A human iPS cell model for gene therapy vector safety evaluation

We are developing a robust human relevant risk assessment system that will improve the safety of novel gene therapy products and reduce the reliance on animal models.


Gene therapy (GT) is now emerging as a medical reality, with clinical efficacy demonstrated in a number of GT trials for rare diseases. Generally the therapeutic DNA sequence is delivered via a vector system, with some vectors integrating permanently into the genome to provide ex vivo or in vivo gene addition or correction for the treatment of inherited and acquired disorders. The integrated sequences are then transmitted to the cell progeny during cell replication. Insertional mutagenesis leading to oncogenesis is a recognised GT safety concern, which has manifested in a number of trials involving ex vivo transduction of hematopoietic stem cells with gamma-retroviral vectors. There is increasing demand for non-clinical tests to assess the safety of GT in patients. Non-clinically, GT safety is mainly assessed through in vivo studies in rodent or non-rodent species. These animal models are costly, time consuming and do not always reliably predict the effects seen in humans.


Supported by funding through the NC3Rs CRACK IT Challenges competition, the team led by GeneWerk GmbH has already set up the basis of a standardized assay for Individualized Genotoxicity testing (InGeTox) to assess vector safety and efficacy using human induced pluripotent stem cells, differentiated to hepatocytes in 3D culture with extended lifespan. Vector-related factors that cause genotoxicity will be measured, including effects on cancer gene expression by vector promoters and enhancers, aberrant transcript forms or gene splicing, host epigenetic responses to gene transfer and therapeutic gene expression. InGeTox will be made expandable to Patient cells and each tissue of interest, representing a personalized safety assessment for each disease targeted by gene therapy.
We are collaborating with Brunel University, Edinburgh University, University College London, King’s College London, The Natural and Medical Sciences Institute at the University of Tubingen (NMI), GlaxoSmithKline and Novartis to deliver InGeTox.

“Whilst avoiding animal experimentation, together we will be accelerating the transition of safe gene therapy from bench to bedside!”
M. Schmidt, CEO GeneWerk

About NC3R´s

About NC3R´s

The NC3Rs is a UK-based scientific organisation dedicated to replacing, refining and reducing the use of animals in research and testing (the 3Rs).
They collaborate with scientists and organisations from across the life sciences sector, nationally and internationally, including universities, the pharmaceutical, chemical and consumer products industries, other research funders, and regulatory authorities.
The NC3Rs support the commitment of the scientific community to the 3Rs by funding research and early career development, supporting open innovation and the commercialisation of 3Rs technologies, and stimulating changes in policy, regulations and practice.

CRACK IT Challenges

CRACK IT Challenges

CRACK IT is an open innovation platform from the NC3Rs to accelerate the development, application and commercialisation of technologies with 3Rs potential as they emerge from the research base.


CRACK IT Challenges is a competition that funds collaborations between industry, academics and SMEs to solve scientific challenges that have the potential to deliver commercial benefits and reduce the reliance on the use of animals in research. Sponsors, typically industry, define the Challenge, and academics and SMEs apply for funding from the NC3Rs to solve the Challenge. There are benefits for all participants - industry gets access to scientific and technological innovations emerging from the science base and an end product which meets their needs; academics have a pathway for exploiting their research; and SMEs are provided with a ready-made market.

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