Year 2

Patients with end-stage heart failure (ESHF), which can result from heart attacks, have a 2-year survival rate of 50% with conventional medical therapy. Unlike cells of other organs, the billions of cardiomyocytes lost due to damage or disease do not regenerate. Recently, implantable mechanical pumps that take over the function of the failing left ventricle (left ventricular assist devices; LVADs) have been used to prolong the lives of heart failure patients. However, these devices carry an increased risk of stroke. The only current bona fide cure for ESHF is heart transplantation, but the shortage of donor organs and the risks associated with life-long use of powerful immunosuppressive drugs limit the number of patients that can be helped.

Human embryonic stem cells (hESCs) have the unique properties of being able to grow without limit and to be converted into all the cell types of the body, including cardiomyocytes. Our project seeks to find ways to treat patients by replacing their lost cardiomyocytes with healthy ones derived from hESC. The ultimate goal of this 4 year project is to evaluate the feasibility, safety, and efficacy of this approach in both small and large animal models of heart disease and to use this data to initiate a clinical trial to test the therapy in patients.

In our first year, we developed methods for producing essentially unlimited quantities of cardiomyocytes from hESCs using a process that is compatible both with clinical needs and large-scale industrial cell production. We also developed models of heart disease in both rats and pigs, and began transplanting the stem cell-derived cardiomyocytes into the rat model. We demonstrated that stem cell-derived cardiomyocytes could engraft in this animal model for at least 1 month, and we observed their effect on the damaged tissue- we saw engraftment of healthy human cardiomyocytes, and noted that the graft induced the formation of new blood vessels.

In the second year, we a) discussed our strategy with FDA to get their advice and input (a “pre-PreIND call”); b) transplanted larger numbers of rats with 2 different doses of hESC-derived cardiomyocytes and will monitor them for longer periods (up to 9 months) to verify that no tumors form and there are no unexpected effects on the animals; c) developed in vitro assays to characterize the cardiomyocytes and to rule out the presence of any significant residual undifferentiated stem cells in the final product that will be used for cell therapy; and d) began designing and evaluating different immunosuppression strategies for the pig model, in order to allow the transplanted human cells to survive.