Cells Cor.At murine ESC derived cardiomyocytes
Species Mouse
Delivery  A study protocol will be sent to initiate the study. Results are sent as draft and final study report.
Timelines
Experiment time: 2 weeks per compound.
Draft report: within 4 weeks
Service content Investigation of pharmacological effects reverting the hypertrophic phenotype
Reporter TagGFP2 or CL or BNP expression analysis

 

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MyCor® cardiomyopathy screen

Cardiomyopathy

Chronic heart failure is a debilitating condition of the cardio-vascular system in which the heart no longer fulfills its pumping function adequately. Despite enormous efforts in health care, the mortality associated with this disease remains extraordinarily high, indicating that current therapies are far from effective. 

A major constraint in the development of effective drug treatment for chronic heart failure has been the lack of suitable cell-based assays with physiological relevance. Over the last decade, ventricular cardiomyocytes prepared from neonatal rats have been used to characterize the myopathic phenotype in vitro. However, the extensive use of rat cardiomyocytes in drug development has been difficult because of their cumbersome handling properties and their limited availability for intense screening campaigns.

At the cellular level, hypertrophic cardiomyocytes are characterized by increased cell size, enhanced protein synthesis, and enhanced organization of the contractile apparatus1,2. These phenotypic changes are due to a switch in the cardiomyocytes’ gene expression pattern: genes are activated that, in normal conditions, would only be expressed during early embryonic development3-5.

 

My.Cor - Induced cardiac hypertrophy

Cor.At®cardiomyocytes faithfully recapitulate these characteristics of diseased cardiomyocytes in vitro when stimulated with specific agonists. Upon stimulation with agonists like endothelin-I and phenylephrine, Cor.At® cardiomyocytes increase in cell size (Fig.1), up-regulate the expression of the hypertrophic marker genes ANP and BNP (Fig.2) as well as other specific marker genes for hypertrophy (Fig. 2).

 

Together with Axiogenesis’ safety pharmacology and toxicology portfolio the My.Cor system is a sound profiling platform that integrates the discovery of new active pharmaceutical ingredients (APIs) for cardiac hypertrophy therapy, and will be used for internal drug discovery efforts and as a drug discovery service for the pharmaceutical industry.

My.Cor is a patented customizable in vitro assay that provides a model for cardiomyopathy in embryonic stem cell (ESC)-derived cardiomyocytes. My.Cor makes the drug discovery process more convenient and efficient, thereby helping to facilitate the development of better drugs for chronic heart failure. 

 

References

[1] Katagiri T, Kitsu T, Akiyama K, Takeyama Y, Niitani H (1987). Alterations in fine structures of myofibrils and structural proteins in patients with dilated cardiomyopathy-studies with biopsied heart tissues. Jpn Circ J. 51, 682-688.
[2] Molkentin JD, Dorn II GW 2nd (2001). Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annu Rev Physiol. 63, 391-426.
[3] Chien R (1992). Signaling mechanisms for the activation of an embryonic gene program during the hypertrophy of cardiac ventricular muscle. Basic Res Cardiol. 87, Suppl 2, 49-58.
[4] Colucci WS (1997). Molecular and cellular mechanisms of myocardial failure. Am J Cardiol. 80, 15L-25L.
[5] Cameron VA, and Ellmers LJ (2003). Minireview: Natriuretic peptides during development of the fetal heart and circulation. Endocrinology. 144, 2191-2194.
[6] Kuwahara K and Nakao K (2010). Regulation and significance of atrial and brain natriuretic peptides as cardiac hormones. Endocr J. Jul 30; 57(7): 555-65.
[7] Richards M (2010). New Biomarkers in Heart Failure: Applications in Diagnosis, Prognosis, and Guidance of Therapy. Rev Esp Cardiol. 63(6): 635-9
Advantages My.Cor® cardiomyopathy screen 
  • Convenient to handle and culture.
  • Easy induction of cardiomyopathy phenotypic characteristics.
  • Early identification of compounds that show promise for drug development.
  • Validation of targets in their physiological cellular environment without transgenic animals.
  • Available in bulk quantities for integration into platforms at your facilities.
  • Full in vitro system eliminates animal testing.
  • Time and cost effectiveness for a more efficient and economical use of human and financial resources.
  • Customizable cardiomyocytes with knock-out, knock-in, knock-down features or over-expression of target genes, tailor-made to client's wishes.