Transfer of the epicardial-cardiac organotypic culture model to support the ex vivo screening of gene therapy candidates

Why did we fund this project?

This award aims to replace rodents in gene therapy studies for cardiac regeneration with the EpCardio-TS model, an ex vivo porcine cardiac slice model.

Investigating gene therapy strategies in the epicardium, the most external layer of the heart, typically uses mice or rats. The genes of interest are over-expressed, and a myocardial infarction induced under general anaesthetic, to determine the effects of the gene on cardiac regeneration. Inducing a myocardial infarction is classified as severe under the UK’s Animals (Scientific Procedures) Act 1986 due to the level of suffering caused. EpCardio-TS was developed by Dr Paola Campagnolo with NC3Rs funding and uses tissue obtained either as a by-product from the abattoir or as surplus material from animals killed in the laboratory for another scientific purpose. The slices are viable in culture, metabolically active and provide a 3D model with multiple relevant cell types that is a better representation of the human heart than other cellular in vitro methods, which are often 2D and include only one cell type. Paola has used the model in her own laboratory to study epicardial cell proliferation, migration and differentiation.

Using nanoneedles, Paola has demonstrated the localised transfer of reporter genes to fluorescently label the epicardial cells and by optimising a decolouration protocol has been able to visualise the labelled epicardial cells within the slice, including during cell migration. Professor Molly Stevens at Imperial College London and Dr Ofelia Martinez-Estrada from the University of Barcelona will collaborate with Paola to facilitate the adoption of EpCardio-TS into their gene therapy studies.

The key aim of this project is to ensure the uptake our Epicardial/Cardiac-Tissue Slices, (EpCardio-TS) model in two end-user laboratories and achieve the reduction of animal models for the screening of epicardial cell gene therapy targets. This project builds on the team's extensive experience in delivering successful training and supporting the uptake of similar techniques in other laboratories and will ultimately propagate the prominence of EpCardio-TS nationally and internationally.

The recovery capacity of the adult heart after injury is severely limited by the low number of regenerating cells within this tissue. The epicardium, the most external layer of the heart, contains cells able to home to the injured heart muscle and promote its recovery. We developed an innovative model based on thin slices obtained from leftover pig heart tissues that mimics in a dish the behaviour of the epicardium. In this project, we will teach other laboratories working on the epicardium how to prepare and use our model in their own research.

The adoption of our model by our partners will provide an alternative strategy to test their innovative gene therapy ideas, reducing the use of regulated procedures (surgeries) performed on animals. In addition, we will present our model to several other interested laboratories and industrial partners working on similar science projects in order to encourage further uptake and further reduction of animal use.

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Skills and Knowledge Transfer grant

Grant reference number

NC/T001216/1

Award date:

Aug 2019 - Sep 2020

Grant amount

£75,562