Inherited cardiac conditions represent a group of largely monogenic disorders that occur with a prevalence ranging from 1 in 500 to 1 in 10,000 either in the presence (cardiomyopathies) or in the absence (channelopathies) of structural heart disease. The most frequently used pre-clinical models for investigating disease pathophysiology and drug testing rely on heterologous cell expression systems and animal disease models. However, these models often fail to predict human responses and are partially responsible for high attrition rate of novel drug candidates and increasing drug development costs.
The human iPS cell-based disease models have great potential for more predictable drug discovery and toxicology studies. The unique feature of this technology is that it enables an unlimited supply of required disease-specific cell types and that the mechanism of the disease and the safety and effectiveness of medical therapies can be studied on the genetic background of the affected patient using multiple cell types. Moreover, large cohorts of disease-specific iPS cell lines may be used to develop new treatments for specific patient populations before these drugs are tested in the clinic. Therefore, publicly-accessible banks of iPS cell lines from patients with different genetic diseases and the corresponding healthy controls have huge potential to facilitate disease research and accelerate drug discovery.
Heart disease-specific lines available from EBiSC
The leading iPS cell repository in Europe, the European Bank for induced pluripotent Stem Cells (EBiSC), now offers a new set of high quality iPS cell lines from patients with genetic heart diseases for in vitro use. They were created by a team of scientists led by Tomo Šarić and Jürgen Hescheler at the Uniklinik Köln (UKK) in Germany with support from the Innovative Medicines Initiative (IMI) and Bayer AG as well as clinical collaborators at the Heart Centre Cologne and the Institute for Genetics of Heart Diseases at the University Hospital Muenster. The panel includes cell lines derived from patients with long QT syndrome type 1 (UKKi029-A,B,C carrying mutation in KCNQ1 gene - lines available soon), long QT syndrome type 2 (UKKi018-A,B,C; UKKi019-A,B,C and UKKi023-A,B,C lines carrying different mutations in KCNH2 gene), Brugada syndrome (UKKi024-A,B,C line carrying mutation in SCN5A gene) and hypertrophic cardiomyopathy (UKKi025-A,B,C line carrying mutation in MYH7 gene). Additional disease-specific and control iPS cell lines from healthy donors will be available through EBiSC later this year.
All iPS cell lines were generated from donated blood cells using highly standardised non-insertional reprogramming procedure under feeder-free conditions. They underwent extensive characterization to ensure quality in terms of sterility, viability, identity, pluripotency, genetic stability, and absence of HIV, HBV, HCV and reprogramming vectors. This data and the associated clinical information are accessible on a searchable public registry for human pluripotent stem cell lines, hPSCreg. This collection offers the greatest flexibility of use by including into the patient consent unlimited banking, world-wide distribution, broad use for research, genetic characterization and commercialization, provided that a proper licencing agreement is closed between the prospective user and the UKK. All interested researchers in academia and industry can order these lines by searching the EBiSC catalogue.
Other iPS cell lines in hPSCreg registry of interest to researchers studying inherited heart diseases were generated previously using integrating reprogramming methods and include two subclones of an iPS cell line for modelling catecholaminergic polymorphic ventricular tachycardia (CPVT, UKKi007-A and –B lines with mutation in RYR2 gene), two subclones of a long QT syndrome type 2 cell line (UKKi009-A and B) as well as one long QT syndrome type 3 cell line (UKKi008-A).
The new panel of heart disease-specific iPS cell lines represents a valuable resource of lines for the study of disease and the development of new treatments. Their value can be further increased by employing gene editing technologies to generate isogenic control lines or transgenic lines expressing lineage- or pathway-specific reporters to enhance developmental studies or establish specific drug screening assays.
Image courtesy of Tomo Šarić, Medical Faculty, University of Cologne, Germany
Cardiomyocytes derived from iPSC line of a patient with hypertrophic cardiomyopathy carrying a mutation in MYH7 gene encoding a myosin heavy chain beta (MHC-β) isoform. Red indicates the muscle protein alpha-actinin and blue the cell nuclei.
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