Surgery – Means for introducing or removing material from body for... – With means for cutting – scarifying – or vibrating tissue
Reexamination Certificate
1999-05-04
2001-05-01
Nguyen, Anthuan T. (Department: 3763)
Surgery
Means for introducing or removing material from body for...
With means for cutting, scarifying, or vibrating tissue
C604S020000, C604S239000, C606S015000, C606S016000
Reexamination Certificate
active
06224566
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to devices and methods for therapeutic treatment of the heart. In particular, the present invention relates to devices for creating a pocket in the myocardium of a mammalian heart and depositing therein therapeutic substances such as angiogenic growth factors or genes coding for such growth factors, or other desirable therapeutics or gene therapy vectors.
BACKGROUND OF THE INVENTION
Coronary Heart Disease and TMLR—Coronary Heart disease is prevalent in modern society, wherein the reduced blood supply to the heart, due to blockages in one or more of the coronary arteries, is the most common cause of heart attacks and death from heart disease. Currently, surgical intervention using coronary artery bypass graft surgery and/or coronary balloon angioplasty is the most common procedure to treat this condition.
Recently, procedures for modifying a human heart to imitate the blood delivery method of a lizard heart is currently being used as an alternative or adjunct to both coronary artery bypass graft surgery and coronary balloon angioplasty. Normally, a person can only undergo coronary bypass surgery twice, since the risks will begin to outweigh the benefits after that point. Thus, in the past, a patient who has already had two coronary bypass surgeries was left with no recourse. Others patients have failed repeated coronary balloon angioplasties, and many persons are not suitable candidates for coronary bypass surgery or coronary balloon angioplasty. These persons likewise are left with no treatment options.
Early attempts to create direct blood supply to the myocardium of mammals, known as transmyocardial revascularization (TMR), consisted of producing tiny channels in mammalian and human hearts with needles or pre-heated wires. These methods met with limited success since, although the channels closed by clotting at the outside surface of the heart due to exposure to air, and did allow for some internal blood delivery, the channels soon healed over entirely and failed to continue to enhance the blood supply. Early attempts were also made to graft a blood vessel from the aorta directly into the heart muscle to provide an internal source of blood. While some benefits were seen, the surgery was technically demanding and the procedure was eclipsed by the introduction of coronary artery bypass graft surgery.
To overcome these problems, Mahmood Mirhoseini and Mary M. Cayton attempted transmyocardial revascularization using a pulsed CO
2
laser to make the channels. This procedure has come to be known as transmyocardial laser revascularization (TMLR). Mirhoseini M., Cayton M. M., “Revascularization of the Heart by Laser”
J Microsurg
2:253, June, 1981. The laser forms each channel by vaporizing a passageway completely through the wall of the heart. The relatively clean channel formed by the laser energy prevents the channel from healing over, and the channel either closes by clotting at the heart's outer surface, due to exposure to air, or manual pressure can be applied until bleeding from the channel ceases. In some cases, a suture is required to close the channel. However, if bleeding cannot be stopped, or if bleeding resumes at a later time, after the patient is no longer in surgery, the patient may require emergency surgery or may die.
While most, if not all of the laser created channels close over time, the reduction in angina pain achieved by TMLR increases over a period of six months and is stable for at least an additional six months. In animal studies, it was found that extensive angiogenesis was seen in the area surrounding the channels, which is belied to be the main reason for TMLR's increasing benefit over six months and further extended benefit.
Since the body stores only small amounts of angiogenic growth factors in the heart, it is obvious that supplementing the body's supply of natural (endogenous) growth factors with growth factors produced by recombinant technology or to infect the myocardium with genes able to cause myocardial cells to express the growth factors, could yield greater angiogenesis and thus greater therapeutic benefits.
Angiogenesis and Atherosclerosis—Angiogenesis is the fundamental process by which mammalian systems form new blood vessels in normal growth and in response to injury. Normal angiogenesis is tightly regulated, and uncontrolled angiogenesis has been implicated in many disease states, including cancer. Specific angiogenic growth factors and other substances have been identified in the art, such as vascular endothelial growth factor or VEGF, fibroblast growth factor or FGF, and angiopoetin. (See for example Folkman and Shing, 1992,
J. Biochemistry
267(16):10931-10934; Thomas, 1996,
J. Biochemistry
271(2):603-606).
Initial work in the area of angiogenesis revolved around the discovery and characterization of angiogenic agents. For example, Abraham, J, et al (“Nucleotide Sequence of a Bovine Clone Encoding the Angiogenic Protein, Basic Fibroblast Growth Factor”
Science,
Vol. 233, 545-548, 1986) taught the nucleotide sequence of acidic FGF (aFGF), and the structures of acidic FGF (aFGF or FGF-I) and basic FGF (bFGF).
Recently it has been shown that the administration of purified human FGF-I was able to induce neoangiogenesis in ischemic myocardium, after injection concurrent with internal mammary artery (IMA)/left anterior descending coronary artery (LAD) anastomosis surgery. Schumacher, B et al., “Induction of Neoangiogenesis in Ischemic Myocardium by Human Growth Factors”
Circulation,
97: 645-650 (1998).
Gene Therapy—With the identification and characterization of various angiogenic agents, it was possible to purse direct molecular intervention in vivo of the processes of neovascularization. Gene therapy has been a long desired goal of biomedical science, but effective introduction of genes causing the expression of VEGF or FGF into cells of the myocardium takes lengthy exposure which is not practical in a beating heart. Inserting an angiogenic gene into the genome of a replication deficient virus, which retains its ability to infect cells, was proposed to overcome this problem. Berlener, K L (“Development of adenovirus vectors for the expression of heterologous genes”
Biotechniques
6:616-629, 1988) was one of the earliest reports on the use of such viruses for gene transfer.
Work in the art of gene expression vectors and delivery has advanced greatly in the last few years. For example, Ziverbel, J A, et al., (“High-level recombinant gene expression in rabbit endothelial cells transduced by retroviral vectors,”
Science,
243: 220-222, 1989) demonstrated the practical use of retroviral vectors to carry genes into endothelial cells. However, prior and subsequent work has shown that the use of retrovirus vectors is problematic, as complete and permanent deactivation of the retrovirus cannot be assured. Stratford-Perricaudet, L D, (“Evaluation of the transfer and expression in mice of an enzyme-encoding gene using a human adenovirus vector”
Hum. Gene Ther.
1:241-256, 1990) was also an early report of human adenovirus gene therapy work. Methods for delivery of gene therapy to specific targets has met with substantial progress, however specific technical issues still require further work (see Mulligan, R C, “The Basic Science of Gene Therapy”,
Science,
260: 926-932 (1993), for review).
Continued research on gene therapy and angiogenic factors have yielded information about coordinated action of various factors, for example, Suri, C et al. (“Increased Vascularization in Mice Overexpressing Angiopoetin-1”
Science,
Vol. 282, 468-471, October 1998), showed that angiopoetin-1 is necessary to mature and maintain new vessels initially created by introduction of VEGF or aFGF. This work demonstrates that additional substances, such as angiopoietin-1, can be used to maintain the integrity of the newly created vessels for a long term effect.
Continued research involving treating blood vessels to either enhance or inhibit angiogenesis related to atherosclerosis usi
CardioDyne, Inc.
Nguyen Anthuan T.
Olson & Hierl Ltd.
Thissell Jerry
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