Inhibition of graft failure, using MARCKS siRNAs (BIDMC 899)

Category:    Therapeutics - Drugs

KeyWords:  Surgery;  Vascular/Thrombosis;  RNAi;  

BIDMC ID:    899

Abstract:

Background: While vein bypass grafting has proven to be an effective treatment for coronary and peripheral atherosclerosis, vein graft failure remains a common clinical occurrence. Given that 20-30% of vein grafts fail within 5 years of placement and over 500,000 vein bypass operations are performed each year in the USA, vein graft disease represents a significant source of morbidity in the treatment of coronary and peripheral artery disease. Intimal hyperplasia remains the most common cause of such delayed vein graft failure and is characterized by the pathologic migration of vascular smooth muscle cells (VSMC) from the media to the intima where they proliferate and produce excessive extracellular matrix leading to graft failure. Invention: The present invention involves the discovery that VSMC migration and proliferation is mediated by the MARCKS family of proteins and that both processes can be inhibited by down regulating one or more MARCKS protein family members in these cells. The inventors describe a method of selective transfection of a human venous graft with silencing RNA (siRNA) targeting MARCKS mRNA. siRNA is a process of post-transcriptional gene control, where short nucleotide segments of RNA are used to degrade specific mRNAs, down regulating the levels of the targeted proteins. Transfection with MARCKS siRNA decreased cellular MARCKS mRNA levels in the cultured vein graft and blocked VSMC migration and proliferation indicating the potential to prevent vein graft failure.

Inventor:   Thomas S. Monahan, MD Frank W. LoGerfo, MD Nicholas D. Andersen

Commercial Opportunity:

Cardiovascular disease is the leading cause of death in the United States. Over 1.4 million surgeries are required annually in an attempt to combat vascular disease. This technology could be used for all autogenous bypass operations including coronary artery bypass grafting, peripheral vascular bypass, hemodialysis fistulae, and potentially organ transplants. All of these procedures are limited by similar pathologic migration and proliferation of vascular smooth muscle cells.

Competitive Advantages:

* siRNA has the distinct advantage of being able to specifically target any gene or combination of genes in the entire genome. * Selectively transfecting the transplanted grafts provides specific, localized therapy.

Related Publications:

“MARCKS silencing differentially affects human vascular smooth muscle and endothelial cell phenotypes to inhibit neointimal hyperplasia in saphenous vein”
Monahan et al. FASEB J. 23, 557-564. 2009.

“Gene silencing in human vein grafts: a novel tool for the prevention of intimal hyperplasia” Andersen et al. J. Surgical Res. 2006. Abstract 425.

“In vitro validation of silencing RNA as a tool to limit the response to surgical injury of vein bypass grafts” Andersen et al. ISACB Meeting. March 2006.

State of Development:

Human saphenous veins have been successfully transfected ex vivo using MARCKS siRNA and cultured ex vivo for the findings reported to date. Animal experiments are planned.

Related Technology URL:

Patent Status:

US application pending

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