CELL TRANSPLANTATION RESEARCH TO IMPROVE MYOCARDIAL RECOVERY

The goal of this project is to stimulate healing of the native heart so that LVAD implantation can potentially be used as bridge to recovery rather than as a bridge to transplantation or left as long-term destination therapy. While some experts believe that unloading the heart with mechanical assistance may allow the heart to recover, in fact relatively few patients (less than 10%) experience sufficient myocardial recovery to permit explantation of the device. Yet if the heart could regain enough of its ability to contract, patients would be spared the adverse effects associated with long-term circulatory support or transplantation.

The left hand panel demonstrates a representative rat heart that has undergone an experimental heart attack. The red depicts viable heart tissue and the blue represents dead heart tissue that has been replaced by scar. In contrast, in the panel on the right the animal has received stem cells resulting in far less dead heart tissue and translating into an improved heart function and prognosis for long term survival.

Led by Silviu Itescu, MD, the cell transplantation project will seek to find ways of regenerating the heart while the LVAD is in place to support heart function. His team will compare the efficacy of transplanting patients' own hematopoietic precursor cells, termed angioblasts, with mesenchymal precursor stem cells (MPCs). Both human angioblasts and human MPCs have been shown to avert heart failure in rodents by preventing the development of large scars after myocardial infarction.

"Both cell types were active in initial animal studies," says Dr. Itescu. "However, we think MPC precursors will be more effective in human trials because they produce larger caliber arterioles and have a greater impact on functional cardiac recovery than angioblasts, which produce small-caliber capillaries." Additional theoretical advantages of using MPC are direct regeneration of new heart muscle, and the potential for allogeneic use since they are not recognized by the immune system of unrelated individuals.

While angioblast isolation can be performed today using existing FDA-approved technologies, Dr. Itescu and colleagues are working to optimize the process of MPC isolation and culture to meet Good Manufacturing Process (GMP) standards in order to obtain FDA approval for this component. Consequently, the cell therapy clinical protocol will be staged sequentially to take into account the FDA approval process: the initial series of patients will receive the FDA-approved angioblasts, while, on receipt of FDA approval for the MPC isolation and culture process, the subsequent series of patients will receive MPCs. Autologous cells will be obtained by bone marrow biopsy at the time of LVAD implantation, and either angioblasts (initially frozen) or culture-expanded MPC will be injected into the myocardium of the native heart four weeks later. Follow-up of each group is expected to be approximately three months, with repeated assessment of the native heart function and histological examination of the explanted native heart at the time of transplantation.

Given the high costs of autologous cell processing, widespread use of cell therapy for the large numbers of patients suffering from cardiovascular disease will require development of more efficient and less expensive methodologies. The immunomodulatory properties of MPC make this type of cell therapy an ideal candidate for possible allogeneic use. Consequently, after obtaining FDA approval for MPC isolation and culture, Dr. Itescu and colleagues will evaluate the safety and efficacy of allogeneic MPC for cardiac regeneration.