Gene therapeutic treatment of blood vessel associated disorders

Details Gene therapeutic treatment of blood vessel associated disorders Gene therapeutic treatment of blood vessel associated disorders

1999-10-26

2002-06-04

Truong, Kevin (Department: 3731)

Surgery

Means for introducing or removing material from body for...

Treating material introduced into or removed from body...

Reexamination Certificate

active

06398757

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a catheter for use in gene therapeutic treatment of local disorders by transfer of a desired gene to a target cell or tissue being part of or being located in the vicinity of a blood vessel. The present invention in a first preferred embodiment relates more in particular to the local transfer of the nitric oxide synthase (Ms) gene into the wall of arteries injured by interventional procedures such as angioplasty or stenting. In another preferred embodiment the invention relates to the gene therapeutical treatment of vasculated tumors by transfer of genes encoding a product that may kill or inhibit growth of tumor cells and/or vascular cells.
Gene therapy as intended by the present invention involves the genetic engineering of cells of a subject in need or therapy. Through genetically engineering cells they will acquire one or more desirable properties they did not or did no longer possess, for example the ability to express a particular protein. As an alternative a cell may be genetically engineered to loose an unwanted property.
Conditions that can be treated by means of gene therapy through local delivery of a gene of interest to a target cell or tissue are for example restenosis and cancer.
Restenosis is a complex biological process, initiated by platelet adhesion and aggregation at the site of arterial injury Platelet activation results in the release of a variety of vasoactive, growth, and mitogenic factors that stimulate vascular smooth muscle cell (VSMC) proliferation and migration, matrix formation, and the late fibroproliferative response. In addition, injury to the endothelial protective barrier results in the loss of constitutively expressed endothelium-derived vasoactive factors including nitric oxide (NO), prostacyclin and bradykinin, which under normal circumstances play an important role in vascular homeostasis.
Over the past 15 years, percutaneous transluminal coronary angioplasty (PTCA) has significantly altered the management of symptomatic coronary artery disease. Despite its overall value in achieving immediate symptomatic relief, restenosis occurs in 30 to 50% of patients within 3 to 6 months. Restenosis following PTCA is caused by progressive elastic recoil, extracellular matrix formation, and fibrointimal hyperplasia at the site of angioplasty. However, in randomized clinical trials most currently used pharmacological agents have failed to demonstrate any beneficial effect on restenosis. The need therefore exists for a new form of treatment of this condition. Gene therapy is a very promising prospect. Local transfer of genes encoding antiproliferative and angiogenic proteins has been effective in animal models of neointima formation following angioplasty in peripheral arteries.
All established tumors, both primary and metastasized, that are larger than a few millimeter in diameter are vascularized. In addition, distant metastases usually emerge after migration of tumor cells from the primary tumor through the blood or lymphatic circulation. Thus, all solid tumors are in close contact with the circulation and, in principle, could be reached via the circulation. Gene therapeutically influencing tumor cells via the circulation is therefore very well possible. Moreover, killing of a solid tumor does not necessarily depend on gene transfer into the tumor cells themselves. Gene therapy strategies have been proposed where genetic material (e.g., the HSV-tk gene) is introduced into endothelial cells of the tumor vasculature (e.g., W096/21416). This should result in destruction of the tumor vasculature, ultimately leading to tumor necrosis.
Gene therapeutic treatment of conditions like restenosis and cancer that are associated with blood or lymphatic vessels can thus be accomplished via the circulation.
However, the first important step in genetically engineering cells in gene therapy is being capable of efficiently transferring a vector harboring the gene of interest to the cell.
Local adenoviral-mediated vascular gene transfer is currently accomplished by different delivery devices, including double balloon, coated balloon and microporous balloon catheters, which by virtue of their design have only resulted in limited vascular gene transfer in animal models. The double balloon catheter creates an isolated space within the artery for instillation of vectors, but delivery/transduction efficacy is hampered by side branches within the central space of the lumen. A balloon catheter coated with a hydrophilic polymer containing plasmid DNA is currently used in a human gene therapy protocol for angiogenesis in peripheral arteries, but is less suited for coronary gene transfer because of washout after exposure to the blood stream. Microporous balloon catheters allow local high pressure delivery with jet-lesion formation including intimal disruption, medial dissection, or subintimal haemorrhage but result in limited transgene expression in the coronary vessel wall of large animals.
In view of the above problems encountered in local delivery of vectors for gene therapy to vessel walls or the vicinity of vessels with the help of catheters, it is the object of the present invention to provide the possibility of a more efficient local vector transfer system than is currently available, in particular for use in the treatment of conditions and disorders associated with or occurring in the vicinity of blood vessels, such as restenosis and solid tumors.


REFERENCES:
patent: 6197013 (2001-03-01), Reed et al.
patent: 0753322 (1997-01-01), None
patent: 0768098 (1997-04-01), None
patent: 9211895 (1992-07-01), None
patent: 9605321 (1996-02-01), None

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