Dual Anti-Proliferative and Pro-Apoptotic Functions of A20 in Smooth Muscle Cells (BIDMC 301)

Category:    Drug Discovery Tools

KeyWords:  Vascular/Thrombosis;  Epithelial;  Tissue Engineering;  

BIDMC ID:    301

Abstract:

Atherosclerosis is responsible for more morbidity and mortality than any other single degenerative disease in the western world. It leads to cardiovascular disease, and is the leading cause of death in men over age 35 and all people over 45. Most heart attacks and strokes are due to atherosclerosis. Transplant-associated vasculopathy (TAV), or transplant arteriosclerosis, which is closely related to atherosclerosis, is a major barrier to successful organ transplantation. Although the initiating factors of atherosclerosis and TAV are different, their fundamental pathological features are similar and relate to the dysregulation of two major cell types of the vessel wall: smooth muscle cells (SMC) and endothelial cells (EC). Drs. Ferran and Arvelo have developed methods for genetic engineering of the vessel wall to protect it from atherosclerosis and TAV. Specifically, they have developed a method to transfect SMCs to express high levels of A20 which renders SMCs less responsive to proliferation-inducing stimuli and sensitizes them to apoptosis. A20's dual functions of producing an anti-inflammatory effect in EC and an anti-proliferative pro-apoptotic effect in SMC make it an ideal gene therapy candidate to protect vessels from the development of arteriosclerosis.

Inventor:   Christiane Ferran, MD, Ph.D. and Marie Arvelo

Commercial Opportunity:

Treatment of vascular conditions such as restenosis, ischemia, reperfusion injuries, and post-angioplasty. Genetic modification of grafts for bypass graft surgery; gene transfer in allografts prior to transplantation; xenotransplantation.

Competitive Advantages:

A20 functions to inhibit both EC activation and SMC proliferation, the two major culprits of atherosclerotic lesion progression. Other approaches for inducing apoptosis of SMC to prevent atherosclerosis do not achieve the same protective effect in EC and are even potentially harmful to EC. A20 is therefore a unique gene therapy candidate for protecting vessels from developing atherosclerosis.

Related Publications:

FASEB J. (2006) 20: 1418.
Blood (2004) 104: 2376.
Circulation (2003) 108: 1113.
A20 inhibits cytokine-induced apoptosis and NF-kB dependent gene activation in islets. J.Exp. Med. 1999. 190; 1135-1145.
A20 blocks endothelial cell activation through a NF-kB-dependent mechanism. J. Biol. Chem., 1996, 271; 18068-18073

State of Development:

A20's anti-proliferative, pro-apoptotic effect has been demonstrated in human aorta SMC?s in culture and in a balloon angioplasty rat model. overexpression.
A20 overexpression sensitization of SMCs to cytokine mediated apoptosis has been shown.

Related Technology URL:

http://research.bidmc.harvard.edu/research/ResearchPIInfo.ASP?Submit=Display&PersonID=194

Patent Status:

Issued US Patent No. 7,297,685

TVO Contact Info:
     Catherine M Lenich
     Senior Associate TVO
     clenich@bidmc.harvard.edu
     Phone: 617-667-0568   Fax: 617-667-0646

     Beth Israel Deaconess Medical Center
     Technology Ventures Office  Room: BR-0200
     330 Brookline Avenue
     Boston, MA 02215