For example, Whitemarsh et al.,4 demonstrated that human neurons derived from iPSCs could function as ideal models to test botulinum lot potency determination. Human neurons showed equal or greater sensitivity and a steeper dose-response curve than rat primary spinal neurons, the current standard for botulinum toxin activity. The human iPSC-derived model has the advantage of employing human cells in an assay for developing human therapeutics. It also has the potential to reduce or eliminate the need for animal models.
In another recent peer-reviewed publication, Phillips et al.,5 reported human T-lymphocytes isolated from a routine blood draw were reprogrammed into iPSCs then differentiated into retinal progenitor cells. These cells then coalesced into optic vesicle-like structures and then further differentiated into different neuroretinal cell types. Similar results were seen with neuroretinal cells derived from ESCs.
The advantages of the model demonstrated in this paper are that (a) both human stem cells and differentiated cells are reliably available, and (b) iPSC technology enables cells to be sourced from patients with diseases, in this case ocular disease. The nature of ESCs does not permit this second advantage.
Much of the initial work validating human iPSC technology has been performed by pharmaceutical companies. Pharma have historically used surrogates, such as primary animal cells and immortal cell lines, to represent human biology in cell-based models used for drug discovery. These are imperfect model systems, and the result has been drug candidates that advanced into more expensive preclinical or even clinical development before toxicities emerged. Human cells should provide better models.
In a recent peer-reviewed publication, Reynolds et al.,6 described using human iPSC-derived cardiomyocytes to evaluate the cardiotoxic effect of an anthracycline-based investigational agent targeting the Her2 signaling pathway associated with breast cancer. While anthracyclines are a mainstay of breast cancer therapy, they are also limited by cardiac toxicity.
Combining anthracycline and trastuzumab, the researchers demonstrated that this new drug agent targeted the cancer cells with little or no effect on human cardiomyocytes. The drug has advanced into Phase I testing. This is the first known use of iPSC-derived cells in support of an IND filing.