Use of pro-apoptotic factors in treatment of atherosclerosis

Abstract

The present invention features a novel method of treating vascular disease that involves modifying smooth muscle cells to express a gene encoding a protein having both anti-inflammatory and pro-apoptotic activity. Preferably, the protein of the invention also has an anti-proliferative effect in smooth muscle cells. In general, the method is useful in preparing vascularized organs and vessels for transplant into a patient. Alternatively, the present invention can be applied to treat atherosclerotic lesions in damaged vessels.

Description

[0001] The present application claims benefit to Provisional application No. 60 / 177,535 filed Jan. 21, 2000, the entire contents of which are incorporated herein by reference.Statement as to Federally Sponsored Research[0002] The present research was supported by a grant from the National Institutes of Health (NIH) (Grant R01 Number HL57791-02).[0003] 1. Field of the Invention[0004] The present invention relates to the field of vascular disease.[0005] 2. Background of the Invention[0006] Vascular disease is the most common cause of morbidity and mortality in the western world, surpassing any other single degenerative disease. The fundamental pathology of vascular disease is an abnormal accumulation of cells within the subintimal space below the surface of the endothelial cell lining, resulting in a decrease in lumen size and tissue perfusion. This accumulation is due to the proliferation and / or migration of smooth muscle cells, and / or inflammatory cells into the intimal layer of a v...

AI Technical Summary

Benefits of technology

[0012] In a related aspect, the method of the present invention can be applied to prevent TAV in a patient at risk for developing TAV. This method involves modifying a mammalian smooth muscle cell by inserting into the smooth muscle cell DNA encoding a protein capable of decreasing inflammation and increasing apoptosis of the smooth muscle cell and transplanting the smooth muscle cell (or tissue or organ having a smooth muscle cell) into the patient. A patient classified as a patient at risk for developing TAV would be, for example, a patient receiving an organ or vessel transplant.

[0015] The present invention also provides a method of preparing a vascularized organ or vessel for transplantation into a patient by obtaining an organ or vessel for transplant and perfusing the organ with nucleic acid encoding the A20 protein. A variety of vectors are available in the art for gene transfer. Particularly preferred vectors are the adenovirus vector and the lentivirus vector. In a preferred embodiment, the organ or vessel is perfused with a gene transfer vector and an immunoregulatory factor (e.g., a cytokine). Alternatively, a therapeutic agent may be perfused into the organ or vessel to enhance the expression of A20.

[0026] By "therapeutic gene" is meant a DNA that achieves an anti-proliferative, pro-apoptotic effect in smooth muscle cells. In addition, the therapeutic gene may also have the effect of decreasing inflammation, (e.g., by inhibiting NF-.kappa.B activation in a smooth muscle cell).

Problems solved by technology

The fundamental pathology of vascular disease is an abnormal accumulation of cells within the subintimal space below the surface of the endothelial cell lining, resulting in a decrease in lumen size and tissue perfusion.

This accumulation is due to the proliferation and / or migration of smooth muscle cells, and / or inflammatory cells into the intimal layer of a vessel, resulting in restricted blood flow through that vessel, i.e. neointimal occlusive lesions.

Despite the substantial benefit attributable to the use of current cholesterol lowering and immunosuppressive drug therapies, these treatments do not achieve an acute reduction in vascular lesion size.

Furthermore, bypass surgery may accelerate progressive lesion stenosis, and interventions such as balloon angioplasty often result in the development of restenosis.

EC activation promotes inflammation and can lead to apoptosis of these cells.

Clinical trials aimed at blocking a single growth or inflammatory factor have failed to show efficacy.

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