Scientific poster: Development of a robust and scalable iPSC platform for predictions of efficacy and in vivo toxicity of RNA therapeutics in the drug discovery pipeline

RNA therapeutics, especially Antisense Oligonucleotides (ASOs), are a relatively new modality for nucleotide-based
therapeutics. They offer a huge potential to specifically modify cellular pathways by reducing target protein expression through RNA cleavage, altered splicing or blocking translation.

Being able to predict acute side effects early in the development process facilitates the confident selection of candidates with higher chances of success in preclinical and clinical stages, saving time and resources.

Human induced pluripotent stem cells (hiPSCs) have become a powerful tool for drug discovery. With their unlimited
proliferation capacity, potential to be differentiated into any cell type and their representation of donor’s genetic
background they bring unprecedented opportunities for directly assessing human specific toxicity and efficacy.

Ncardia developed two robust assays using two Ncardia’s hiPSC-derived neuronal cell models to screen both
for efficacy and neurotoxicity of ASOs:

• Cortical neurons (hiPSC-CNs) to study effects on target knockdown by RT-qPCR in a fully automated experimental
setting including cell seeding, maintenance, ASO treatment and RT-qPCR which enabled the development of a
highly robust assay with both intra- and inter-plate variation (%CV) of <5%.

• CNS cultures (hiPSC-CNS) to assess acute ASO neurotoxicity by quantification of intracellular calcium fluxes.