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CN-122028930-A - Recovery of TIM4 in liver macrophages for the treatment of nonalcoholic steatohepatitis (NASH)

CN122028930ACN 122028930 ACN122028930 ACN 122028930ACN-122028930-A

Abstract

Compositions and methods for treating or preventing non-alcoholic steatohepatitis (NASH). In one aspect, the disclosed methods involve targeting macrophage receptors known as T cell immunoglobulin and mucin-containing domain 4 (TIM 4). The compositions and methods disclosed herein can be used as disease modifying therapies to enable the treatment of NASH and related conditions and to improve clinical outcome early in disease progression.

Inventors

  • I. Tabas
  • Shi Hongxue

Assignees

  • 纽约市哥伦比亚大学理事会

Dates

Publication Date
20260512
Application Date
20240920
Priority Date
20230922

Claims (20)

  1. 1. A method of treating or preventing non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject a composition that increases the expression level of macrophage receptors.
  2. 2. A method of treating or preventing non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising: (i) Identifying the subject as having a reduced level of expression of macrophage receptor, and (Ii) Administering to the subject a composition that increases the expression level of the macrophage receptor.
  3. 3. A method of treating or preventing non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising: (i) Identifying the subject as having an elevated ratio of macrophage-associated apoptotic cells to macrophage-free apoptotic cells, and (Ii) Administering to the subject a composition that increases the expression level of the macrophage receptor.
  4. 4. The method of claim 2, wherein the subject has a reduced level of expression of macrophage receptors compared to a subject not having NASH or a subject having early NASH.
  5. 5. The method of claim 3, wherein the subject has an elevated ratio of macrophage-related apoptotic cells to macrophage-free apoptotic cells compared to a subject not having NASH or a subject having early NASH.
  6. 6. The method of any one of claims 1-3, wherein the composition increases expression of the macrophage receptor as compared to a subject having NASH or as compared to expression prior to administration of the composition.
  7. 7. The method of claim 3, wherein the composition reduces the ratio compared to a subject with NASH or compared to the ratio of apoptotic cells associated with macrophages to apoptotic cells without macrophages prior to administration of the composition.
  8. 8. The method of any one of claims 1 to 7, wherein the macrophage receptor is a cytodoline receptor.
  9. 9. The method of any one of claims 1 to 8, wherein the macrophage receptor is a T-cell immunoglobulin-and-mucin-containing domain 4 (TIM 4).
  10. 10. The method of any one of claims 1 to 9, wherein administration of the composition causes inhibition or reduction of liver fibrosis.
  11. 11. The method of any one of claims 1 to 9, wherein administration of the composition causes inhibition or reduction of Hepatic Stellate Cell (HSC) activation.
  12. 12. The method of any one of claims 1 to 9, wherein administration of the composition causes inhibition or reduction of biliary tract reactions.
  13. 13. The method of any one of claims 1 to 9, wherein administration of the composition causes inhibition or reduction of liver imperial crown-like structure formation.
  14. 14. The method of any one of claims 1-13, wherein administration of the composition does not cause liver steatosis or a change in plasma alanine Aminotransferase (ALT) activity.
  15. 15. The method of any one of claims 1 to 14, wherein the subject is a mammal.
  16. 16. The method of claim 15, wherein the mammal is a human.
  17. 17. The method of any one of claims 1 to 16, wherein the composition increases the expression level of the macrophage receptor in a macrophage.
  18. 18. The method of claim 17, wherein the composition increases the expression level of the macrophage receptor in liver macrophages.
  19. 19. The method of any one of claims 1 to 18, wherein the composition comprises a nucleic acid encoding TIM 4.
  20. 20. A composition for treating or preventing NASH comprising a nucleic acid sequence encoding a macrophage receptor.

Description

Recovery of TIM4 in liver macrophages for the treatment of nonalcoholic steatohepatitis (NASH) The present international patent application claims the benefit and priority of U.S. provisional application No. 63/584,805, entitled "RESTORING TIM4 IN LIVER MACROPHAGES TO TREAT NONACOHOLIC STEATOHEPATITIS (NASH) (recovering TIM4 in liver macrophages to treat non-alcoholic steatohepatitis (NASH))", filed on month 9 and 22 of 2023, the contents of which are hereby incorporated by reference in their entirety. All patents, patent applications, and patent publications, and other references cited herein are hereby incorporated by reference in their entirety. The disclosures of these patent publications are hereby incorporated by reference in their entireties in order to more fully describe the state of the art known to those skilled in the japanese arts to the application described and claimed herein. The disclosure of this patent contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the patent and trademark office patent file or records, but otherwise reserves all copyright rights whatsoever. Statement regarding federally sponsored research or development The present invention is supported by government funds in the HL127464 and DK137021 programs sponsored by the national institutes of health (National Institutes of Health). The government has certain rights in this invention. Background Nonalcoholic liver disease, particularly nonalcoholic steatohepatitis (NASH), is a major cause of chronic liver disease worldwide, however, treatments for NASH are very limited due to inadequate understanding of NASH pathology. More specifically, the current understanding is also very limited for the conversion from relatively benign steatosis to NASH. Recent genetic evidence suggests that expression of T cell-containing immunoglobulin and mucin domain 4 (TIM 4) by NASH liver macrophages is significantly reduced. However, in NASH, the role of TIM4 in cyto-burying and liver fibrosis is still unknown. Disclosure of Invention In certain aspects, described herein is a method of treating or preventing non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject a composition that increases the expression level of macrophage receptors. In some embodiments, the macrophage receptor is a cytochromes receptor. For some embodiments, the macrophage receptor is a T cell immunoglobulin and mucin domain 4 (TIM 4). In certain aspects, described herein is a method of treating or preventing non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising (i) identifying the subject as having a reduced level of expression of a macrophage receptor, and (ii) administering to the subject a composition that increases the level of expression of a macrophage receptor. In some embodiments, the macrophage receptor is a cytochromes receptor. For some embodiments, the macrophage receptor is a T cell immunoglobulin and mucin domain 4 (TIM 4). In certain aspects, described herein is a method of treating or preventing non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising (i) identifying the subject as having an elevated ratio of macrophage-related apoptotic cells to non-macrophage apoptotic cells, and (ii) administering to the subject a composition that increases the level of expression of a macrophage receptor. In some embodiments, the macrophage receptor is a cytochromes receptor. For some embodiments, the macrophage receptor is a T cell immunoglobulin and mucin domain 4 (TIM 4). In some embodiments, the subject has a reduced level of expression of macrophage receptors compared to a subject not having NASH or a subject having early NASH. In some embodiments, the subject has an elevated ratio of macrophage-related apoptotic cells to macrophage-free apoptotic cells as compared to a subject not having NASH or a subject having early NASH. In some embodiments, the composition increases expression of macrophage receptors compared to a subject having NASH or compared to expression prior to administration of the composition. In some embodiments, the composition reduces the ratio of apoptotic cells to macrophage-free apoptotic cells compared to a subject having NASH or compared to the ratio of macrophage-related apoptotic cells prior to administration of the composition. In some embodiments, administration of the composition causes inhibition or reduction of liver fibrosis. In some embodiments, administration of the composition causes inhibition or reduction of Hepatic Stellate Cell (HSC) activation. In some embodiments, administration of the composition causes inhibition or reduction of the biliary response. In some embodiments, administration of the composition causes inhibition or reduction of liver imperial structure formation. In some embo