Antisense restenosis composition and method

Abstract

The present invention provides an improved method for reducing the risk or severity of restenosis following cardiac angioplasty. The method includes administering to a target vessel region, a morpholino antisense compound having uncharged phosphorus-containing backbone linkages, and spanning the start codon of a human c-myc mRNA. Also disclosed are novel antisense compounds and compositions, and a method for assaying the effectiveness of antisense delivery and uptake to a target vessel region.

Description

[0001] This application is a continuation of U.S. patent application Ser. No. 09 / 493,427, filed Jan. 29, 2000, which claims priority to U.S. Provisional Application No. 60 / 117,846, filed Jan. 29, 1999, all of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION [0002] The present invention relates to compositions and methods for treating restenosis, and in particular to an antisense composition directed against c-myc, and a method of administering the composition to reduce the risk of restenosis in transluminal angioplasty, such as percutaneous transluminal coronary angioplasty (PTCA). REFERENCES [0003] Alfke H; et al.; Cardiovasc Intervent Radiol, 21(1) p. 50-6, (1998). [0004] Allen R T; et al.; Scanning, 20(8):577-86, (1998). [0005] Badimon L; et al.; Z Kardiol, 84(Suppl 4):145-9, (1995). [0006] Barath P; et al.; Cathet Cardiovasc Diagn, 41 (3) p. 333-41, (1997). [0007] Bartorelli A L; et al. Cathet Cardiovasc Diag, 42(3):313-20, (1997). [0008] Bauri...

AI Technical Summary

Benefits of technology

[0050] In one aspect, the invention includes a method of reducing the risk of restenosis in a region of a patient's coronary vessel which has been treated by coronary angioplasty using a catheter with a distal-end expandable balloon, or which is at a vessel junction formed in a coronary bypass operation. The method includes administering to the patient, by direct local administration to the vessel site or injury, a morpholino antisense compound having (i) from 8 to 40 nucleotides, including a targeting base sequence that is complementary to a region that spans the translational start codon of a c-myc mRNA, and (ii) uncharged, phosphorous-containing intersubunit linkages, in an amount effective to reduce the risk or severity of restenosis in the patient.

[0058] In a related aspect, the invention includes a method of reducing the risk of restenosis in a region of a patient's coronary vessel that has been treated by coronary angioplasty using a catheter with a distal-end expandable balloon. The method includes administering to the patient, by direct administration to the site of injury, a morpholino antisense compound having (i) the base sequence identified as SEQ ID NO:1, and (ii) a phosphorodiamidate backbone shown in. FIG. 2B-B, where X=NH2, Y=O, and Z=O. The antisense compound may be derivatized, e.g., at its 5′ end, with a moiety that enhances the solubility of the compound in aqueous medium, and / or with a moiety that imparts a charge to the compound at physiological pH. The compound is preferably delivered by direct application of the compound to the target vessel region, immediately following balloon angioplasty, or during a coronary bypass operation, in an amount of between about 1-30 mg, to achieve a final amount of compound administered to the target region of between about 0.5 to 2 mg.

Problems solved by technology

Despite improvements in equipment and techniques, restenosis persists as the limiting factor in the maintenance of vessel patency in angioplasty, occurring in 30% to 50% of patients, and accounting for significant morbidity and health care expenditures (Casterella).

Clinical trials in restenosis prevention using various revascularization devices, antiplatelet drugs, antithrombotic drugs, and anti-inflammatory agents have produced limited improvement in the incidence of restenosis.

Despite these advances, the incidence of restenosis, and the inability to predict the response to treatment, remains a serious risk factor in vascular angioplasty.

Images