8, 2013, pages 1156 - 62, XP028798091, DOI: 10.1016/j.jval.2013.10.003
THEIN ET AL., J. PROTEOME RES., vol. 9, no. 12, 2010, pages 6135 - 6147
VUKMANOVIC-STEJIC MREED JRLACY KERUSTIN MHAKBAR AN: "Mantoux Test as a model for a secondary immune response in humans", IMMUNOL LETT., vol. 107, no. 2, 2006, pages 93 - 101, XP024999090, DOI: 10.1016/j.imlet.2006.08.002
WALKER, W.A.: "The Microbiota in Gastrointestinal Pathophysiology", 2017, article "Dysbiosis"
WALSH JAMCFADDEN MWOODCOCK JCLEGG DOHELLIWELL PDOMMASCH E ET AL.: "Product of the Physician Global Assessment and body surface area: a simple static measure of psoriasis severity in a longitudinal cohort.", J AM ACAD DERMATOL., vol. 69, no. 6, 2013, pages 931 - 7
WEISKOPF DSCHMITZ KSRAADSEN MPGRIFONI AOKBA NMAENDEMAN HVAN DEN AKKER JPCMOLENKAMP RKOOPMANS MPGVAN GORP ECM: "Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome", SCI IMMUNOL., vol. 5, no. 48, 26 June 2020 (2020-06-26), pages eabd2071, XP055896273, DOI: 10.1126/sciimmunol.abd2071
WEISSTHIERRY: "Mechanisms and consequences of intestinal dysbiosis", CELLULAR AND MOLECULAR LIFE SCIENCES, vol. 74, no. 16, 2017, pages 2959 - 2977, XP036272294, DOI: 10.1007/s00018-017-2509-x
YOSIPOVITCH GREANEY MMASTEY VECKERT LABBE ANELSON L ET AL.: "Peak Pruritus Numerical Rating Scale: psychometric validation and responder definition for assessing itch in moderate-to-severe atopic dermatitis.", BR J DERMATOL., vol. 181, no. 4, 2019, pages 761 - 9

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