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Module 1

Disease modeling

The utility of a cell-based disease model relies upon generation of a demonstrable phenotype that closely reflects the underlying biology of the disease. We develop human iPSC-derived cardiac and neuronal disease models of your choice depending on your requirements to enable target or phenotypic drug discovery, as well as guiding structure–activity relationship (SAR) studies.

(A) Control or ET-1 treated cardiomyocytes were stained for BNP (green) and nuclei (blue). (B) Quantification of high content images showing total nuclear area (left) or BNP expression (right) in the presence or absence of ET-1. (C) ET-1 induced NT-proBNP secretion, measured by AlphaLISA, was rescued by treatment with Verapamil.

Module 2

Manufacturing

DiscoverHIT features a bioprocessing pipeline comprised of state-of-the-art bioreactor systems to assess and optimize critical process parameters at small scale, validate conditions at mid scale, and manufacture at 3-10 L scale in an automated closed system.

We operate enough bioreactors for full factorial design = 2n , where n = the number of factors having impact on the process.

  • String speed
  • pH
  • Inoculum size
  • Chemical concentrations
  • Media refreshment pattern
  • Others

(A) Bioreactor derived cardiomyocytes exhibit consistent Troponin expression within a population and (B) across numerous production runs.

Module 3

Assay Development

Reproducibility is crucial for a successful compound screening. We assess key assay parameters such as Z-factor, coefficient variation of controls and Pearson correlation of replicates between plates with a small set of reference compounds. Qualified assays are released for subsequent drug screening.

(A) Pathological hypertrophy is characterized by asymmetric hypertrophy (or thickening) of the left ventricular wall, and is typically accompanied by contractile functional deficit, fibrosis, and cardiomyocyte disarray1 (B) Endothelin-induced secretion of NT-proBNP, a clinical marker of cardiac injury/hypertrophy, was rescued by verapamil treatment in iPSC-derived cardiomyocytes (C) Functional activity was assessed by calcium transient screening in 384 well format.

1Maron BJ et al. (2003)J Am Coll Cardiol, vol. 42; 1687-1713

Module 4

High Throughput Screening

Efficient drug discovery requires assays that are robust, reliable, translational, and compatible with automated high throughput screening (HTS) platforms. hiPSC technology has substantially expanded the availability of human cells (at commercial scale and reproducibility) with primary-like features. Our breakthroughs in development of HTS-compatible phenotypic screening assays with a clear link to human disease can now be utilized for target-validation, hit identification, hit confirmation, and for further development of candidates.

(A) Assay performance from 15 x 384 well plates screened in succession. (B) Hits grouped by % effect (rescue of hypertrophy) from >3000 compound screened. (C) Dose response curve for Bosentan, one of the validated hits identified from the primary screen.

INQUIRIES

Personalized consultation

If you are interested in discussing the possibilities available with our DiscoverHIT Platform, please contact us to arrange a further conversation.

Johan te Koppele, PhD

Chief Services Officer, Ncardia

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