Bioprosthetic heart valves

• US 20040058444A1
• Filed: 09/22/2003
• Published: 03/25/2004
• Est. Priority Date: 09/21/1999
• Status: Abandoned Application

• Current Assignee: Nalini M. Rajamannan
• Original Assignee: Nalini M. Rajamannan
• Inventors: Rajamannan, Nalini M.
• Application Number:
  US10/667,625
• Publication Number:
  US 20040058444A1
• Time in Patent Office: Days
• US Class Current: 435/366
• 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 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 38/44 Oxidoreductases (1)
• CPC Class Codes: A61K 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• CPC Class Codes: A61K 48/0075 characterised by an aspect of the delivery route, e.g. oral, subcutaneous
• CPC Class Codes: A61L 27/3625 Vascular tissue, e.g. heart valves
• CPC Class Codes: A61L 27/3645 Connective tissue
• 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 27/3695 characterised by the function or physical properties of the final product, where no specific conditions are defined to achieve this A61L27/3687, A61L27/3691 take precedence
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/507 for artificial blood vessels apparatus for applying cells on a blood vessel prosthesis A61F2/062
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2501/03 Compounds acting on the NO pathway, e.g. nitrososarginine
• CPC Class Codes: C12N 2501/70 Enzymes
• CPC Class Codes: C12N 2510/00 Genetically modified cells
• CPC Class Codes: C12N 2710/10343 : viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 5/0602 : Vertebrate cells
• CPC Class Codes: C12Y 114/13039 : Nitric-oxide synthase (NADPH dependent) (1.14.13.39)
• CPC Class Codes: G01N 33/5008 : for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• CPC Class Codes: G01N 33/5011 : for testing antineoplastic activity
• CPC Class Codes: G01N 33/5061 : Muscle cells
• CPC Class Codes: G01N 33/5064 : Endothelial cells
• CPC Class Codes: G01N 33/5088 : of vertebrates

Abstract

The invention provides methods and materials related to heart valves and the treatment of valvular heart disease. Specifically, the invention provides non-murine heart valve cells and heart valve cusps as well as methods for making heart valves. The invention also provides methods and materials for (1) slowing heart valve degeneration, thrombosis, and calcification, (2) treating carcinoid heart disease, (3) identifying inhibitors of heart valve degeneration, thrombosis, and calcification, and (4) determining the safety of drugs.

Claims

1. A non-murine heart valve cell containing an exogenous nucleic acid that encodes a polypeptide having nitric oxide synthase activity.

2. The cell of claim 1, wherein said cell is an endothelial cell.

3. The cell of claim 1, wherein said cell is a myocyte.

4. The cell of claim 1, wherein said polypeptide is endothelial nitric oxide synthase.

5. An isolated heart valve cusp, wherein a cell of said cusp contains an exogenous nucleic acid that encodes a polypeptide having nitric oxide synthase activity.

6. The cusp of claim 5, wherein said cell is porcine.

7. The cusp of claim 5, wherein said cell is human.

8. The cusp of claim 5, wherein said polypeptide is endothelial nitric oxide synthase.

9. A method for making a bioprosthetic heart valve, said method comprising:

a) obtaining a heart valve cusp, and

b) introducing nucleic acid into a cell of said cusp, wherein said nucleic acid encodes a polypeptide having nitric oxide synthase activity.

10. The method of claim 9, wherein said cell is porcine.

11. The method of claim 9, wherein said cell is human.

12. The method of claim 9, wherein said polypeptide is endothelial nitric oxide synthase.

13. The method of claim 9, wherein said nucleic acid is introduced into said cell via adenoviral-mediated nucleic acid transfer.

14. The method of claim 9, wherein said nucleic acid integrates into the genome of said cell.

15. The method of claim 9, wherein said method comprises fixing said cusp.

16. The method of claim 15, wherein said fixation step occurs after said introduction step.

17. The method of claim 9, wherein said method comprises freezing said cusp.

18. The method of claim 17, wherein said freezing step occurs after said introduction step.

19. A method for slowing the degeneration of a heart valve within a non-murine mammal, said method comprising introducing nucleic acid encoding a polypeptide having nitric oxide synthase activity into a cell of said heart valve such that said polypeptide is expressed.

20. The method of claim 19, wherein said introduction step is performed in vitro.

21. The method of claim 19, wherein said heart valve is an autograft.

22. The method of claim 19, wherein said heart valve is an allograft.

23. The method of claim 19, wherein said heart valve is a xenograft.

24. The method of claim 19, wherein said method comprises administering an inhibitor of hydroxymethylglutaryl coA reductase activity to said mammal.

25. The method of claim 24, wherein said inhibitor comprises pravastatin, atorvastatin, simvastatin, or lovastatin.

26. A method for slowing heart valve degeneration, said method comprising:

a) identifying a mammal at risk of developing heart valve degeneration, and

b) administering an inhibitor of hydroxymethylglutaryl coA reductase activity to said mammal.

27. The method of claim 26, wherein said mammal contains a heart valve replacement.

28. The method of claim 26, wherein said mammal has congenital valvular disease.

29. The method of claim 26, wherein said mammal has bicuspid valvular disease.

30. A method for treating carcinoid heart disease in a mammal, said method comprising administering a serotonin receptor antagonist to said mammal.

31. The method of claim 30, wherein said antagonist is specific for a 5HT_1B receptor.

32. The method of claim 30, wherein said antagonist comprises a β

-blocker.

33. The method of claim 30, wherein said antagonist is pindolol.

34. A method for identifying an inhibitor of heart valve degeneration, said method comprising:

a) contacting heart valve cells with a stimulant such that said cells proliferate,

b) contacting said cells with a test compound, and

c) determining if said test compound reduced the proliferation of said cells, wherein the reduction of proliferation indicates that said test compound is an inhibitor of heart valve degeneration.

35. A method for determining the safety of a drug, said method comprising:

a) contacting heart valve cells with said drug, and

b) determining if said drug induced proliferation of said cells, wherein the induction of proliferation indicates that said drug promotes heart valve degeneration.