Abstract

Abstract

Current drug development strategies are
very expensive and lead to high drug attrition rates. One major reason for low
success rates is the lack of predictive preclinical models for efficacy
testing. The availability of induced pluripotent stem cell (hiPSC) technologies
holds great promise to bring human biology to drug discovery but is still
compromised by problems related to scalability, biological relevance,
robustness and costs.

Here we demonstrate an end-to-end solution
covering large-scale manufacturing, disease model generation and assay development
up to high throughput screening, using cardiac hypertrophy as an example.

The basis is formed by Ncardia’s
proprietary differentiation technology, which allows reproducible manufacturing
of highly purified, relatively mature cardiomyocytes, with high predictivity in
cardiac toxicity and efficacy assays. Large scale manufacturing in
state-of-the-art stirred tank bioreactor systems enabled the production of
cardiomyocyte batch sizes suitable for high throughput screening. We
demonstrate the development and validation of a scalable assay for induction of
cardiac hypertrophy, using NT-proBNP secretion as a readout.

To ensure highly reproducible and accurate
drug efficacy screening using our hypertrophy assay in a high throughput mode
we have set up and validated an automated platform for cell culturing, assay
readout and data handling. Using verapamil as a reference compound to reduce
hypertrophy we confirm assay robustness (S/B > 2) and reproducibility
(Z’-factor > 0.4). A selected panel of anti-hypertrophic compounds was used
for further assay validation and proved a high level of predictivity. Finally,
the assay was used to screen a collection of 1280 off-patent drugs (95%
approved drugs) with high chemical and pharmacological diversity (Prestwick Chemical
Library) for anti-hypertrophic activity.

Altogether, with the current results we
demonstrate an end-to-end solution for more efficient and cost-effective drug
discovery using a combination of cutting edge hiPSC, bioprocessing and high
throughput screening technologies.