Antisense inhibition of c-myc to modulate the proliferation of s

Details Antisense inhibition of c-myc to modulate the proliferation of s Antisense inhibition of c-myc to modulate the proliferation of s

1995-07-07

2000-12-12

Brusca, John S.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

435 6, 435375, 435455, 536 231, 536 241, 536 245, C07H 2104, A61K 4800

Patent

active

061599468

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention is directed to the modulation of smooth muscle cell proliferation by antisense therapies directed against the c-myc proto-oncogene.


BACKGROUND OF THE INVENTION

Coronary angioplasty results in successful nonsurgical revascularization in more than 90% of patients. More than 300,000 coronary angioplasty procedures were performed in the United States in 1990. However, the major limitation of coronary angioplasty is a 30-40% restenosis rate which occurs in the first six months following the procedure.
Vascular smooth muscle cells (SMC) have been identified as playing an important role in the development of atherosclerosis and restenosis following coronary angioplasty. Their presence has been confirmed in both types of lesions, and is due primarily to a change from a contractile to a synthetic phenotype of SMCs. This remarkable characteristic is associated with SMC proliferation, migration from media to intima, and the synthesis of extracellular matrix, all of which results in neointimal formation (narrowing of the artery). In contrast to atherosclerosis, where this process is extended over several decades, vascular restenosis represents an acute response to balloon injury culminating in a significant renarrowing by neointimal formation of an initially patent vessel in the course of a few months. Hence, it has become apparent that the inhibition of SMC growth is necessary to control the restenosis process.
Intensive experimental and clinical investigation for the prevention of restenosis has been conducted over the past decade. Several interventions, such as anti-platelet, anti-coagulation, anti-inflammatory and vasodilator therapies have shown favorable reduction in the severity of neointimal proliferation following experimental balloon injury. Powell et al., Science 1989, 245, 186-188; Castellot, J. et al., J. Cell Physiol. 1985, 124, 21-38; Fox et al., Science 1988, 241, 453-456.
Recently, attempts have also been made to apply new mechanical devices to limit restenosis (e.g., stent, atherectomy, laser, rotablator, etc.). However, preliminary data showed a limited role of these interventions because while mechanical interventions improve the primary result of coronary angioplasty, the mechanical techniques extend vessel wall injury related to the procedure and are therefore unable to reduce SMC proliferation and the restenosis rate. Furthermore mechanical interventions can be applied only to a small group of patients with optimal coronary anatomy.
Application of antimitogenic therapy has also been suggested for prevention of restenosis. For example, concentrated heparin has been tested as an antiproliferative agent to control the problem of restenosis after angioplasty. Wolinsky and Thung, JACC 1990, 15(2), 475-481. .gamma.-interferon has been identified as another potentially useful therapeutic for treatment of restenosis. WO 90/03189 issued Apr. 5, 1990. However the dose of antiproliferative agents given by systemic administration is likely not high enough to achieve the desired effect. Therefore, agents which have been tested are not powerful enough to show a beneficial effect in more complex clinical situations.
Recent advances in cellular and molecular biology have provided insight into the molecular mechanisms of SMC proliferation which is due to the transduction of signals from the extracellular environment (e.g., growth factors) to the cell nucleus. Several genes become transiently activated during phenotypic modulation of SMCs (Gabbiani et al., J Clin Invest 1984, 73, 148-152; Walker et al., Proc Natl Acad Sci USA 1986, 83, 7311-7315; Miano et al., Am J Pathol 1990, 137, 761-765; Majesky et al., Circulation Research 1992, 71, 759-768). These findings have stimulated interest in defining the role of abnormal gene expression in SMC growth and in selecting potential therapeutic targets for molecular-based approaches for acquired cardiovascular disorders such as vascular restenosis. Recently, Speir and Epstein, Circulation 1992, 86, 538-547, showed the growth inhi

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