Treatment of Clostridium difficile infection
Inventors
Schneider, Jessica • Kim, Yun-gi • Olle, Bernat • Reddy, Shilpa • Norman, Jason • Patarroyo, Juan
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11701396-B2
Publication Date
2023-07-18
Expiration Date
Abstract
Provided herein are compositions and methods for the treatment or prevention of pathogenic infections.
Core Innovation
The invention relates to a purified bacterial mixture pharmaceutical composition comprising 7 to 10 bacterial strains, wherein at least 7 of the bacterial strains comprise 16S rDNA sequences having at least 97% sequence identity to sequences independently selected from SEQ ID NO:10, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21, and wherein the bacterial strains are lyophilized. In some embodiments, the composition includes one or more enteric polymers, is in the form of a capsule, and comprises between 1×10^7 and 1×10^10 colony forming units (CFUs) per bacterial strain.
The disclosed material also describes bacterial taxonomic assignments and strain identifiers using whole-genome-sequencing with PacBio and Sanger 16S region homology results to identify bacterial strains via consensus and closest-species matching, including permissible strain substitutions for certain bacterial strains. The work reports LBP preparation and testing associated with defined compositions labeled Composition B, Composition F, and Composition I, together with extensive 16S rRNA sequence data supporting strain identification.
The pharmaceutical composition is used for treating infectious disease, including Clostridium difficile infection, by administering the disclosed pharmaceutical composition to a subject in an amount sufficient to treat the infection, with further embodiments directed to recurrent Clostridium difficile infection. The disclosed work also reports in vivo and in vitro evaluation, including murine models, survival/mortality, weight monitoring, fecal C. difficile CFU enumeration, toxin-related assessment, competition against C. difficile growth, SCFA production, and induction of regulatory T cells.
Claims Coverage
The independent claims cover two core inventive features: a purified bacterial mixture of 7 to 10 strains defined by 16S rDNA sequence identity and lyophilized in one claim, and a second formulation claim with one or more enteric polymers, capsule form, and specified CFUs per bacterial strain. The claims are directed to treatment of Clostridium difficile infection, including recurrent infection embodiments.
Purified lyophilized bacterial mixture with 16S rDNA identity
A pharmaceutical composition comprising a purified bacterial mixture consisting of 7 to 10 bacterial strains, wherein at least 7 of the bacterial strains comprise 16S rDNA sequences of at least 97% sequence identity to sequences independently selected from SEQ ID NO:10, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21, wherein the bacterial strains are lyophilized.
Enteric polymer capsule composition with defined CFUs
A pharmaceutical composition comprising a purified bacterial mixture consisting of 7 to 10 bacterial strains, wherein at least 7 of the bacterial strains comprise 16S rDNA sequences of at least 97% sequence identity to sequences independently selected from SEQ ID NO:10, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21; and one or more enteric polymers; wherein the pharmaceutical composition comprises between 1×10^7 and 1×10^10 CFUs per bacterial strain; and wherein the pharmaceutical composition is in the form of a capsule.
The claims are centered on a purified bacterial mixture of 7 to 10 strains with at least 7 strains meeting a 16S rDNA sequence-identity criterion to specified SEQ ID NOs, with lyophilization in one claim and enteric polymers, capsule form, and defined CFU ranges per strain in the other.
Stated Advantages
Compositions with BaiCD− strains are stated to be more effective at treating C. difficile.
Compositions with BaiCD− strains are stated to reduce C. difficile Toxin B versus BaiCD+ compositions.
The mixture can induce regulatory T cells, including via production of short-chain fatty acids.
Protects and/or treats C. difficile infection, as assessed by survival/mortality, weight, and fecal C. difficile CFUs.
Documented Applications
Treatment of a Clostridium difficile infection in a subject, including recurrent Clostridium difficile infection.
Colon-targeted delivery.
Protecting and/or treating C. difficile infection in a murine Clostridium difficile infection model, with outcomes assessed via survival/mortality, weight monitoring, and fecal C. difficile CFU enumeration.
Treating a recurrent Clostridium difficile infection.
Suppressing an abnormal or excessive immune response by inducing the proliferation and/or accumulation of regulatory T cells.
Delivering the pharmaceutical composition to the colon.
Assessment of C. difficile toxin-related effects, including C. difficile toxin B effects on Vero/epithelial cells and reduced toxin after treatment.
In vitro competition against C. difficile growth using a composition and associated inhibition effects.
SCFA profiling, including short-chain fatty acid production of acetate, propionate, and butyrate by individual consortium strains.
Immune modulation, including induction of regulatory T cells (Foxp3+ CD4+ Tregs) after colonization with a composition.
Interested in licensing this patent?