Lead Optimization Services

Patient stratification

The use of iPSC-derived cells for efficacy, the screening of therapeutic candidates is gaining increasing acceptance across the drug development industry.

In particular this technology has allowed ourselves and others to develop functional cell-based bioassays for a number of disease which can produce robust data which is not only indicative of clinical outcome but in many cases is more informative that some in vivo models.

This latter point has been recognised in recent FDA guidance which now provides researchers with the ability to submit cell-based data in lieu of the in vivo data which was for many years considered to be the gold standard for our industry.

Whilst it is clear that whilst iPSC-derived cells for the most part display an immature phenotype when compared to primary cells, these changes in guidance recognised that they are however sufficiently functional to provide informative data in a wide variety of applications.

Alpha-1 antitrypsin deficiency patient panel

DefiniGEN offer a panel of human iPSC male and female donors which capture a degree of ethnic variance and come with comprehensive sequencing data (WGS, RNA-seq, Exome-seq etc) which can be used to produce both wildtype and disease model hepatocyte cultures for both in house screening services and assay-ready plate products. This resource can be used to support preclinical drug development looking at inter-donor variance in drug candidates. As may be expected, the response to stimulus will inevitably vary from donor to donor, and these data may be used to assure researchers that observed responses are not restricted to just the iPSC line used during the screening phase of the project.

However perhaps the most interesting result from screening multiple donors is that of a non or significantly reduced response; patients that do not respond to a drug may be genetically diverse from others in the panels, and by using the associated genomic data it may be possible to identify the genotype in which a drug is less likely to be efficacious, which in turn may inform the stratification of a clinical trial cohort. In this way, iPSC derived models in combination with well characterised bioassays can be used to screen drug candidates for efficacy, examine the effects of donor variance and perhaps ultimately inform the make-up of clinical cohorts.

Figure 1. Phenotype validation of ZZ-A1ATD HLCs. A) Representative images of untreated ZZ-HLCs from a panel of A1ATD patients stained for the polymeric form of A1AT compared to their corrected MM-HLCs . B) Quantification of polymeric A1AT in ZZ-HLCs versus their corrected MM-HLCs (n=3). *p<0.05 ** p<0.01

Figure 2. Dose-response of patient A1ATD HLCs to reference drug CBZ A) Quantification of polymeric A1AT in 3 different patient-derived ZZ-A1AT HLCs in response to CBZ (n=1) B) Representative images of the polymeric staining

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iPSC-derived cells for efficacy screening of therapeutic candidates

Patient stratification

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Alpha-1 antitrypsin deficiency patient panel

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