Compositions for the treatment of fibrosis
Inventors
Lian, Brian • Masamune, Hiroko • Barker, Geoffrey E.
Assignees
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Publication Number
US-11707472-B2
Publication Date
2023-07-25
Expiration Date
Abstract
The present disclosure is directed to methods of treating fibrotic conditions by administration of TRβ agonists. The disclosure provides methods wherein the abnormal deposition of extracellular matrix components, such as collagen, keratin, or elastin, is reduced, either through interaction of TRβ agonists with TGF-β-dependent inflammatory pathways, or by other mechanisms, thereby ameliorating fibrotic symptoms.
Core Innovation
The disclosed subject matter relates to therapeutically treating fibrosis by administering at least one compound, or pharmaceutically acceptable salt thereof, having a structure selected from a group of TRβ agonist compounds and phosphorus-containing aromatic compounds. The therapeutic method results in the reduction in the amount of extracellular matrix proteins present in one or more tissues in a subject in need thereof.
The fibrosis treatment is described as reducing abnormal extracellular matrix deposition, including collagen, elastin, keratin, and related fibrotic extracellular matrix proteins. The disclosure further characterizes the approach by reduction of specific collagen types, including Type I, Type Ia, and Type III, and by reduction of gene expression markers including Cola1, Col3a1, αSMA, and Galectin1.
The disclosure provides compound structures selected from groups that include a Formula I scaffold and phosphorus-containing aromatic compounds with phenolic groups and a phosphate/phosphonate moiety. The described embodiments cover fibrosis conditions, tissues, administration routes, formulations, and in vivo liver fibrosis outcomes in NASH/biopsy-related models, including comparisons using hydroxyproline, collagen staining such as Picro-Sirius Red, collagen marker assessments, and fibrogenic marker gene expression.
Claims Coverage
The independent claims cover two closely related methods: therapeutically treating fibrosis and reducing extracellular matrix proteins in one or more tissues by administering compounds selected from disclosed structure groups. The claim coverage includes 7 inventive features, with refinements directed to collagen types, gene-expression markers, subject condition, disease context, and administration routes/formulations.
Therapeutically treating fibrosis by administering selected compounds
A method of therapeutically treating fibrosis in a subject in need thereof, resulting in reduction in the amount of extracellular matrix proteins present in one or more tissues, by administering at least one compound, or pharmaceutically acceptable salt thereof, having a structure selected from the disclosed group.
Reducing extracellular matrix proteins by administering selected compounds
A method of reduction in the amount of extracellular matrix proteins present in one or more tissues in a subject, comprising administering one or more compounds, or pharmaceutically acceptable salts thereof, having a structure selected from the disclosed group to a subject in need thereof.
Reducing specific collagen types
The method administers a compound such that it reduces the amount of Type I, Type Ia, or Type III collagen in one or more tissues of the subject.
Reducing extracellular matrix gene expression markers
The method includes administering a compound that reduces the expression of one or more genes selected from Cola1, Col3a1, αSMA, and Galectin1.
Treating fibrosis subjects with abnormal or excessive collagen deposition
The subject exhibits abnormal or excessive collagen deposition.
Treatment for subjects with specified fibrotic and ecM-overdeposition conditions
The subject has one or more listed diseases or conditions associated with excessive deposition of extracellular matrix components, including collagen, that may be affected in the TRβ pathway context.
Route-of-administration formulation for specified routes
The composition is formulated for administration by one or more routes selected from oral, intravenous, intraarterial, intestinal, rectal, vaginal, nasal, pulmonary, topical, intradermal, transdermal, transbuccal, translingual, sublingual, or ophthalmic, or any combination thereof.
The claims center on administering compounds of the stated structural group, including cis/trans and chiral variants, to therapeutically treat fibrosis and reduce extracellular matrix proteins in one or more tissues. The refinements further specify reduction of particular collagen types, reduction of Cola1, Col3a1, αSMA, and Galectin1 expression, subject qualification by abnormal or excessive collagen deposition and listed fibrotic conditions, and formulation for specified administration routes.
Stated Advantages
Reduction in the amount of extracellular matrix proteins present in one or more tissues in a subject in need thereof.
Reduction in extracellular matrix deposition in fibrotic contexts, including reduction of Type I, Type Ia, and Type III collagen.
Reduction in expression of fibrosis-associated genes selected from Cola1, Col3a1, αSMA, and Galectin1.
Therapeutic treatment of fibrosis via reduction in extracellular matrix proteins.
Reduces abnormal extracellular matrix deposition, including collagen and other extracellular matrix proteins described in the disclosure.
Reduces collagen types including Type I, Type Ia, and Type III collagen.
Reduces expression of fibrosis-associated genes including Cola1, Col3a1, αSMA, and Galectin1.
Documented Applications
Treating fibrosis by reducing extracellular matrix protein deposition in one or more tissues.
Fibrosis associated with non-alcoholic steatohepatitis (NASH).
Pulmonary fibrotic conditions and pulmonary, dermal, and fibrotic disease models described in the document.
Reducing extracellular matrix proteins in one or more tissues of a subject with fibrosis-associated conditions.
Treatment of fibrosis in a subject in need thereof, including in vivo liver fibrosis outcomes described for NASH/biopsy models.
Therapeutically treating fibrosis in subjects associated with fibrotic diseases and conditions described as associated with excessive deposition of extracellular matrix components, including collagen-related disorders.
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