Genetic Modification of Cells Prior to Delivery to the Heart so as to Improve Electrical and Contractile Function
Heart failure (HF) is a major public health problem in the United States. Despite great strides in the management of HF, it is still associated with high mortality and morbidity. Cardiac transplantation is the only definitive treatment for end stage heart failure, but is limited by the availability of organs, which has led to a great deal of interest in cellular cardiomyoplasty. The general goal of such therapy is to improve cardiac function by seeding the heart with exogenous cells. The hope is that such transplanted cells will function within the heart as contracting, electrically-excitable cells. The problem is that such cells, when implanted, may not become part of the electrical syncytium of the heart. Instead, they may create islands of non-connected tissue that disrupt normal electrical conduction to produce arrhythmias. Electrically-isolated cells also may undermine rather than improve contractile function. JHU researchers have developed an invention that ?improves? cells prior to transplantation, so that they end up being better-coupled to the cardiac syncytitium. The example here, which has been reduced to practice, is the genetic modification of skeletal myoblasts with genes that improve electrical coupling (connexins). However, such pretreatment can be generalized to any cells destined for transplantation. Such genetic modification may also be important for cells that will be transplanted into other organs (e.g., skeletal muscle, uterus, brain). Skeletal muscle has the capacity to regenerate because of satellite cells that provide a source of cells for cardiac repair. Injection of myoblasts derived from skeletal muscle satellite cells has been shown to improve cardiac performance in phase 1 studies of patients with HF. However, the enthusiasm for myoblast transplantation has been tempered by the high incidence of ventricular tachycardia observed in patients (10 of the first 22 reported cases) after myoblast transplantation. Until now, the mechanisms of arrhythmias induced by myoblast transplantation have remained an enigma, possibly because there have been no reproducible models of such arrhythmias. JHU researchers have now successfully reproduced reentrant arrhythmias by co-culturing myoblasts and neonatal rat ventricular myocytes (NRVMs) in an in vitro (monolayer) system. Myoblast-myocyte co-cultures are arrhythmogenic due to lack of coupling between them. This results in wavebreaks and reentry. Description (Set) Proposed Use (Set) Cellular myoplasty of the heart is a novel therapy for ischemic cardiomyopathy. Genetic modification of stem cells to increase cell-cell connectivity would be very helpful in cell transplantation to improve integration of the transplants in the host organ. It could have potential in cell transplants in the heart and brain.Inventor(s): Marban, Eduardo
Type of Offer: Licensing
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