Background
The project “HEAL” entitled “HLA-homozygous iPSC-cardiomyocytE Aggregate manufacturing technologies for allogenic cell therapy to the heart” will focus on overcoming general hurdles to human induced pluripotent stem cell (iPSC)-based therapies, with the particular focus on heart failure, which remains a major global cause of morbidity and mortality with very few treatment options at present.
Human leukocyte antigen (HLA)-homozygous iPSC-derived cardiomyocyte aggregates offer the prospect for a restorative allogeneic heart therapy applicable to larger patient populations, overcoming economic barriers associated with autologous approaches. By developing solutions for the GMP-compliant mass-production and cryopreservation of iPSC-cardiomyocyte aggregates, we will enable allogeneic treatment with minimum requirements for immunosuppression. Assays for the assessment of immunogenicity will provide data for the development of an artificial intelligence-powered algorithm to predict recipients’ immune responses.
The project will develop a potency assay for in vitro monitoring the effectiveness of the cell therapy product together with assays for monitoring the tumorgenicity potential in line with current regulatory requirements. To address other key safety aspects, a genetic integrity pipeline will be generated for defining the most sensitive assays for rigorous assessment of cells’ genetic stability. Moreover, a genetic rescue tool in the form of a biallelic suicide gene for inducing a controlled, programmed cell death will be established as another addition to the safety toolbox for iPSC-cell therapies. For the optimization of cell-product administration, we will advance technologies for iPSC-cardiomyocyte aggregates retention and engraftment, including catheter-based cell delivery as a minimally invasive alternative to surgical applications. Subsequently, we will perform thorough assessment of graft-induced arrhythmia risks in a sensitive pig model.
Early dialogue, via established links, to the regulatory authorities, e.g. Paul- Ehrlich-Institute (https://www.pei.de/EN/medicinal-products/atmp/atmp-node.html) and the European Medicines Agency (https://www.ema.europa.eu/en/human-regulatory/overview/advanced-therapy-medicinal-products-overview), will ensure proper development according to GMP requirements. Freedom to operate and licensing strategies with a healthy technology and infrastructure assessment of European centers will set the scene for approval of the cell product and related assays and protocols for storage and distribution required to progress towards a first in-man study of cell-based heart repair.
