Co-Delivery Of Stimulatory And Inhibitory Factors To Create Temporally Stable And Spatially Restricted Zones

• US 20130302396A1
• Filed: 06/27/2011
• Published: 11/14/2013
• Est. Priority Date: 06/25/2010
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Mooney, David J., Yuen, William W., Arany, Praveen
• Granted Patent: US 9,693,954 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61F 2/30756 Cartilage endoprostheses A61F2/3603 takes precedence
• CPC Class Codes: A61F 2002/30766 Scaffolds for cartilage ingrowth and regeneration
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/4192 1,2,3-Triazoles
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61K 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61K 35/545 Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
• CPC Class Codes: A61K 38/1808 Epidermal growth factor [EGF] urogastrone
• CPC Class Codes: A61K 38/1841 Transforming growth factor [TGF]
• CPC Class Codes: A61K 38/185 Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• CPC Class Codes: A61K 38/1866 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: A61K 38/1875 Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0087 Galenical forms not covered by A61K9/02 - A61K9/7023
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system

Abstract

The invention provides methods and compositions for local manipulation of regenerative processes via exogenous factor delivery.

Claims

1. A method for promoting a morphogenic process, comprising administering to a subject a device comprising a purified morphogen and a purified inhibitor of said morphogen, wherein said morphogen and said inhibitor

(a) interact inside said device or

(b) are released from said device and interact outside said device, thereby leading to promotion of said morphogenic process over a sustained period of time at a spatially restricted zone at or near a site at which said morphogen and said inhibitor interact in said subject.

2. The method of claim 1, wherein said morphogenic process is angiogenesis, tissue regeneration, cell differentiation, organ regeneration, cartilage regeneration, bone regeneration, or neural regeneration.

3. The method of claim 1, wherein said morphogen is released at a first rate and said inhibitor is released at a second rate.

44. The method of claim 1, wherein said device comprises at least five layers.

45. The method of claim 1, wherein said composition or device comprises at least two purified morphogens and at least two purified morphogen inhibitors.

46. The method of claim 45, wherein said at least two purified morphogens comprise TGF-β

1 and BMP4, and said at least two purified inhibitors of said morphogens comprise an anti-TGF-β

1 antibody and an anti-BMP4 antibody.

47. The method of claim 1, wherein said purified morphogen comprises Latent TGF-B1 and said purified inhibitor of said morphogen comprises a small molecule inhibitor SB431542.

48. The method of claim 1, wherein said device further comprises cells.

49. The method of claim 48, wherein said cells comprise mesenchymal stem cells, embryonic stem cells, or induced pluripotent stem cells.

50. The method of claim 1, wherein said morphogenic process comprises differentiation of two juxtaposed tissues.

51. The method of claim 50, wherein said morphogenic process comprises tooth regeneration, lung regeneration, liver regeneration, kidney regeneration, cardiac valve regeneration, joint regeneration, or pancreas regeneration.

4. A method for inducing sustained angiogenesis in a spatially restricted zone comprising:

contacting a tissue with a purified angiogenesis-promoting agent; and

contacting said tissue with a purified inhibitor of angiogenesis,

wherein said agent and said inhibitor interact thereby inducing sustained angiogenesis in a spatially restricted zone at or near a site at which said agent and said inhibitor interact.

5. The method of claim 4, wherein said agent and said inhibitor are administered simultaneously.

6. The method of claim 4, wherein said agent and said inhibitor are incorporated in or on a device comprising a scaffold composition.

7. The method of claim 6, wherein said agent and said inhibitor are spatially segregated in or on said scaffold composition.

8. The method of claim 4, wherein temporal stability of said agent is maintained.

9. The method of claim 4, wherein said angiogenesis results in heterogeneous distribution of blood vessels in said spatially restricted zone.

10. The method of claim 4, wherein said angiogenesis-promoting agent comprises vascular endothelial growth factor (VEGF), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), placenta growth factor (PIGF), leptin, hematopoietic growth factor (HGF), VEGF receptor-1 (VEGFR-1), or VEGFR-2.

11. The method of claim 4, wherein said inhibitor of angiogenesis comprises anti-VEGF antibody, anti-aFGF antibody, anti-bFGF antibody, anti-PIGF antibody, anti-leptin antibody, anti-HGF antibody, anti-VEGFR-1 antibody, or anti-VEGFR-2 antibody.

12. The method of claim 4, wherein said inhibitor of angiogenesis comprises a small molecule inhibitor selected from the group consisting of batimastat (BB-94), marimastat (BB-2516), thalidomide, O-(chloroacetylcarbamoyl)-fumagillol (TNP-470), carboxyamidotriazole (CAI), and SU5416.

13. The method of claim 4, wherein said agent comprises VEGF and said inhibitor comprises an anti-VEGF antibody.

14. The method of claim 4, wherein said agent and said inhibitor are encapsulated.

15. The method of claim 4, wherein said angiogenesis is induced in ischemic tissue, a narrowed or occluded vascular conduit, or an injured vascular tissue.

16. The method of claim 15, wherein the narrowed or occluded vascular conduit is a narrowed or occluded artery, narrowed or occluded vein, or a narrowed or occluded synthetic graft.

17. The method of claim 4, wherein said angiogenesis is induced in a mammal.

18. The method of claim 17, wherein said mammal is a human.

19. The method of claim 4, wherein said method is performed in vivo or in vitro.

20. A method of inducing regeneration in a spatially restricted zone comprising:

contacting a target site with an agent that promotes regeneration; and

contacting said target site with an inhibitor of regeneration;

wherein said agent and said inhibitor interact thereby inducing regeneration in a spatially restricted zone at or near a site at which said agent and said inhibitor interact.

21. The method of claim 20, wherein said agent and said inhibitor are administered simultaneously.

22. The method of claim 20, wherein said agent and said inhibitor are incorporated in or on a device comprising a scaffold composition.

23. The method of claim 22, wherein said agent and said inhibitor are spatially segregated in or on said scaffold composition.

24. The method of claim 20, wherein temporal stability of said agent is maintained.

25. The method of claim 20, wherein said regeneration comprises tissue regeneration, organ regeneration, cartilage regeneration, bone regeneration, or neural regeneration.

26. The method of claim 25, wherein said regeneration comprises bone regeneration.

27. The method of claim 26, wherein said agent comprises transforming growth factor-β

(TGF-β

), bone morphogenetic protein (BMP), insulin-like growth factor (IGF-1), fibroblast growth factor-2 (FGF-2), or platelet-derived growth factor (PDGF).

28. The method of claim 26, wherein said inhibitor comprises anti-TGF-β

antibody, anti-BMP antibody, anti-IGF-1 antibody, anti-FGF-2 antibody, or anti-PDGF antibody.

29. The method of claim 25, wherein said regeneration comprises tissue regeneration.

30. The method of claim 29, wherein said agent comprises epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor-α

(TGF-α

) or VEGF.

31. The method of claim 29, wherein said inhibitor comprises anti-EGF antibody, anti-PDGF antibody, anti-TGF-α

antibody, or anti-VEGF antibody.

32. The method of claim 25, wherein said regeneration comprises neural regeneration of the peripheral or central nervous system.

33. The method of claim 32, wherein said agent comprises nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), ciliary neurotrophic factor (CNTF), or glial cell line-derived neurotrophic factor (GDNF).

34. The method of claim 20, wherein said method comprises performed in vivo or in vitro.

35. A method for inducing cell differentiation in a spatially restricted zone comprising:

contacting a cell with a promoter of differentiation; and

contacting said cell with an inhibitor of differentiation,

wherein said agent and said inhibitor interact thereby inducing cell differentiation in a spatially restricted zone at or near a site at which said agent and said inhibitor interact.

36. The method of claim 35, wherein said agent and said inhibitor are administered simultaneously.

37. The method of claim 35, wherein said agent and said inhibitor are incorporated in or on a device comprising a scaffold composition.

38. The method of claim 35, wherein said agent and said inhibitor are spatially segregated in or on said scaffold composition.

39. The method of claim 35, wherein temporal stability of said agent is maintained.

40. The method of claim 35, wherein said promoter of differentiation comprises BMP-4 or TGF-β

1.

41. The method of claim 35, wherein said inhibitor of differentiation comprises anti-BMP-4 or Latency Associated Peptide (LAP).

42. The method of claim 35, wherein said cell is a bone cell or a tooth cell.

43. A method for selectively destroying tissue in a spatially restricted zone comprising:

contacting a target site with an agent that promotes tissue destruction; and

contacting said target site with an inhibitor of tissue destruction or a tissue destruction primer,

wherein said agent and said inhibitor or said primer contact a cell at said target site leading to selective destruction of said cell in a spatially restricted zone at or near a site at which said agent and said inhibitor interact.

52. A method for promoting a morphogenic process, comprising administering to a subject a first device comprising a purified morphogen and a second device comprising an antagonist of said morphogen at a first anatomical implantation site and a second anatomical implantation site of said subject, wherein the area between said first and said second implantation sites defines a zone of interaction between said morphogen and said antagonist and wherein said morphogenic process occurs in said zone of interaction.

53. A polymeric device comprising at least 2 spatially distinct zones, wherein a first zone comprises a purified morphogen and a second zone comprises an antagonist of said morphogen.

54. The device of claim 53, wherein said device further comprises a second morphogen.

55. The device of claim 53, wherein said device further comprises purified cells.