Apoptotic regression of intimal vascular lesions

• US 5,776,905 A
• Filed: 08/08/1996
• Issued: 07/07/1998
• Est. Priority Date: 08/08/1996
• Status: Expired due to Fees

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Inventors: Pollman, Matthew J., Gibbons, Gary H.
• Primary Examiner(s): Marschel, Ardin H.
• Application Number:
  US08/694,927
• Time in Patent Office: 698 Days
• Field of Search: 435/69.1, 435/810, 436/501, 436/63, 514/44, 514/2, 935/77.78
• US Class Current: 514/44.00A
• 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: C07K 14/47 from mammals
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/315 Phosphorothioates

Abstract

Neointimal cells are shown to express high levels of an anti-apoptotic gene, bcl-x, while the medial cells of the vessel itself express only low levels. The difference in gene expression exploited to provide for selective deletion of the neointimal cells. Apoptosis is induced by administering anti-sense bcl-x oligonucleotides to the affected vessel. Apoptosis is desirable as a treatment because it does not induce inflammation, further tissue injury or reactive hyperplasia. A significant reduction in lesion size is seen after treatment.

Claims

1. A method of reducing the dimensions of a neointimal vascular lesion in a patient, the method comprising:

administering an effective amount of a synthetic anti-sense oligonucleotide that specifically blocks expression of bcl-x;

wherein apoptosis is induced in said neointimal cells, thereby reducing the dimensions of said neointimal vascular lesion.

2. A method according to claim 1, wherein said synthetic antisense oligonucleotide comprises a phosphorothioate backbone.

3. A method according to claim 1, wherein said antisense oligonucleotide is administered by pressure-mediated delivery.

4. A method according to claim 1, wherein said antisense oligonucleotide is administered by liposome delivery.

5. A method according to claim 1, wherein said neointimal hyperplasia is an athersclerotic lesion.

6. A method according to claim 1, wherein said synthetic antisense oligonucleotide is complementary to the region of the translation initiation codon of bcl-x.

7. A method of reducing the dimensions of a neointimal vascular lesion in a patient, the method comprising:

administering an effective amount of a synthetic anti-sense oligonucleotide that (a) specifically blocks expression of bcl-x; and

(b) is complementary to the region of the translation initiation codon of bcl-x;

wherein apoptosis is induced in said neointimal cells, thereby reducing the dimensions of said neointimal vascular lesion.

8. A method according to claim 7, wherein said synthetic antisense oligonucleotide comprises a phosphorothioate backbone.

9. A method according to claim 7, wherein said antisense oligonucleotide is administered by pressure-mediated delivery.

10. A method according to claim 7, wherein said antisense oligonucleotide is administered by liposome delivery.

11. A method according to claim 7, wherein said neointimal hyperplasia is an athersclerotic lesion.