MICA: Exploiting in silico modelling to address the translational bottleneck in regenerative medicine safety

Stem cells have great potential in medicine as then can grow into many different cell types in the body. One way of treating damaged tissues and organs is to transplant stem cells or cells derived from stem cells into the damaged organ - this kind of treatment is know as a cell therapy and an example of this used today is bone marrow transplantation. Whilst this treatment is successful for many diseases, in some cases this treatment does not work and the cells do not grow well. To develop new treatments for patients we require research tools that look at the safety of using cell therapies as well as look at the "immune response" e.g. how our body naturally reacts when a cell therapy is introduced. It is also important to look at how safe and efficient a cell therapy is.

Our project team want to develop a range of tools that will answer these questions and speed up the process for developing new treatments for patients who are currently suffering form untreatable diseases. For this project, the team are going to look at liver disease. There are many problems with giving a patient a cell therapy: (1) making sure that the new cells end up at the site of injury/damaged tissue; (2) will the body can end up "attacking" these cells as part of the body's natural immune system; (3) do the cells attach onto the injured organ; (4) do the cells carry out their role within the body.

The project team are going to use a combination of maths and biology in order to answer these questions. The project has the potential to produce a framework that could be used to help get new treatments out of a laboratory situation and heading towards being used as a treatment for a patient. Whilst liver disease is being used as a disease example for this project, the same tools could be used for a range of different diseases.

Successful clinical translation of regenerative medicine therapies requires robust preclinical tools for safety, immunogenicity and efficacy purposes. We will develop a translational preclinical toolkit for the clinical translation of regenerative medicine therapies by combining in silico, in vitro and in vivo approaches. The current clinical translational bottleneck in liver cell therapy development concerns safe delivery of the cell therapy to the site of liver disease; protection of the delivered cells from the host immune systems; as well as ensuring successful cell engraftment and subsequent function at the injury site. We will address this translational bottleneck by encapsulating cells in a biocompatible and biodegradable micromatrix. Mathematical modelling in combination with state-of-the art experimental approaches will provide mechanistic understanding into the role of cell encapsulation in ensuring the safety, immune system evasion and efficacy of these next-generation liver cell therapies. We will develop predictive mathematical models that integrate data obtained from complementary in vitro and in vivo approaches thus providing a bridge from understanding gained through reductionist in vitro assays to in vivo animal models. The quantitative and predictive approach will enable identification and optimisation of cell therapeutic approaches in terms of encapsulation protocols ensuring desired mechanical, anti-inflammatory, engraftment and functional properties and dosing regimens, thereby providing quantitative preclinical evidence for or against the use of encapsulation technologies. This preclinical toolkit will therefore facilitate successful clinical translation of next-generation cell therapies for liver disease. The in silico approach will have wider impact across the UKRMP Hub disease exemplars, such as lung and joint, and beyond into wider disease conditions, e.g. cardiovascular, by enabling translational bottlenecks to be overcome.

The disease exemplar that will be investigated during the course of this project is liver regeneration. Liver disease is the 5th most common cause of death in the UK and the deaths from cirrhosis are rapidly rising (British Liver Trust, www.britishlivertrust.org.uk). Most liver deaths occur in people under 70, while one in ten deaths of all people in their 40s were from liver conditions. The only curative option for end-stage liver disease is liver transplantation but donor organ availability cannot meet current demand and may patients die whilst waiting for a suitable organ. Many patients with severe liver disease are not eligible for transplantation.

It is foreseen that the results generated from the proposed cell therapy research would allow further funding to be leveraged (this would be the subject of a future funding application). It is likely that this next stage of research would involve input from the Cell and Gene Therapy Catapult.

All the research organisations involved in this project have strong outreach programmes which will help to disseminate the results to appropriate stakeholders. To maximise the scientific and clinical impact, the investigators will closely involve the UKRMP network. The investigators involved have a record of publishing in high impact journals with wide readership in the relevant scientific and clinical communities. Any intellectual property generated during the course of the project will be appropriately protected by the relevant partner University/Universities and exploited by the relevant technology transfer organisation.