METHOD OF TREATING PATHOLOGIC HETEROTOPIC OSSIFICATION

• US 20140220154A1
• Filed: 06/28/2012
• Published: 08/07/2014
• Est. Priority Date: 07/01/2011
• Status: Abandoned Application

• Current Assignee: The United States of America As Represented By The Secretary of Agriculture
• Original Assignee: The United States of America As Represented By The Secretary of Agriculture
• Inventors: Regard, Jean, Yang, Yingzi
• Application Number:
  US14/130,220
• Publication Number:
  US 20140220154A1
• Time in Patent Office: Days
• US Class Current: 424/623
• CPC Class Codes: A61K 31/015 carbocyclic
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 33/36 Arsenic; Compounds thereof
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease

Abstract

What is described is a method of preventing or treating heterotopic ossification, vascular calcification, and pathologic mineralization, comprising administering an drug, wherein the drug is an antagonist of the Hedgehog (Hh) pathway. For example the antagonist consists of arsenic trioxide, sodium arsenite, phenylarsine, GANT-58, GANT-61, zerumbone vismodegib (GDC-0449, Genentech), bevacizumab, gemcitabine, nab-paclitaxel, FOLFIR, FOLFOX, RO4929097, cixutumumab, cisplatin, etoposide, LDAC, decitabine, daunorubicin, cytarabin, rosiglitazone, goserelin, leuprolide, capecitabine, fluorouracil, leucovorin, oxaliplatin, irinotecan, diclofenac, BMS-833923 (XL139), IPI-926—Infinity Pharmaceuticals, Inc., LDE225, LEQ506—Novartis Pharmaceuticals, TAK-441 Millennium Pharmaceuticals, Inc., and PF-04449913—Pfizer, alone or in combination therapy. The method targets pluripotent mesenchymal cells, wherein the antagonist inhibits expression of a gene encoding a Hh pathway component, for example by decreasing levels of mRNA encoded Ptch1, Gli1 or HIP.

Claims

1. A method of preventing or treating heterotopic ossification comprising administering a drug, wherein the drug is an antagonist of the Hedgehog pathway.

2. The method of claim 1, wherein the antagonist is selected from the group consisting of zerumbone epoxide, staurosporinone, 6-hydroxystaurosporinone, arcyriaflavin C, 5,6-dihyroxyarcyriaflavin A, physalin F, physalin B, cyclopamine, HPI-1, HPI-2, HPI-3, and HPI-4, vismodegib (GDC-0449, Genentech), bevacizumab, gemcitabine, nab-paclitaxel, FOLFIR, FOLFOX, R04929097, cixutumumab, cisplatin, etoposide, LDAC, decitabine, daunorubicin, cytarabin, rosiglitazone, goserelin, leuprolide, capecitabine, fluorouracil, leucovorin, oxaliplatin, irinotecan, diclofenac, BMS-833923 (XL139), IPI-926—

Infinity Pharmaceuticals, Inc., LDE225, LEQ506—

Novartis Pharmaceuticals, TAK-441 Millennium Pharmaceuticals, Inc., PF-04449913—

Pfizer, arsenic trioxide, sodium arsenite, phenylarsine, GANT-58, GANT-61, and zerumbone, alone or in combination therapy.

6. The method of claim 2, wherein the antagonist comprises is arsenic trioxide (ATO).

9. The method of claim 1, wherein the antagonist targets pluripotent mesenchymal cells.

10. The method of claim 9, wherein the antagonist prevents proliferation or differentiation of mesenchymal cells.

11. The method of claim 10, wherein the antagonist alters expression of a gene expressed in the mesenchymal cells.

12. The method of claim 11, wherein the gene encodes a component of the Hedgehog pathway.

3-5. -5. (canceled)

7-8. -8. (canceled)

13-17. -17. (canceled)

18. A method of inhibiting formation of heterotopic ossification comprising administering an antagonist of the Hedgehog pathway.

19. The method of claim 18, wherein the antagonist is administered to a human patient that is susceptible to heterotopic ossification.

22. The method of claim 19, wherein the patient experienced trauma.

23. The method of claim 22, wherein the patient experienced spinal cord injury, trauma and brain injuries, burns, fractures, muscle contusion, joint arthroplasty, lower motor neuron disorders, or hereditary disorders.

24. The method of claim 22, wherein the trauma is combat-related.

20-21. -21. (canceled)

25-28. -28. (canceled)

29. A method of treating heterotopic ossification (HO), vascular calcification, or pathologic mineralization using an antagonist of the Hedgehog pathway, comprising administering said antagonist to a subject in need thereof.

30. The method of claim 29, wherein the antagonist is selected from the group consisting of zerumbone epoxide, staurosporinone, 6-hydroxystaurosporinone, arcyriaflavin C, 5,6-dihyroxyarcyriaflavin A, physalin F, physalin B, cyclopamine, HPI-1, HPI-2, HPI-3, and HPI-4, arsenic trioxide, sodium arsenite, phenylarsine, GANT-58, GANT-61, and zerumbone.

31. The method of claim 30, wherein the antagonist comprises arsenic trioxide (ATO).

32. (canceled)

33. A method of using an antagonist of the Hedgehog pathway, comprising exposing mesenchymal cells to said antagonist to prevent activation of said cells.

34. The method of claim 33, wherein the antagonist prevents proliferation or differentiation of mesenchymal cells.

35-40. -40. (canceled)