Compositions and methods for treating organ dysfunction

• US 9,132,172 B2
• Filed: 03/24/2014
• Issued: 09/15/2015
• Est. Priority Date: 07/15/2005
• Status: Active Grant

• Current Assignee: Cormatrix Cardiovascular, Inc.
• Original Assignee: Cormatrix Cardiovascular, Inc.
• Inventors: Matheny, Robert G
• Primary Examiner(s): Gamett, Daniel C
• Application Number:
  US14/223,909
• Publication Number:
  US 20140205565A1
• Time in Patent Office: 540 Days
• Field of Search: None
• US Class Current: 1/1
• 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 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/726 Glycosaminoglycans, i.e. mucopolysaccharides chondroitin sulfate, dermatan sulfate A61K31/737
• CPC Class Codes: A61K 35/38 Stomach; Intestine; Goblet cells; Oral mucosa; Saliva
• CPC Class Codes: A61K 38/18 Growth factors; Growth regulators
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 38/1841 Transforming growth factor [TGF]
• CPC Class Codes: A61K 38/20 Interleukins [IL]
• CPC Class Codes: A61K 38/39 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/426 Immunomodulating agents, i.e. cytokines, interleukins, interferons
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 27/3629 : Intestinal tissue, e.g. small intestinal submucosa
• CPC Class Codes: A61L 27/3633 : Extracellular matrix [ECM]
• CPC Class Codes: A61L 27/367 : Muscle tissue, e.g. sphincter
• CPC Class Codes: A61L 27/3683 : subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
• CPC Class Codes: A61L 27/3873 : Muscle tissue, e.g. sphincter
• CPC Class Codes: A61L 27/54 : Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence

Abstract

A method of retarding cellular senescence comprising (i) providing an extracellular matrix (ECM) composition comprising ECM from an adolescent tissue source, the ECM comprising an exogenously added cytokine, and (ii) administering ECM composition to an organ with cells exhibiting cellular senescence, wherein, the cytokine interacts with at least one molecule in the ECM composition and modulates ROS production of the cells, whereby, the cellular senescence is abated.

Claims

1. A composition for treating organ dysfunction, comprising:

an extracellular matrix (ECM) composition comprising ECM from a mammalian tissue source comprising small intestine submucosa, said ECM comprising endogenous proteoglycans, transforming growth factors-β

(TGF-β

), fibroblast growth factors-2 (FGF-2) and vascular endothelial growth factor (VEGF), said ECM further comprising an exogenously added cytokine, said cytokine comprising at least 0.1% by weight of said composition,

said cytokine being linked to said ECM, wherein, when said composition is administered to biological tissue, said cytokine interacts with at least one molecule in said ECM composition, wherein said ECM composition modulates ROS production and, thereby, telomere activity.

2. The composition of claim 1, wherein said cytokine is selected from the group consisting of interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-9 (IL-9), interleukin-10 (IL-10), interleukin-13 (IL-13), interleukin 31 (IL-31), and interleukin-33 (IL-33).

3. The composition of claim 1, wherein said mammalian tissue source comprises an adolescent tissue source.

4. The composition of claim 1, wherein said ECM composition further comprises an exogenously added growth factor selected from the group consisting of a transforming growth factor-alpha (TGF-α

), transforming growth factor-beta (TGF-β

), fibroblast growth factor-2 (FGF-2), basic fibroblast growth factor (bFGF), vascular epithelial growth factor (VEGF) and hepatocyte growth factor (HGF).

5. The composition of claim 1, wherein said ECM composition further comprises an exogenously added HMG-CoA reductase inhibitor selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

6. A composition for treating mammalian organ dysfunction, comprising:

an extracellular matrix (ECM) composition comprising ECM from a mammalian tissue source comprising mesothelial tissue, said ECM comprising endogenous proteoglycans, transforming growth factors-β

(TGF-β

), fibroblast growth factors-2 (FGF-2) and vascular endothelial growth factor (VEGF), said ECM further comprising an exogenously added cytokine, said cytokine comprising at least 0.1% by weight of said composition,

said cytokine being linked to said ECM, wherein, when said composition is administered to biological tissue, said cytokine interacts with at least one molecule in said ECM composition, wherein said ECM composition modulates ROS production and, thereby, telomere activity.

7. The composition of claim 6, wherein said cytokine is selected from the group consisting of interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-9 (IL-9), interleukin-10 (IL-10), interleukin-13 (IL-13), interleukin 31 (IL-31), and interleukin-33 (IL-33).

8. The composition of claim 6, wherein said mammalian tissue source comprises an adolescent tissue source.

9. The composition of claim 6, wherein said ECM composition further comprises an exogenously added growth factor selected from the group consisting of a transforming growth factor-alpha (TGF-α

), transforming growth factor-beta (TGF-β

), fibroblast growth factor-2 (FGF-2), basic fibroblast growth factor (bFGF), vascular epithelial growth factor (VEGF) and hepatocyte growth factor (HGF).

10. The composition of claim 6, wherein said ECM composition further comprises an exogenously added HMG-CoA reductase inhibitor selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

11. A method of retarding cellular senescence of an organ, comprising the steps of:

providing an extracellular matrix (ECM) composition, said ECM composition comprising ECM from an adolescent tissue source, said ECM comprising endogenous proteoglycans, transforming growth factors-β

(TGF-β

), fibroblast growth factors-2 (FGF-2) and vascular endothelial growth factor (VEGF), said ECM further comprising an exogenously added cytokine, said cytokine comprising at least 0.1% by weight of said composition; and

administering said ECM composition to an organ with cells exhibiting cellular senescence, wherein, said cytokine interacts with at least one molecule in said ECM composition, wherein said ECM composition modulates ROS production of said cells and, wherein, said cellular senescence is abated.

12. The method of claim 11, wherein said tissue source comprises small intestine submucosa.

13. The method of claim 11, wherein said tissue source comprises mesothelial tissue.

14. The method of claim 11, wherein said cytokine is selected from the group consisting of interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-9 (IL-9), interleukin-10 (IL-10), interleukin-13 (IL-13), interleukin 31 (IL-31), and interleukin-33 (IL-33).

15. The method of claim 11, wherein said ECM composition further comprises an exogenously added growth factor selected from the group consisting of a transforming growth factor-alpha (TGF-α

), transforming growth factor-beta (TGF-β

), fibroblast growth factor-2 (FGF-2), basic fibroblast growth factor (bFGF), vascular epithelial growth factor (VEGF) and hepatocyte growth factor (HGF).

16. The method of claim 11, wherein said ECM composition further comprises an exogenously added HMG-CoA reductase inhibitor selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.