Arteriovenous and venous graft treatments: methods and compositions

• US 6,323,184 B1
• Filed: 04/19/1995
• Issued: 11/27/2001
• Est. Priority Date: 10/15/1993
• Status: Expired due to Fees

• Current Assignee: Thomas Jefferson University (Main Line Health System)
• Original Assignee: Thomas Jefferson University (Main Line Health System)
• Inventors: Shi, Yi, Zalewski, Andrew
• Primary Examiner(s): McGarry, Sean
• Application Number:
  US08/424,991
• Time in Patent Office: 2,414 Days
• Field of Search: 514/44, 435/6, 435/91.1, 435/172.1, 435/240.2, 435/455, 435/375, 536/23.1, 536/24.5
• US Class Current: 514/44.00R
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12N 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/315 Phosphorothioates

Abstract

A method and compounds are provided for inhibiting the synthesis of extracellular matrix proteins. Compounds of the invention comprise oligonucleotides specific for nuclear proto-oncogenes. Preferably, oligonucleotides of the invention are selected from the group consisting of c-myc and c-myb and are locally administered. The invention finds use in the treatment of a variety of disorders, including sclerotic disorders and restenosis, associated with the inappropriate synthesis of extracellular matrix proteins, particularly collagen.

Claims

1. A method for inhibiting failure of a hemodialysis access site of a hemodialysis patient, comprising:

contacting said hemodialysis access site with locally administered oligonucleotide complementary to c-myc mRNA.

2. The method of claim 1 wherein said hemodialysis access site is selected from the group consisting of Brescia-Cimino fistula, snuffbox fistula, brachiocephalic fistula, PTFE hemodialysis graft, and bovine carotid artery graft and autogenous grafts.

3. The method of claim 1 wherein said contacting comprises injection, catheterization or infusion.

4. The method of claim 1 wherein said contacting comprises diffusion from an implant, or diffusion from a reservoir located in perivascular tissue.

5. The method of claim 1 wherein said contacting comprises injection into the perivascular tissue either by perivascular injection prior to surgical site closure or percutaneous injection after closure of the surgical site.

6. The method of claim 5 wherein said contacting is repeated following construction of said hemodialysis access site.

25. The method according to claim 1 wherein the antisense oligonucleotide has a nucleotide sequence selected from the group consisting of SEQ ID NOS:

1, 6 and 7.

7. A method for treating vascular grafts, comprising:

contacting said vascular graft with a locally administered oligonucleotide complementary to c-myc mRNA.

8. The method of claim 7 wherein said contacting comprises diffusion from an implant, or diffusion from a reservoir located in perivascular tissue.

9. The method of claim 7 wherein said contacting comprises injection into the perivascular tissue either by perivascular injection prior to surgical site closure or percutaneous injection after closure of the surgical site.

26. The method according to claim 7 wherein the antisense oligonucleotide has a nucleotide sequence selected from the group consisting of SEQ ID NOS:

1, 6 and 7.

10. An ex vivo method for inhibiting failure of vascular grafts made with veins, comprising:

contacting ex vivo said veins with an oligonucleotide complementary to c-myc mRNA.

11. The method of claim 10 wherein said contacting comprises incubating said vein with said oligonucleotide for at least 10 minutes in a sterile and physiologically acceptable buffer.

12. The method of claim 11 wherein said physiologically accetable buffer is at 20 to 37°

C.

13. The method of claim 12 wherein said oligonucleotide has a concentration of 10 to 200 μ

M.

14. The method of claim 13 wherein said vein is selected from a group consisting of saphenous vein, cephalic vein, basilic vein, brachial vein, and femoral vein.

27. The method according to claim 10 wherein the antisense oligonucleotide has a nucleotide sequence selected from the group consisting of SEQ ID NOS:

1, 6 and 7.

15. A composition comprising:

an isolated vascular graft, and

an oligonucleotide complementary to c-myc mRNA located in at least one layer of said vascular graft.

16. The composition of claim 15 wherein said graft is a prosthetic fistula, arteriovenous shunt, native vein fistula, venous grafts, immunosuppressed allografts, immunosupressed xenografts, and venous autografts.

17. The composition of claim 15 wherein said layer is selected from the group consisting of endothelial layer, media, adventitia and perivascular tissue.

18. The composition of claim 17 wherein said oligonucleotide has of a concentration of at least 10 μ

M in at least one said layer.

19. The composition of claim 18 wherein said oligonucleotide has of a concentration of at least 1 μ

M inside a cell of said layer.

20. The composition of claim 19 wherein said cell is either a smooth muscle cell, myofibroblast or a fibroblast.

28. The method according to claim 15 wherein the antisense oligonucleotide has a nucleotide sequence selected from the group consisting of SEQ ID NOS:

1, 6 and 7.

21. A composition comprising:

an excised human-compatible vein, and

an oligonucleotide complementary to c-myc mRNA located in a vessel wall of said human-compatible vein.

22. The composition of claim 21 wherein said excised human-compatible vein is selected from the group of saphenous vein, cephalic vein, basilic vein, brachial vein, and femoral vein.

23. The composition of claim 21 wherein said oligonucleotide is located in a layer of said vessel wall selected from the group consisting of endothelial layer, media, and adventitia.

24. The composition of claim 23 wherein said oligonucleotide has of a concentration of at least 10 μ

M in at least one said layer.

29. The method according to claim 21 wherein the antisense oligonucleotide has a nucleotide sequence selected from the group consisting of SEQ ID NOS:

1, 6 and 7.