Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-05-24
2004-04-13
Myers, Carla J. (Department: 1634)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023500, C536S024310, C536S024330
Reexamination Certificate
active
06720141
ABSTRACT:
1. BACKGROUND OF THE INVENTION
Restenoisis
Percutaneous transluminal coronary angioplasty (PTCA) is used to treat obstructive coronary artery disease by compressing atheromatous plaque to the sides of the vessel wall. PTCA is widely used with an initial success rate of over 90%. Approximately 666,000 angioplasties were conducted in the United States alone in 1996, and more of these procedures were performed on men (452,000) than women (214,000). Of this total, 482,000 were percutaneous transluminal coronary angioplasty (P.T.C.A. (American Heart Association; www.amhrt.org). Despite the frequent application of this procedure and its high initial success rate, the long-term success of PTCA is limited by intraluminal renarrowing or restenosis at the site of the procedure. This occurs within 6 months following the procedure in approximately 30% to 40% of patients who undergo a single vessel procedure and in more than 50% of those who undergo multivessel angioplasty.
Stent placement has largely supplanted balloon angioplasty because it is able to more widely restore intraluminal dimensions which has the effect of reducing restenosis by approximately 50%. Ironically, stent placement actually increases neointimal growth at the treatment site, but because a larger lumen can be achieved with stent placement, the tissue growth is more readily accommodate, and sufficient luminal dimensions are maintained, so that the restenosis rate is nearly halved by stent placement compared with balloon angioplasty alone.
The pathophysiological mechanisms involved in restenosis are not fully understood. While a number of clinical, anatomical and technical factors have been linked to the development of restenosis, at least 50% of the process has yet to be explained. However, it is known that following endothelial injury, a series of repair mechanisms are initiated. Within minutes of the injury, a layer of platelets and fibrin is deposited over the damaged endothelium. Within hours to days, inflammatory cells begin to infiltrate the injured area. Within 24 hours after an injury, vascular smooth muscle cells (SMCs) located in the vessel media commence DNA synthesis. A few days later, these activated, synthetic SMCs migrate through the internal elastic lamina towards the luminal surface. A neointima is formed by these cells by their continued replication and their production of extracellular matrix. An increase in the intimal thickness occurs with ongoing cellular proliferation matrix deposition. When these processes of vascular healing progress excessively, the pathological condition is termed intimal hyperplasia or neointimial hyperplasia. Histological studies in animal models have identified neointimal hyperplasia as the central element in restenosis.
Neointimal hyperplasia is understood to figure prominently in peripheral vascular restenosis following reconstructive procedures. One series of 5,000 arterial reconstructions reports 50% of late failures to be due to neointimal hyperplasia (Imparato et al. (1972) Surg. 72:1107-1117). Restenosis following stenting is similarly thought to involve an important component of neointimal hyperplasia (Dussaillant et al. (1995) J. Am. Coll. Cardiol 26:720-724). In the coronary system, by contrast, restenosis following balloon angioplasty involves vascular remodeling as well as neointimal hyperplasia. The importance of vascular remodeling in this setting may be attributable to the nature of the injury to the vessel wall following balloon angioplasty. Commonly, the injury to the vessel wall with this procedure involves dissection planes extending through the atherosclerotic plaque into the vessel media (Mintz et al. (1996) Circ. 94:35043). Furthermore, plaque fracture, medial stretch, focal medial rupture and adventitial stretch all may occur following angioplasty. Repair of the deeper layers of the vessel wall takes place by the general processes of wound healing, including inflammation, neovascularization, fibroblast proliferation and eventual collagen deposition. Cumulatively, these processes lead to remodeling of the coronary vessel wall that may culminate in restenosis.
The biology of vascular wall healing implicated in restenosis therefore includes the general processes of wound healing and the specific processes of neointimal hyperplasia. Inflammation is generally regarded as an important component in both these processes. (Munro and Cotran (1993) Lab. Investig. 58:249-261; and Badimon et al. (1993), Supp II 87:3-6). Understanding the effects of acute and chronic inflammation in the blood vessel wall can thus suggest methods for diagnosing and treating restenosis and related conditions.
In its initial phase, inflammation is characterized by the adherence of leukocytes to the vessel wall. Leukocyte adhesion to the surface of damaged endothelium is mediated by several complex glycoproteins on the endothelial and neutrophil surfaces. Two of these binding molecules have been well-characterized: the endothelial leukocyte adhesion molecule-1 (ELAM-1) and the intercellular adhesion molecule-1 (ICAM-1). During inflammatory states, the attachment of neutrophils to the involved cell surfaces is greatly increased, primarily due to the upregulation and enhanced expression of these binding molecules. Substances thought to be primary mediators of the inflammatory response to tissue injury, including interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-&agr;), lymphotoxin and bacterial endotoxins, all increase the production of these binding substances.
After binding to the damaged vessel wall, leukocytes migrate into it. Once in place within the vessel wall, the leukocytes, in particular activated macrophages, then release additional inflammatory mediators, including IL-1, TNF, prostaglandin E
2
, (PGE
2
), bFGF, and transforming growth factors &agr; and &bgr; (TGF&agr;, TGF&bgr;). All of these inflammatory mediators recruit more inflammatory cells to the damaged area, and regulate the further proliferation and migration of smooth muscle. A well-known growth factor elaborated by the monocyte-macrophage is monocyte- and macrophage-derived growth factor (MDGF), a stimulant of smooth muscle cell and fibroblast proliferation. MDGF is understood to be similar to platelet-derived growth factor (PDGF); in fact, the two substances may be identical. By stimulating smooth muscle cell proliferation, inflammation can contribute to the development and the progression of neointimal hyperplasia.
Leukocytes, attracted to the vessel wall by the abovementioned chemical mediators of inflammation, produce substances that have direct effects on the vessel wall that may exacerbate the local injury and prolong the healing response. First, leukocytes activated by the processes of inflammation secrete lysosomal enzymes that can digest collagen and other structural proteins. Releasing these enzymes within the vessel wall can affect the integrity of its extracellular matrix, permitting SMCs and other migratory cells to pass through the wall more readily. Hence, the release of these lysosomal proteases can enhance the processes leading to neointimal hyperplasia Second, activated leukocytes produce free radicals by the action of the NADPH system on their cell membranes. These free radicals can damage cellular elements directly, leading to an extension of a local injury or a prolongation of the cycle of injury-inflammation-healing.
The responses to vascular injury that lead to restenosis have certain features in common with the processes leading to the development of the vascular lesions of atherosclerosis. Currently, it is understood that the lesions of atherosclerosis are initiated by some form of injury to arterial endothelium, whether due to hemodynamic factors, endothelial dysfunction or a combination of these or other factors (Schoen, “Blood vessels, ”pp. 467-516 in Pathological Basis of Disease (Philadelphia: Saunders, 1994)). Inflammation has been implicated in the formation and progression of atherosclerotic lesions. Several inflammatory products, including IL-1&bgr;, have been identified in
Crossman David C.
Duff Gordon W.
Francis Sheila E.
Kornman Kenneth S.
Stephenson Katherine
Elrifi, Esq. Ivor R.
Interleukin Genetics Inc.
Mintz Levin Cohn Ferris Glovsky and Popeo P.C.
Myers Carla J.
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