Bioprosthetic heart valves

• US 6,660,260 B1
• Filed: 09/21/1999
• Issued: 12/09/2003
• Est. Priority Date: 09/21/1999
• Status: Expired due to Term

• Current Assignee: Mayo Foundation For Medical Education And Research (Mayo Clinic)
• Original Assignee: Mayo Foundation For Medical Education And Research (Mayo Clinic)
• Inventors: Rajamannan, Nalini M.
• Primary Examiner(s): Guzo, David
• Assistant Examiner(s): Nguyen, Quang
• Application Number:
  US09/399,704
• Time in Patent Office: 1,540 Days
• Field of Search: 514/44, 435/69.1, 435/370.1, 435/1.1, 435/1.31, 435/455, 435/456, 435/320.1, 435/455.1, 435/456.1, 536/23.1, 536/23.2, 424/423.1, 424/93.21, 424/423, 623/2, 623/11
• US Class Current: 424/93.21
• 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. An isolated heart valve cusp, wherein a cell of said cusp contains an exogenous nucleic acid that encodes a nitric oxide synthase, and wherein said cell expresses said nitric oxide synthase and has a reduced susceptibility to calcification.

2. The cusp of claim 1, wherein said cell is porcine.

3. The cusp of claim 1, wherein said cell is human.

4. The cusp of claim 1, wherein said nitric oxide synthase is an endothelial nitric oxide synthase.

5. A method for making a bioprosthetic heart valve cusp, 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 nitric oxide synthase, and wherein said cell expresses said nitric oxide synthase and has a reduced susceptibility to calcification.

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

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

8. The method of claim 5, wherein said nitric oxide synthase is an endothelial nitric oxide synthase.

9. The method of claim 5, wherein said nucleic acid is introduced into said cell via adenoviral-mediated nucleic acid transfer.

10. The method of claim 5, wherein said nucleic acid integrates into the genome of said cell.

11. The method of claim 5, wherein said method comprises fixing said cusp.

12. The method of claim 11, wherein said fixation step occurs after said introduction step.

13. The method of claim 5, wherein said method comprises freezing said cusp.

14. The method of claim 13, wherein said freezing step occurs after said introduction step.

15. A method for providing a mammal with a non-murine heart valve, said method comprising:

a) providing an isolated non-murine heart valve;

b) introducing a nucleic acid encoding a nitric oxide synthase into a cell of said heart valve such that said cell expresses said nitric oxide synthase, and

c) introducing said heart valve of step (b) into said mammal, wherein said heart valve is an autograft or allograft.

16. The method of claim 15, wherein said method comprises administering an inhibitor of hydroxymethylglutaryl coA reductase activity to said mammal.

17. The method of claim 16, wherein said inhibitor comprises pravastatin, atorvastatin simvastatin or lovastatin.

18. A method for providing a mammal with a non-murine heart valve, said method comprising:

a) providing an isolated non-murine heart valve;

b) introducing a nucleic acid encoding a nitric oxide synthase into a cell of said heart valve such that said cell expresses said nitric oxide synthase,

c) fixing or freezing said heart valve of step (b), and

d) introducing said heart valve of step (c) into said mammal, wherein said heart valve is a xenograft.

19. The method of claim 18, wherein said method comprises administering an inhibitor of hydroxymethylglutaryl coA reductase activity to said mammal.

20. The method of claim 19, wherein said inhibitor comprises pravastatin, atorvastatin, simvastatin, or lovastatin.