HEAL: HLA-homozygous iPSC-cardiomyocytE Aggregate manufacturing technologies for allogenic cell therapy to the heart

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 and the European Medicines Agency , 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.

The overarching goal of the network is to establish new tools, technologies and expertise for accelerating the development of advanced human induced pluripotent stem cell (iPSC)-based therapies. The project also aims at overcoming scientific, regulatory and in particular safety hurdles, necessary to initiate a first in-man (FIM) clinical trial for the therapeutic administration of allogeneic, human leukocyte antigen (HLA)-homozygous iPSC-cardiomyocyte aggregates, for improving the function of damaged hearts.

Both academic and industrial research communities will be able to use the results of the project to advance their R&D efforts in cell therapies towards the clinic. New tolls, logistic solutions and AI powered technologies as an outcome of the project will strengthen Europe’s leadership in healthcare technology development, including the ability to scale up and bring iPSC-based therapies to the patient. Citizens will benefit more rapid translation of cell therapy research to the clinic for better patient outcome and well-being. This in mind, the realization of a therapy for heart disease is particularly important since very few alternatives currently exist for heart failure patients. Finally, project outcome will facilitate decision-making by authorities and clinicians in a secure and ethical manner, for respecting individual integrity and underpinned with public acceptance and trust.

The consortium is composed of world leading-expertise of academic, clinical and industrial partners in the field of iPSC technology, bioprocessing, genomic engineering, analysis and safety, immunology and clinical translation.

The project is coordinated by Dr. Robert Zweigerdt and Prof. Ulrich Martin (Hannover Medical School, Germany) and includes the following partners: Dr. Boris Greber and Thomas Marx (Catalent Düsseldorf), Prof. Joost Sluijter and Prof. Klaus Neef (Universitair Medisch Centrum Utrecht, Netherlands), Prof. Dirk Strunk (Paracelsus Medizinische Privatuniversität, Austria), Prof. Nissim Benvenisty (Hebrew University of Jerusalem, Israel), Prof. David Fiorentini (Biological Industries Ltd, Israel), Dr. David Morrow (European Infrastructure for Translational Medicine), Dr. Yanick Fanton (InnoSer, Belgium), Prof. Gesine Kögler (Heinrich-Heine-University Düsseldorf, Germany), and Prof. Michael Morrison (University of Oxford, UK; associated partner funded through UK Research and Innovation).

WP 1: GMP-compliant upscaling of iPS-cardiomyocyte aggregate production

WP 2: Immunogenicity of HLA homozygous iPS-cardiomyocytes

WP 3: Safety, genetic integrity, and suicide gene technologies

WP 4: Regulations and Advanced Therapy Medicinal Product (ATMP) development

WP 5: Cost effectiveness HTA, Dissemination Exploitation

WP 6: Management and Dissemination

in progress...