Therapy of Kidney Diseases and Multiorgan Failure with Mesenchymal Stem Cells and Mesenchymal Stem Cell Conditioned Media

• US 20080241112A1
• Filed: 05/10/2005
• Published: 10/02/2008
• Est. Priority Date: 05/10/2005
• Status: Abandoned Application

• Current Assignee: University of Utah Research Foundation (State of Utah)
• Original Assignee: University of Utah Research Foundation (State of Utah)
• Inventors: Westenfelder, Christof
• Application Number:
  US11/913,900
• Publication Number:
  US 20080241112A1
• Time in Patent Office: Days
• US Class Current: 424/93.7
• 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: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/20 : Hypnotics; Sedatives
• CPC Class Codes: A61P 25/26 : Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 : without antiinflammatory effect
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/08 : for leprosy
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/02 : Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/24 : of the sex hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12N 2501/165 : Vascular endothelial growth factor [VEGF]
• CPC Class Codes: C12N 2502/1358 : Bone marrow mesenchymal stem cells (BM-MSC)
• CPC Class Codes: C12N 2510/00 : Genetically modified cells
• CPC Class Codes: C12N 2533/52 : Fibronectin; Laminin
• CPC Class Codes: C12N 5/0663 : Bone marrow mesenchymal stem cells (BM-MSC)
• CPC Class Codes: C12N 5/069 : Vascular Endothelial cells

Abstract

Methods and a composition for the treatment of organ dysfunction, acute renal failure, multi-organ failure, early dysfunction of kidney transplant, graft rejection, chronic renal failure, wounds, and inflammatory disorders including media conditioned by mesenchymal stem cells are provided. Methods for modulation of growth factor and cytokine expression including administering a therapeutic amount of mesenchymal stem cells, endothelial cells derived from mesenchymal stem cells, or media conditioned by mesenchymal stem cells are also provided.

Claims

1. A method of treating organ dysfunction, acute renal failure, multi-organ failure, early dysfunction of kidney transplant, graft rejection, chronic renal failure, wounds, and inflammatory disorders, said method comprising delivering a therapeutic amount of a pharmaceutically acceptable media that has been conditioned by exposure to mesenchymal stem cells (MSC) in culture to a patient in need thereof.

2. The method of claim 1 wherein said media is conditioned by exposure to MSC grown in culture conditions where oxygen pressure is less than or equal to 5%.

3. The method of claim 1 wherein said media is conditioned by exposure to MSC grown in culture under room air oxygen conditions.

4. The method of claim 1 wherein said media is conditioned by exposure to said MSC in culture for greater than 24 hours.

5. The method of claim 1 wherein said media has been conditioned by exposure to highly-subconfluent MSC.

6. The method of claim 1 wherein said media is administered systemically.

7. The method of claim 1 wherein said media is administered intra-arterially.

8. The method of claim 1 wherein said media is administered intravenously.

9. The method of claim 1 wherein said media is administered intraperitoneally.

10. The method of claim 1 wherein said media has been conditioned by genetically modified MSC.

11. The method of claim 1 wherein said media is administered by continuous infusion for about 24 hours.

12. The method of claim 1 wherein said media is administered at a dose of 0.07 ml/100 g.

13. The method of claim 1 further comprising delivering a therapeutic amount of MSC to said patient.

14. The method of claim 1 further comprising delivering a therapeutic amount of Endothelial Cells (EC) generated by differentiation of MSC in vitro to said patient.

15. A composition comprising a pharmaceutically acceptable media that has been conditioned by exposure to MSC in culture.

16. The composition of claim 15 wherein said media is serum free.

17. The composition of claim 15 wherein said media is conditioned by exposure to MSC in culture where oxygen pressure is less than or equal to 5%.

18. The composition of claim 15 wherein said media is conditioned by exposure to MSC in culture under room air oxygen conditions.

19. The composition of claim 15 wherein said media has been conditioned by exposure to highly-subconfluent MSC.

20. The composition of claim 15 wherein said MSC have been genetically modified.

21. The composition of claim 15 wherein said media is a concentrated media compared to said media obtained by exposure to MSC in culture.

22. The composition of claim 15 wherein said MSC are human cells.

23. The composition of claim 15 wherein said media has been exposed to said MSC for greater than 24 hours.

24. A method of modulating expression of at least one growth factor in an injured organ of a patient, said method comprising administering an effective amount of MSC, EC, or MSC-conditioned media to the patient to modulate expression of said growth factor.

25. The method of claim 24 wherein said expression is modulated in cells in a kidney of said patient.

26. The method of claim 24 wherein said growth factor is selected from GM-CSF, G-CSF, bFGF and combinations thereof.

27. A method of modulating expression of at least one cytokine in an injured organ of a patient, said method comprising administering an effective amount of MSC, EC, or MSC-conditioned media to the patient to modulate expression of said cytokine.

28. The method of claim 27 wherein said inflammatory cytokine is a pro-inflammatory cytokine.

29. The method of claim 28 wherein said pro-inflammatory cytokine is selected from the group consisting of TNF-α

, IL-1β

, IL-6, IL-8, lipopolysaccharide-binding protein, MCP-1, CD-14, IFN-γ

, a chemokine and combinations thereof.

30. The method of claim 27 wherein said inflammatory cytokine is an anti-inflammatory cytokine.

31. The method of claim 30 wherein said anti-inflammatory cytokine is selected from the group consisting of TNF-RI, TNF-RII, IL-IRA, IL-4, IL-10, IL-12, IL-13, TGF-β

, and combinations thereof.