How iPSC derived cells can support drug and gene therapy development

Researchers in a lab

DDW recently hosted a webinar ‘Discover how iPSC derived cells can be used to support the development of drug and gene therapies’, supported by DefiniGEN. The event outlined how iPSC derived cells can be used to advance the efficiency and efficacy of disease modelling and covered topics including functionality, modelling disease phenotypes, therapeutic modalities and delivery and efficacy.

The keynote speaker was Professor Ludovic Vallier, Chief Scientific Officer, DefiniGEN. Dr Chris Kirton, Chief Executive Officer of DefiniGEN, provided an introduction.

Chris explained that DefiniGEN is a liver cell company focussed on hepatocytes, particularly supporting the drug development industry in producing liver therapies. It was founded to crack one of the big problems – the rate of attrition in the drug development pipeline.

A roadblock in the successful triaging of new therapeutics for liver and metabolic related diseases is the reliability and effectiveness of pre-clinical disease models.

Methods employing animal models may have limited success in replicating liver diseases, primarily because of species-specific differences, furthermore, the utilisation of animal models to simulate liver disease phenotypes frequently leads to limited success.

Primary hepatocytes represent the gold standard in vitro cell model for functionality, however, when isolated from liver tissue, primary cells maintain expression of key proteins for only a short period. Extending culture of primary hepatocytes beyond 24 hours may result in rapid dedifferentiation, characterised by loss of function and apoptosis.

Initial screening of treatments may utilise the highly proliferative Chinese Hamster Ovarian (CHO) or Human Embryonic Kidney (HEK) cell lines with the liver protein(s) of interest exogenously expressed. This system allows researchers to investigate the effect of the treatment on the target protein, but the cellular environment bears little resemblance to that of the human liver, an impediment to reliable compound triaging.

Hepatocellular carcinoma-derived cell lines, such as HepG2s, are less proliferative than CHO or HEK cells but remain readily expandable and retain aspects of hepatocyte function. However, hepatoma lines may lack the key proteins essential for modelling. In addition, stable cell lines derived from cancers represent a single and karyotypically abnormal genotype.

An ideal model for the study of liver disease would combine the expansion capacity and phenotypic stability of hepatoma cell lines with the functionality and normal karyotype of primary hepatocytes. Human induced pluripotent stem cell-derived hepatocyte-like cells (HLCs) have the potential to fulfil this role.

Ludovic discussed the liver, its function and its cells. He outlined the major global healthcare challenge that liver disease creates. He discussed the limitations of using animal models and explained why the company decided to use HESCs / HIPSCS and organoids.

Focal points within Ludovic’s presentation included the development of a GMP protocol for generating HLCs for gene therapy, and how HLCs grown in 3D cultures allow modelling

of acute liver failure induced by paracetamol. He also discussed Alpha-1 antitrypsin (A1AT) deficiency (Z); using IPSCS for cell-based therapy of TD1 and liver diseases; the identification of new biomarkers involved in ATT polymerisation, and Wilson’s disease, among other points.

Audience questions included:

  • Is there an advantage to using iPSC-derived hepatocytes over liver cell lines like HepG2?
  • Is it better to use an iPSC line from a patient with the disease I am interested in or is it better to use a gene-edited line?
  • Can iPSC-derived hepatocytes be used to replace primary cells in toxicology?
  • Are there any ethical boundaries behind the use of iPSCs?

Watch on demand.

DDW Volume 25 – Issue 1, Winter 2023/2024

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