Engineered Heart Muscle Repairs Failing Rhesus Hearts, Goes First-in-Human

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Engineered Heart Muscle Repairs Failing Rhesus Hearts, Goes First-in-Human


Engineered Heart Muscle Repairs Failing Rhesus Hearts, Goes First-in-Human
Credit: mustafahacalaki / Getty Images / DigitalVision Vectors

In a groundbreaking study, German researchers demonstrated the long-term safety and efficacy of tissue-engineered myocardial heart muscle (EHM) allografts and autografts in a clinically relevant rhesus macaque model, resulting in sustained remuscularization without harmful side effects, such as tumor formation or arrhythmia. These preclinical findings in non-human primates (NHPs) paved the way for a first-in-human clinical trial in which EHM implantation resulted in promising remuscularization in a patient with advanced heart failure, ushering in a new era of regenerative heart therapies.

From small animals to non-human primates

As the field of myocardial remuscularization advances, researchers are discovering the difficulties of translating small-animal studies into clinical success. While rodent and rabbit models have demonstrated feasibility for cardiomyocyte implantation and tissue-engineered allografts, their predictive value for human outcomes is limited due to immune response challenges in xenograft models.

To enable clinical testing of myocardial remuscularization, researchers from the University Medical Center Göttingen and the German Centre for Cardiovascular Research (DZHK) sought advice from Germany’s Paul-Ehrlich-Institut, which recommended rhesus macaques as the large animal model for homologous allograft studies due to the availability of stable-induced iPSCs and the limitations of xenografting and clinical autografting.

In this Nature article, German researchers used rhesus macaque iPSC-derived EHM, which had structural and functional similarities to human EHM but with species-specific characteristics such as higher beating rates. Before moving on to larger animals, the rhesus EHM was tested in a preclinical rat model of cardiac injury. Implantation of viable rhesus EHM improved heart function, as evidenced by increased ejection fraction and stroke volume, without forming teratomas or residual stem cells, demonstrating its therapeutic potential.

Toward the first-in-human trial

In rhesus macaques, the rhesus EHM was safely and effectively implanted, with dose-dependent improvements in heart wall thickness and function observed across various experimental conditions. In chronic heart failure models, EHM implantation enhanced cardiac function without significant safety concerns, confirming this approach’s therapeutic potential and safety for future translational studies.

Based on these results, the BioVAT-HF-DZHK20 Phase I/II clinical trial was approved to evaluate EHM-based heart repair in humans. Clinical data from a patient who underwent heart transplantation in the BioVAT-HF trial confirmed the retention of implanted EHM composed of iPSC-derived cardiomyocytes and stromal cells. The engrafted cardiomyocytes were smaller and less mature than the recipient heart’s cardiomyocytes, with lower capillary density localized to the EHM graft. While a localized immune response was observed, no donor-specific antibodies were detected.

These findings demonstrate the translatability of EHM therapy from rhesus macaques to humans and support its continued evaluation in clinical trials for advanced heart failure, with ongoing efforts to optimize immunosuppression strategies. With regulatory guidance, these findings provide a crucial foundation for clinical trials, marking a significant leap toward regenerative heart therapies.



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