Chemistry: molecular biology and microbiology – Process of mutation – cell fusion – or genetic modification – Introduction of a polynucleotide molecule into or...
Reexamination Certificate
1998-12-30
2002-04-16
Ketter, James (Department: 1632)
Chemistry: molecular biology and microbiology
Process of mutation, cell fusion, or genetic modification
Introduction of a polynucleotide molecule into or...
C604S019000, C604S022000, C604S028000, C424S093200, C424S093210, C435S325000, C536S023100, C514S04400A
Reexamination Certificate
active
06372498
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to medical methods and devices. More particularly, the present invention relates to methods, systems, and kits for the delivery of nucleic acids to smooth muscle cells which line the lumen of blood vessels.
A number of percutaneous intravascular procedures have been developed for treating atherosclerotic disease in a patient's vasculature. The most successful of these treatments is percutaneous transluminal angioplasty (PTA) which employs a catheter having an expansible distal end, usually in the form of an inflatable balloon, to dilate a stenotic region in the vasculature to restore adequate blood flow beyond the stenosis. Other procedures for opening stenotic regions include directional atherectomy, rotational atherectomy, laser angioplasty, stents and the like. While these procedures, particularly PTA, have gained wide acceptance, they continue to suffer from the subsequent occurrence of restenosis.
Restenosis refers to the re-narrowing of an artery within weeks or months following an initially successful angioplasty or other primary treatment. Restenosis afflicts up to 50% of all angioplasty patients and results at least in part from smooth muscle cell proliferation in response to the injury caused by the primary treatment, generally referred to as “hyperplasia.” Blood vessels in which significant restenosis occurs will require further treatment.
A number of strategies have been proposed to treat hyperplasia and reduce restenosis. Such strategies include prolonged balloon inflation, treatment of the blood vessel with a heated balloon, treatment of the blood vessel with radiation, the administration of anti-thrombotic drugs following the primary treatment, stenting of the region following the primary treatment, and the like. While enjoying different levels of success, no one of these procedures has proven to be entirely successful in treating all occurrences of restenosis and hyperplasia.
Of particular interest, it has recently been proposed to deliver nucleic acids to smooth muscle cells within blood vessels for the treatment of hyperplasia and other disease conditions. See, e.g. U.S. Pat. No. 5,328,470. Progress in vascular gene therapy, however, has been hindered by the limited efficiency and/or toxicity of most currently available transfection materials and techniques. Current methods used to achieve nucleic acid transfer into vascular smooth muscle cells comprise the delivery of naked DNA, cationic liposomes, and specialized adenoviral and retroviral vectors. Each of these approaches are problematic. While the use of adenoviral vectors can achieve relatively high transfection efficiencies, the use of viruses raises concern among many experts in the field.
For these reasons, it would be desirable to provide additional and/or improved methods, systems, kits, and the like for the delivery of nucleic acids to vascular smooth muscle cells and other cells which comprise the vascular wall. It would be particularly desirable if such gene delivery methods were useful for the treatment of hyperplasia in regions of a blood vessel which have previously been treated by angioplasty, atherectomy, stenting, and other primary or secondary treatment modalities for atherosclerotic disease. Such methods should provide efficient gene delivery, result in minimum necrosis of the cells lining the vasculature (particularly smooth muscle cells and endothelial cells), permit targeting of vascular smooth muscle cells, be capable of being performed with relatively simple catheters and other equipment, and suffer from minimum side effects. At least some of these objectives will be met by the invention described hereinafter.
2. Description of the Background Art
Catheters and methods for intravascular transfections are described in U.S. Pat. No. 5,328,470 and published in PCT applications WO 97/12519; WO 97/11720; WO 95/25807; WO 93/00052; and WO 90/11734.
Ultrasound-mediated cellular transfection is described or suggested in Kim et al. (1996) Hum. Gene Ther. 7:1339-1346; Tata et al. (1997) Biochem. Biophy. Res. Comm. 234:64-67; and Bao et al. (1997) Ultrasound in Med. & Biol. 23:953-959. The effects of ultrasound energy on cell wall permeability and drug delivery are described in Harrison et al. (1996) Ultrasound Med. Biol. 22:355-362; Gao et al. (1995) Gene Ther. 2:710-722; Pohl et al. (1993) Biochem. Biophys. Acta. 1145:279-283; Gambihler et al. (1994) J. Membrane Biol. 141:267-275; Bommannan et al. (1992) Pharma. Res. 9:559-564; Tata and Dunn (1992) J. Phys. Chem. 96:3548-3555; Levy et al. (1989) J. Clin. Invest. 83:2074-2078; Feschheimer et al. (1986) Eur. J. Cell Biol. 40:242-247; and Kaufinan et al. (1977) Ultrasound Med. Biol. 3:21-25. A device and method for transfection, endothelial cells suitable for seeding vascular prostheses are described in WO 97/13849.
Local gene delivery for the treatment of restenosis following intravascular intervention is discussed in Bauters and Isner (1998) Progr. Cardiovasc. Dis. 40:107-116 and in Baek and March (1998) Circ. Res. 82:295-305.
A high frequency ultrasonic catheter employing an air-backed transducer which may be suitable for performing certain methods according to the present invention is described in He et al. (1995) Eur. Heart J. 16:961-966. Other catheters suitable for performing at least some methods according to the present invention are described in co-pending application Ser. Nos. 08/565,575; 08/566,740; 08/566,739; 08/708,589; 08/867,007, and 09/223,225, assigned to the assignee of the present invention, the full disclosures of which are incorporated herein by reference.
SUMMARY OF THE INVENTION
The present invention comprises methods, systems, and kits for the delivery of nucleic acids to the smooth muscle cells of the type which line coronary arteries and other blood vessels. The delivery of nucleic acids to target cells is generally referred to as “transfection,” and the transfection methods of the present invention are advantageous since they are capable of significantly increasing transfection efficiency, i.e. the amount of nucleic acid materials taken up by the smooth muscle cells to which they are delivered. The methods of the present invention are useful with a wide variety of nucleic acid types. For example, it has been found that significant transfection efficiencies can be obtained even with naked DNA and RNA molecules i.e., nucleic acids which are not incorporated into liposomes, viral vehicles, plasmids, or other conventional nucleic acid vehicles. The methods are not limited to such naked nucleic acids, however, they are also suitable for the delivery of nucleic acids incorporated into liposomes and other vesicles; viral vectors, including both adenoviral vectors and retroviral vectors; plasmids, and the like.
The methods of the present invention are particularly suitable for delivering nucleic acids incorporated into liposomes often referred to as “lipofection,” to the vascular smooth muscle cells. As is demonstrated in the Experimental section hereinafter, transfection of vascular smooth muscle cells with naked DNA is enhanced significantly by vibratory energy (by a factor of 7.5 in the particular data shown), but overall transfection efficiency still remains at a relatively low level. In contrast, lipofection enhanced with vibratory energy according to the present invention shows a lesser enhancement over lipofection without vibrational energy (by a factor of three in the particular data which are shown), but the overall transfection efficiency, is substantially greater than that which can be achieved with naked nucleic acids, even with vibrational energy enhancement. Thus, the combination of lipofection with vibrational energy enhancement will frequently be preferred. While similar overall transfection efficiencies may be achieved with vibrational enhancement of viral vectors, the use of viral vectors will often not be preferred because of the safety concerns which have been raised with respect to such delivery vehicles. Add
Brisken Axel F.
Newman Christopher M. H.
Ketter James
Li Q Janice
Pharmasonics, Inc.
Townsend and Townsend / and Crew LLP
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