Background

The world’s aging population suffers from an increasing incidence of coronary heart disease. Indeed, the World Health Organisation reported that in 2015 ischemic heart disease is still the top cause of mortality worldwide accounting for about 7.4 million cases of deaths p.a.. Despite pharmacological and interventional therapies, the morbidity and mortality of patients with severely impaired ventricular function after myocardial infarction (MI) remain high. Currently, patients suffering from heart failure due to severe MI or various cardiomyopathies have few options. One avenue is heart transplantation (HTx), which is limited by the number of available donor organs, or bridging to HTx through left ventricular assist devices. Congenital cardiac malformations also often lead to terminal cardiac failure in adulthood, despite early surgery, due to the lack of contractile repair elements.

 

Stem cell (SC)-based approaches have been proposed for heart repair, but a multitude of experimental and clinical studies applying various adult stem cells did not achieve functional improvement, or showed only minor effects, which are most likely due to paracrine mechanisms (Jiang, M., Expert opinion on biological therapy, 2010. 10: 667). More recently, however, patient-derived human induced pluripotent stem cells (hiPSCs), which for the first time provide a potential source of patient-derived cardiomyocytes (CMs) for heart repair, have become available. Intense research has driven forward dramatic progress in virtually all areas of iPSC technology relevant to the proposed project. This includes highly efficient technologies for the transgene-free reprogramming of easily accessible cell sources such as blood (Haase, A., Cell Stem Cell, 2009. 5: 434.; Lachmann, N., American journal of respiratory and critical care medicine, 2014. 189: 167), efficient and safe site-specific genetic engineering of iPSCs (Merkert, S., Stem cell reports, 2014. 2: 107) and the development of technologies for the expansion and differentiation of iPSCs at clinical scale (Zweigerdt, R., Nat Protoc, 2011. 6: 689; Olmer, R., Tissue Eng Part C, 2012. 18: 772; Kempf, H., Stem cell reports, 2014. 6:1132). Intense research on safety issues of iPSC-based cell transplants, the most critical aspect for clinical applications, is ongoing.

 

Importantly, the extremely low incidence of CM-derived tumours in human hearts suggests a low risk factor for a malignant transformation of terminally differentiated iPSC-derived CMs, and potential implant-related arrhythmias could be controlled through technical pacemaker devices. Remarkably, a proof-of-concept study (published in 2012) demonstrated the formation of electrically coupled and well-structured cardiac muscle islands from injected human PSC-derived myocytes in a guinea pig model of MI (Shiba, Y., Nature, 2012. 489: 322). The same group has also demonstrated the extremely promising formation and functional coupling of large contractile human embryonic stem cell (ESC)-derived heart muscle islands in a non-human primate (NHP) model of MI (Chong, J.J., Nature, 2014. 510: 273).

Based on these developments and our own scientific progress and clinical experience, we consider myocardial transplantation of iPSC-derived CMs to be a realistic option for therapeutic heart repair.

 

 

Aims of the project

  1. Generation and characterisation of genetically enriched hiPSC derived CMs, and transplantation in a preclinical model of heart repair (large animal).

  2. Development of GMP compliant processes for the reprogramming and genetic modification of iPSCs as well as scale up of hiPSC-CM production for clinical use.

  3. Enrichment of CM subtypes.

  4. Development of an in vitro potency assay.

  5. Discussion of the regulatory requirements for intramyocardial transplantation of autologous hiPSC-CMs in patients suffering from right-sided heart failure as a long-term consequence of a Mustard operation and submission of a first draft of an application protocol.

  6. Updating the ‘Freedom to Operate (FtO)’ analysis and the business and exploitation plan.

  7. Create a legal, ethical and commercial framework within which translation is facilitated.