Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-07-30
2001-07-10
Martin, Jill D. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S455000, C435S320100, C435S069100, C435S069400, C435S069600, C435S069800
Reexamination Certificate
active
06258787
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed to a method for enhancing the relining of a blood vessel by use of an endothelial cell (EC) mitogen. This method is particularly useful for reendothelialization of an injured blood vessel.
Atherosclerosis, a common form of arteriosclerosis, results from the development of an intimal lesion and subsequent narrowing of the vessel lumen. As the lesions increase in size, they reduce the diameter of the arteries and impede blood circulation.
Many therapeutical alternatives have been considered for the treatment of atherosclerosis, including surgery and medical treatment. One potential therapy is percutaneous transluminal angioplasty (balloon angioplasty). In balloon angioplasty, a catheter equipped with an inflatable balloon is threaded intravascularly to the site of the atherosclerotic narrowing of the vessel. Inflation of the balloon compresses the plaque enlarging the vessel.
While such angioplasty has gained wider acceptance, it suffers from two major problems, i.e., abrupt closure and restenosis. Abrupt closure refers to the acute occlusion of a vessel immediately after or within the initial hours following a dilation procedure. Abrupt closure occurs in approximately one in twenty cases and frequently results in myocardial infarction and death if blood flow is not restored in a timely manner.
Restenosis refers to the re-narrowing of an artery after an initially successful angioplasty. Restenosis of the blood vessel is thought to be due to injury to the endothelial cells of the blood vessel during angioplasty, or during inflation of the balloon catheter. During healing of the blood vessel after surgery, smooth muscle cells proliferate faster than endothelial cells narrowing the lumen of the blood vessel, and starting the atherosclerotic process anew. In recent years, smooth muscle cell proliferation has been recognized as a major clinical problem limiting the long-term efficacy of percutaneous transluminal coronary angioplasty.
In an effort to prevent restenosis of the treated blood vessel, the search for agents that can reduce or prevent excessive proliferation of smooth muscle cells have been the object of much research. (The occurrence and effects of smooth muscle cell proliferation after these types of surgery have been reviewed, for example, in Ip, et al., (June 1990)
J. Am. College of Cardiology
15:1667-1687, and Faxon, et al. (1 987)
Am. J. of Cardiology
60: 5B-9B.)
An alternative to prevent problems associated with angioplasty, places endovascular stents in the dilated segments to mechanically block abrupt closure and restenosis. Unfortunately, the use of such stents are limited by direct (subacute thrombosis) or indirect (bleeding, peripheral vascular complications) complications. After stent implantation the patients are threatened with stent thrombosis until the struts of the stent are covered by endothelium. Thus, an aggressive therapy using anticoagulation and/or antiplatelet agents is necessary during this period of time. While these therapies are able to decrease the rate of stent thrombosis, they are the main source of indirect complications.
Thus, the need for a simple and effective means to reduce restenosis is extremely important.
SUMMARY OF THE INVENTION
It has now been discovered that surprisingly nucleic acid (DNA or RNA) capable of expressing an endothelial cell mitogen when delivered to the site of a blood vessel injury, i.e., the denuded endothelial lining of a blood vessel wall, induces reendothelialization of the injured blood vessel and consequently reduces restenosis.
While not wishing to be bound by theory we believe that in contrast to the typical strategies, which have been designed to reduce restenosis by directly inhibiting smooth muscle cell proliferation, our method indirectly inhibits smooth muscle cell proliferation by directly facilitating reendothelialization of the injured vessel.
The present invention provides a method for inducing reendothelialization of the lining of an injured blood vessel comprising contacting the injured portion of the blood vessel with an effective amount of a nucleic acid capable of expressing an endothelial cell mitogen.
The method of the present invention may be used to treat any blood vessel injury that results in denuding of the endothelial lining of the vessel wall, including, for example, those injuries resulting from balloon angioplasty and related devices (e.g., directional atherectomy, rotational atherectomy, laser angioplasty, transluminal extraction, pulse spray thrombolysis) and deployment of an endovascular stent.
The injured portion of the blood vessel may be contacted with the nucleic acid by any means of administration. One preferred means of administration is the use of standard catheter delivery systems known in the art, for example, a double balloon catheter, a porous balloon catheter or a hydrogel polymer coated balloon.
In another embodiment, the blood vessel is contacted with the nucleic acid at the time of vessel injury, for example, at the time of balloon angioplasty or stent deployment. This can be accomplished by incorporating the nucleic acid on the surface of the balloon or stent. The nucleic acid can be incorporated on the balloon surface by means a hydrophilic polymer coating on the balloon surface.
The hydrophilic polymer is selected to allow incorporation of the nucleic acid to be delivered to the site of injury and thereafter released when the hydrophilic polymer contacts the site. Preferably, the hydrophilic polymer is a hydrogel polymer. Other hydrophilic polymers will work, so long as they can retain the nucleic acid, so that, on contact with site, transfer of genetic material occurs.
The injured vessel may also be contacted with the hydrophilic polymer incorporating the nucleic acid by means of an applicator such as a catheter which is coated with the nucleic acid-bearing hydrophilic polymer. Preferably, the applicator can exert some pressure against the arterial cells, to improve contact between the nucleic acid-bearing hydrophilic polymer and the arterial cells. Thus, the use of a balloon catheter is preferred. Preferably, the hydrophilic polymer coats at least a portion of an inflatable balloon of the balloon catheter.
As aforesaid, the nucleic acid may be administered by other means. For example, it may be carried by a microdelivery vehicle such as cationic liposomes or target specific vectors. Such vectors have been described in the art and include those comprising a target moiety and a nucleic acid moiety. Nucleic acid encoding different mitogens may be used separately or simultaneously.
As used herein the term “endothelial cell mitogen” means any protein, polypeptide, mutein or portion that is capable of inducing endothelial cell growth. Such proteins include, for example, vascular endothelial growth factor (VEGF), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (j catter factor), and colony stimulating factor (CSF). VEGF is preferred.
The term “effective amount” means a sufficient amount of nucleic acid delivered to the cells at the site of injury to produce an adequate level of the endothelial cell mitogen, i.e., levels capable of inducing endothelial cell growth. Thus, the important aspect is the level of mitogen expressed. Accordingly, one can use multiple transcripts or one can have the gene under the control of a promoter that will result in high levels of expression. In an alternative embodiment, the gene would be under the control of a factor that results in extremely high levels of expression, e.g., tat and the corresponding tar element.
REFERENCES:
patent: 5304121 (1994-04-01), Sahatjian
patent: 5332671 (1994-07-01), Ferrara et al.
patent: 5792453 (1998-08-01), Hammond et al.
patent: WO 89/03875 (1989-05-01), None
Levy et al., Journal of Controlled Release, vol. 36, No. 1-2, pp. 137-147, Sep. 1995.*
Friesel, R. E. et al. “Molecular mechanisms of angiogenesis: fibroblast growth factor signal transduction”, FASEB J. 9: 919-925 (1995).
Nabe
Conlin David G.
Dike Bronstein Roberts & Cushman
Martin Jill D.
St. Elizabeth's Medical Center of Boston, Inc.
LandOfFree
Treatment of vascular injury does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Treatment of vascular injury, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Treatment of vascular injury will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2482726