Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
1998-07-09
2001-03-13
Kennedy, Sharon (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C604S500000, C604S507000, C128S898000
Reexamination Certificate
active
06200304
ABSTRACT:
The present invention relates to a transfection system comprising one or more Infiltrator catheters, one or more nucleic acids, and, where appropriate, suitable ancillary substances and/or additives, and to its preparation and use in somatic gene therapy.
Local gene therapeutic treatment of vascular disorders represents a very promising prospect in interventional cardiology which might, for example, prevent reocclusion of vessels (restenosis) after mechanical widening of the blocked vessel with a balloon catheter (so-called percutaneous transluminal coronary angioplasty; PTCA), because restenosis still occurs in 30-40% of all cases after PTCA treatment.
Systemic administration of drugs has, despite very promising theoretical ideas, not produced an improvement in the long-term success of PTCA, presumably because the concentration of the therapeutic agent in the region of the treated stenosis was inadequate at the time. These results have led to the development of various special catheters permitting local treatment of a damaged section of vessel with specific drugs.
One disadvantage of the local administration of medicines, especially of medicines with a low molecular weight, using special catheters is, however, rapid perfusion out of the treated section of vessel. The required depot formation persists for only a short time.
A prolongation of the therapeutic effect can be achieved, for example, by therapeutically effective genes being transferred, by somatic gene transfer, locally into the vessel wall and being expressed there.
For gene transfer into the vessel wall, essentially three components are necessary:
A therapeutically effective gene which, on local expression, for example, results in the synthesis of a factor which inhibits restenosis formation.
A transfection system which permits
(a) maximally efficient transfection of the vessel wall with the therapeutic gene and
(b) localization of the transfection.
An efficient catheter technology which allows
(a) in vivo transfections of specific individual sections of vessels in a hypo- or atraumatic manner using minimally invasive techniques,
(b) in combination with the transfection system, minimal distribution of the therapeutic gene into the perivascular space or into the blood circulation to be ensured, and
(c) a guarantee of short vessel occlusion times.
Schrader, J. & Gödecke, A. (DE 44 11 402) have now found that transfection with the nitric-oxide synthase gene in the form of a liposome complex in blood vessels leads to a therapeutically relevant inhibition of vessel stenosis and restenosis after PTCA. However, a polyethylene catheter was used for transfection with the DNA-liposome complexes, which interrupted the blood flow in the vessel for 15-20 minutes. In addition, transfection led to a thrombosis after reopening of the vessel in a few cases.
Some other special catheters have already been described in the literature with the intention of solving the problem of local administration of drugs (Wilenksy, R. L. et al. (1993) Trends Cardiovasc. Med. 3(5), 163-170).
For example, a double balloon catheter allows a defined section of vessel to be separated from the circulation by inflating balloons, one distal and one proximal of the section of vessel to be transfected (see, for example, Nathan, A. & Edelman E. R. (1995) in Edelman, E. R. (ed.), “Frontiers in Cardiology; Molecular Interventions and Local Drug Delivery” Saunders Company Ltd., london, GB, 29-52). The lumen isolated in this way is then filled with the therapeutic agent, which enters the vessel wall by diffusion. However, the disadvantages of this catheter are the long vessel occlusion times on use, and essentially only the innermost vessel cell layers are reached (Flugelman, M. Y. (1995), Thrombosis and Haemostasis, 74(1), 406-410). This type of catheter is therefore unsuitable for somatic gene transfer.
The porous balloon was developed in order to force a therapeutic agent under pressure through pores in an inflated balloon into the vessel wall and thus to achieve transmural distribution of the therapeutic agent. The high pressures required for the injection (2-5 atm.) frequently resulted, however, in serious mechanical damage to the vessel wall, which was manifested either by dissection or the development of necrotic zones in the media. In addition, the transfection efficiency is extremely low and not localized (Flugelman, M. Y. (1995), supra; Flugelman, M. Y. et al. (1992) Circulation, 85(3), 1110-1117). This type of catheter was therefore also found to be unsuitable for somatic gene transfer.
The principle of the functioning of the Dispatch catheter resembles in principle the double balloon catheter described above (see, for example, McKay, R. G. et al. (1994), Catheterization and Cardiovascular Diagnosis, 33, 181-188). The section of vessel to be treated is, however, in this case not separated from the remainder of the circulation by two peripheral balloons but is separated by a coil which makes contact with the vessel wall after inflation. The vectors are injected into the closed chamber through orifices in the catheter shaft between the helical elements. Transfection takes place by diffusion. In order to make the required long transfection time of about 30 minutes possible without cutting off the distal regions from the blood flow, a conduit passing through the shaft of the inflated catheter was fitted to make blood flow possible.
The needle injection catheter (NIC) is characterized by three injection needles which can be advanced out of the rounded tip of a catheter and then penetrate into the vessel wall (see, for example, Gonschior, P. et al. (1995) Coronary Artery Disease, 6, 329-344). It has already been possible to inject drugs through these needles into the vessel wall.
However, manipulation of the NIC is difficult because it is not easily possible to check how far the needles have emerged from the head of the catheter, although this defines the depth of injection. This entails the risk of perforation of the vessel wall and thus transfection of perivascular tissue, but also of bleeding from the vessel. This danger applies particularly on transfection of eccentric plaques.
Janssens, S. et al., The Second Annual International Symposium, Oct. 13-15, 1996, Cambridge, Mass., describe gene transfer with the aid of an adenoviral vector and of an Infiltrator catheter which is not described in detail. However, the disadvantage of this transfection system is that cytotoxic effects have been observed with adenoviral vectors (Flugelman, M. Y. (1995), supra).
It was therefore an object of the present invention to find a transfection system which makes it possible to perform somatic gene transfer into vessels efficiently and with minimum damage.
The present invention therefore relates firstly to a transfection system comprising one or more Infiltrator catheters, one or more nucleic acids in nonviral form and, where appropriate, suitable ancillary substances and/or additives.
The Infiltrator catheter is a special catheter developed for intravascular injection of drugs into the vessel wall. It takes the form of a balloon catheter from whose surface injector ports (tubular, stud-like extensions for administering one or more active substances) project. The height of the injector ports is normally about 100-500 &mgr;m, preferably about 100-250 &mgr;m, in particular about 100 &mgr;m, and the number of injector ports per balloon is normally about 5×7, preferably about 3×7. Inflation of the balloon to, normally, about 2 atm forces these injector ports into the vessel wall. It is then possible to inject through the injector ports in general up to about 500 &mgr;l, preferably about 250-300 &mgr;l, of active substance or active substances under low pressure, preferably about 100-200 mm Hg, in particular about 150 mm Hg, into the vessel wall.
The catheter normally has more than one lumen and is, in particular, a double lumen, particularly preferably a triple lumen, catheter.
The double lumen catheter generally consists of a tubular shaft and the inflatable ball
Cardiogene Gentherapeutische Systeme AG
Frommer & Lawrence & Haug LLP
Hayes Michael J
Kennedy Sharon
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