Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1995-04-19
2001-11-27
McGarry, Sean (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S006120, C435S091100, C435S455000, C435S375000, C536S023100, C536S024500
Reexamination Certificate
active
06323184
ABSTRACT:
FIELD OF INVENTION
The invention relates generally to oligonucleotides and their use as therapeutic agents, and more particularly to the use oligonucleotide antisense and anti-gene compounds to inhibit the synthesis of extracellular matrix proteins, particularly from fibroblasts and smooth muscle cells.
INTRODUCTION
Arteriovenous shunts and fistulae provide hemodialysis access sites to the circulatory system for hemodialysis patients. Unfortunately, arteriovenous shunts and fistulae fail over time, which can create serious medical complications for more than 300,000 world-wide hemodialysis patients (Newman, G. E., in
Vascular Disease: Surgical and Interventional Therapy,
E. Strandness, Ed. (1994)). Depending on the study, 12 to 45 percent of arteriovenous shunts and fistulae fail within the first year (Newman, G. E., (1994) cited herein). The major reason for access site failure is progressive venous stenosis (Sedberg et al.,
Circulation
80: 1726-1736 (1989)). Failed or dysfunctional hemodialysis access sites require medical treatment, either surgery to replace the arteriovenous shunt or transcatheter intervention (e.g. balloon angioplasty or stent) to enlarge the venous vessel exiting the shunt or fistulae (Newman, G. E., (1994) cited herein). Consequently, chronic hemodialysis patients with arteriovenous shunt and fistula complications spend approximately 30 days per year in the hospital to maintain the patency of their access sites.
Hemodialysis access sites are thus known as the “Achilles heel” of a hemodialysis patient, even though the construction of an arteriovenous shunt or fistula is necessary for convenient hemodialysis. Arteriovenous shunts and fistulae are usually constructed as Brescia-Cimino arteriovenous fistulae or polytetrafluoroethylene (PTFE, Gor-Tex™) grafts. In most instances the vein is surgically connected to the artery, either directly, or indirectly via a PTFE graft, in the forearm area, shoulder area or thigh area.
Arteriovenous fistulae are but one example of arteriovenous grafts that progressively become compromised over time. Other types of grafts (i.e., venous grafts) that cause medical conditions requiring treatment include: aortocoronary bypass grafts, carotid grafts, iliofemoral grafts and fermoropopliteal grafts. In these grafts a segment of a vein is placed in the arterial system. One of the predominate medical conditions affecting arteriovenous grafts of all types, or venous grafts placed in the arterial system, is the decrease in the interior diameter of the vessel over time. This usually occurs in the vein exiting, or forming part of the body of, the graft (referred to herein as the “vein portion” of the graft). It is believed that exposure of a vein to high, arterial pressure changes the morphology of the vein; notably the interior diameter of the vein portion of the graft decreases in diameter. Grafts also suffer from thrombosis and other medical disorders, such as infection.
Prior to the present invention, treatments for arteriovenous and venous grafts were of limited effectiveness and usually required invasive treatment. Efforts have focused on mechanically increasing the interior diameter of the graft in the section with thickened vessel walls, such as in failing hemodialysis access sites. Other methods simply rely on surgical revision of the failed graft site, as in arteriovenous shunt replacement. These types of prior art treatments need considerable physician supervision, often require hospitalization and in the case of some hemodialysis access sites, may ultimately lead to an inability to find a suitable hemodialysis access site, as discussed herein.
Several studies focusing on the morphology of veins in failing grafts, such as arteriovenous grafts and venous grafts (e.g., aortocororary bypasses) have provided information on the pathomechanism of these disorders. Thin-walled veins respond early to exposure to arterial blood flow and pressure. The vein starts to develop neointima. The response to high arterial pressure and flow ultimately leads to a significant narrowing of the lumen, causing diminished patency of the vein. Vascular smooth muscle cells, are primarily found in the media and neointima. Fibroblasts are found in the adventitia and perivascular tissue. Fibroblasts contribute to the granulation of the perivascular tissue during wound repair of the vein. In response to injury, both smooth muscle cells and fibroblasts increase matrix protein synthesis in the vessel wall and perivascular tissue. Consequently, the vein becomes narrowed and stiffer due to an increase of vessel wall thickness and an increase in scar formation in the perivascular tissue, which leads to irreversible failure of grafts, as in the case of arteriovenous fistulae or venous grafts.
The inappropriate synthesis of extracellular matrix proteins and/or the synthesis of aberrant forms of such proteins is associated with wide range of deleterious conditions, including many rare heritable diseases as well as more commonly acquired disorders, such a loss of arteriovenous and venous graft patency (Sedberg et al.,
Circulation
80: 1726-1736 (1989)), fibrotic skin disease, pulmonary fibrosis, osteoarthritis, vascular restenosis, and the like, e.g., Weiss and Jayson, Editors,
Collagen in Health and Disease
(Churchill Livingstone, Edinburgh, 1982); Gardner, Editor,
Pathological Basis of the Connectve Tissue Diseases
(Lea & Febiger, Philadelphia, 1992). Extracellular matrix consists primarily of collagens, proteoglycans, elastin, and fibronectin.
Many of these conditions are associated with very complex biological responses to physical, chemical, and/or biological insults. Such responses include the proliferation and migration of a variety of cell types and the synthesis of a growth factors that contribute to or modify the response. For example, vascular disorders, such as atherosclerosis and vascular restenosis, are associated with local cell proliferation and migration, as well as the production of several classes of structural proteins and many growth factors, including platelet-derived growth factor (PDGF), basis fibroblastic growth factor, tumor necrosis factor &agr;, interleukin-1, prostaglandins, and a variety of proto-oncogenes, e.g., Ross,
Nature,
362: 801-809 (1993); and Morishita et al,
Proc. Natl. Acad. Sci.,
90:8474-8478 (1993). Unfortunately, the precise role of these factors in the various disease processes is not well understood.
The tremendous economic impact of disorders associated with inappropriate production of extracellular matrix proteins, especially vascular disorders, has served as a strong impetus to develop drugs or other methods of treament to cure or ameliorate their debilitating effects. In this class of disease, as well as others, where a disease condition is associated with the apparent aberrant expression of a endogenous gene, the use of so called antisense compounds provides many advantages, e.g. Milligan et al,
J. Med. Chem.,
36:1923-1937 (1993); Uhlmann and Peyman, Chemical Reviews, 90:543-584 (1990); Goodchild,
Bioconjugate Chemistry,
1:165-187 (1990); Crooke,
Ann. Rev. Pharmacol. Toxicol.,
32:329-376 (1992); Stein et al,
Science,
261:1004-1012 (1993); and the like.
A particularly compelling advantage of the antisense approach is that one need not carry out one or more initial screening steps to identify candidate compounds capable of binding to a therapeutic target. If the aberrant expression of a gene is known to cause a disease for which a drug is sought, then the structures of candidate antisense drugs are determined automatically from the nucleotide sequence of the aberrantly expressed gene. One need only provide an oligonucleotide or an analog thereof capable of forming a stable duplex or triplex with such a gene, or associated target polynucleotide, based on Watson Crick or Hoogsteen binding, respectively. It will be recognized that the invention is not limited to a particular mechanism of action. Such compounds may have additional non-antisense, sequence specific affects that rely on other mechanism
Shi Yi
Zalewski Andrew
Drinker Biddle & Reath LLP
McGarry Sean
Thomas Jefferson University
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