Methods and compositions for treating conditions associated with an abnormal inflammatory response
Inventors
Glick, Gary D. • Franchi, Luigi
Assignees
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Publication Number
US-10849867-B2
Publication Date
2020-12-01
Expiration Date
Abstract
This disclosure features chemical entities (e.g., a compound exhibiting activity as a mitochondrial uncoupling agent or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof; e.g., a compound, such as niclosamide or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof; e.g., a compound, such as a niclosamide analog, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof) that are useful, e.g., for treating one or more symptoms of a pathology characterized by an abnormal inflammatory response (e.g., inflammatory bowel diseases) in a subject (e.g., a human). This disclosure also features compositions as well as other methods of using and making the same.
Core Innovation
The disclosed subject matter is directed to methods for treating gastrointestinal tissue damage in a subject by administering an effective amount of niclosamide or a pharmaceutically acceptable salt thereof. The gastrointestinal tissue damage is associated with unregulated recruitment and/or retention and/or activation of an immune cell in the subject, including activated T cells, and the disclosure also describes niclosamide analogues, salts, hydrates, cocrystals, and pharmaceutical compositions.
The approach extends to local administration and to specific anatomical associations within the gastrointestinal tract, including intestinal epithelium, Peyer’s patches, mucosa, lamina propria, GALT, submucosa, muscular layer, and serosa. Gut-tropic T cells are further defined by gut-homing receptor markers, and the disclosure emphasizes a GI-tract concentration that is higher than the concentration in plasma.
The document also provides chemical-structure embodiments of niclosamide analogues, including generalized structural formulas with modular substituent definitions. The described embodiments emphasize mitochondrial uncoupling, induced death of activated immune cells, and pharmaceutical compositions intended to provide controlled bioavailability and improved dissolution and solubility.
Claims Coverage
The independent claim covers treating gastrointestinal tissue damage by administering niclosamide, or a pharmaceutically acceptable salt, where the damage is associated with unregulated recruitment and/or retention and/or activation of an immune cell. The inventive features further refine local administration, immune-cell location in the intestinal epithelium or Peyer’s patches, gut-tropic T-cell marker definitions, and a GI-tract versus plasma concentration relationship.
Treating gastrointestinal tissue damage via niclosamide for immune-cell dysregulation
Administering an effective amount of niclosamide, or a pharmaceutically acceptable salt thereof, for treating gastrointestinal tissue damage in a subject where the gastrointestinal tissue damage is associated with unregulated recruitment and/or retention and/or activation of an immune cell.
Locally administering niclosamide
Administering the effective amount of niclosamide, or a pharmaceutically acceptable salt thereof, by local administration to the subject for treating the gastrointestinal tissue damage.
Immune-cell unregulated recruitment/retention/activation at intestinal epithelium
Associating the gastrointestinal tissue damage with unregulated recruitment, retention and/or activation of an immune cell at the intestinal epithelium of the subject.
Immune-cell unregulated recruitment/retention/activation in Peyer’s patches
Associating the gastrointestinal tissue damage with unregulated recruitment, retention and/or activation of an immune cell in the Peyer’s patches of the subject.
Gut-tropic T cells defined by gut-homing receptor markers
Gut-tropic T cells express at least one gut-homing receptor selected from CD3+CCR9+, CD3+α4+β27+, CD3+α4+β227+, CD3+CCR4+, and CD3+CCR10+.
Higher niclosamide concentration in the GI tract than in plasma
Upon administration, achieving a niclosamide concentration in the GI tract that is higher than the concentration of niclosamide in the plasma compartment.
Overall, the claim set centers on niclosamide administration to treat gastrointestinal tissue damage driven by unregulated immune-cell recruitment, retention, and/or activation, with added specificity through local delivery, location-specific immune-cell association within the gastrointestinal tract, immune-cell subtype definition using gut-tropic T cells and gut-homing receptors, and a comparative concentration relationship emphasizing higher niclosamide levels in the GI tract than in plasma.
Stated Advantages
Improved dissolution and solubility of niclosamide cocrystals.
Controlled bioavailability attributed to niclosamide cocrystals.
Local GI delivery achieving higher GI than plasma concentrations.
Documented Applications
Treating gastrointestinal tissue damage associated with unregulated immune-cell recruitment and/or retention and/or activation, including inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease, autoimmune colitis, and checkpoint-inhibitor-associated colitis.
Rectal efficacy in a murine TNBS colitis model, including reduced cytokine expression.
Inducing T-cell death in human IBD lamina propria T cells.
Inducing death of activated T cells via mitochondrial uncoupling to reduce colitis and modulate cytokines.
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