Patients with end-stage heart failure (ESHF) have a particularly grave prognosis, with a 2-year survival rate of 25% despite optimized medical and device therapy. ESHF develops typically after myocardial infarction (MI). For most of these patients, orthotopic heart transplantation (OHT) is the only curative therapeutic option, but cannot be delivered to the necessary extent due to donor organ shortage- it is estimated that there are 200,000 patients diagnosed with ESHF annually, yet there are only 3,000 OHT performed per year. Thus, there is a clear unmet need for the development of alternative treatments for the growing ESHF patient population.
In ESHF patients, a left ventricular assist device (LVAD) is regularly implanted as a bridge to OHT. This device takes over the pumping role of the left ventricle and in some cases (e.g., when no suitable donor heart is available) may remain in the patient for the rest of his/her life. These LVADs represent a significant step forward in therapy, but have some associated risks: there is an increased incidence of stroke in these patients, and because the LVADs are powered by batteries residing outside the body, these patients have wires protruding through their chests that makes them susceptible to life-threatening infections. In this project, we have investigated the possibility of generating a biological LVAD: a patch composed of human embryonic stem cell-derived cardiomyocytes (heSC-CMs) that would be implanted over the damaged region of a patient’s heart. This patch (also called engineered heart muscle; EHM) could potentially provide both contractile function and also allow the cardiomyocytes in the patch to secrete factors that improve the survival and function of the host’s heart.
In order to assess the potential of this new therapy, we established a collaboration between the laboratories of Dr. Joseph Wu at Stanford (an expert in understanding heart disease through the use of stem cell-derived cardiomyocytes), Dr. Wolfram Zimmerman at Göttingen (a leader in the design and generation of engineered heart muscle patches), and Dr. Larry Couture at City of Hope (a facility with the unique ability to produce billions of hESC-CMs). After transferring procedures for hESC-CM generation from the Wu lab to City of Hope, the latter developed methods to produce essentially unlimited quantities of hES-CMs. These cells were shipped to Göttingen to use in EHM generation. The subsequent EHMs were sent to Stanford for transplants into both immunodeficient rat and immunosuppressed pig models of heart failure to test the safety and efficacy of the EHMs. (Rat models are typically used to show safety of cell therapies; large animal models such as pigs are typically used because they have hearts with similar sizes and properties to humans. The large animal models are particularly challenging, because they have intact immune systems that mount strong responses against human cells and typically reject the grafts).
We were able to demonstrate long-term survival of the EHMs in immunodeficient rat models with no evidence of tumor formation and showed that the transplanted EHM helped preserve diastolic function (i.e., the function of the heart during the relaxation phase) in the damaged hearts. We also developed a new immunosuppression regimen to prolong survival of the human cell-derived EHMs in pigs, and have transplanted a series of animals with the EHMs and are monitoring effects on heart function, as well as the safety of the approach in a human-sized heart.