Scale up and In-vitro Testing of Exosomes for Regenerative Medicine Applications

Stem cell-secreted exosomes are gaining significant attention as a candidate therapeutic platform for 21st century healthcare. This is because a growing body of research into exosomes has revealed that they can drive desirable behavioural changes in target cells, modifying or reversing pathological processes. The potential applications of exosomes are broad and include cell-free regenerative medicine at one end of the spectrum and cancer therapeutic at the other. To fully understand the therapeutic repertoire of exosomes, it is necessary to systematically characterise exosome populations isolated from a range of different cell culture scenarios. Critical for commercial development, it is also necessary to generate exosomes in therapeutically relevant quantities, which requires the creation of a cell culture process that can be scaled up to deliver industrial quantities of exosome product. Using bench-scale bioreactors that mimic industrial bioreactor technologies, this project will draw on expertise across bioprocess engineering for regenerative medicines in order to scale up production of stem cells and their exosomes. It will then use microfluidics and analytics for in vitro testing of exosome potency. This can be achieved using automated, perfused cell culture devices that support in situ monitoring of how exosomes influence the behaviour of 3D microtissues. 3D microtissues will be created using cells and biomaterials to create self-assembled tissues. The microfluidic devices will result in minimal operator error and increased measurement consistency.

Humanised, 3D tissue models are finding interest due to current overly-simplified immortal cell lines and non-human in vivo models providing poor prediction of drug safety, dosing and efficacy; 43% of drug fails are not predicted by traditional screening and move into phase I clinical trials1. Phase I sees a 48% success rate, phase II a 29% success rate and phase III a 67% success rate [1]. The drug development pipeline is pressurised due to adoption of high throughput screening / combinatorial libraries. However, while R&D spend has increased to meet this growing screening programme, success, measured by launched drugs, remains static [2]. This poor predictive power of the >1 million animals used in the UK each year drives the 12-15 year, £1.85B pipeline, for each new drug launch [3]. Contract research organisations (CROs) are also similarly hit by these problems.

Drive to reduce animal experimentation in toxicology and outright banning of animal testing for e.g. cosmetics in the UK has driven companies to outsource or to adopt the limited number of regulator approved NAT models for e.g. skin [4,5].

Another key area that uses 3D tissues is the field of advanced therapeutic medicinal products (ATMPs), i.e. tissue engineering/regenerative medicine. Regulation is a major ATMP bottleneck. It is thus noteworthy that regulators, such as the UKs Medicines and Healthcare Products Regulatory Agency (MHRA), are receptive to the inclusion of NAT-based data in investigative medicinal product dossiers [6].

The lifETIME CDT will directly address these issues through nurturing of a cohort training not only in the research skills required to conceive and design new NATs, but also in skills based on:

- GMP and manufacture.
- Commercialisation and entrepreneurship.
- Regulation.
- Drug discovery and toxicology - a focus on the end product.
- Policy.
- Public engagement.

Our NAT graduate community will impact on:

- Pharma - access to skills that develop tools to unlock their drug discovery and testing portfolios. By helping train graduates who can create and deploy NATs, they will increase efficiency of drug development pipelines.

- ATMP manufacturers - the same skills and tools used to deliver NAT innovation will help to deliver tissue engineered / combination product ATMPs.

- CROs - access to skills to create platform tools providing more sophisticated approaches to the diverse research challenges they face.

- Catapult Centres - access to skills that provide innovation that can be deployed across the broader healthcare sector.

- Regulatory agencies e.g. MHRA - better education for the next generation of scientists on development of investigational new drug / medicinal product dossiers to speedup approvals.

- Clinicians and NHS - access to more medicines more quickly through provision of highly skilled scientists, manufacturers and regulators. NATs will help drive the stratified/personalised medicine revolution and understand safety and efficacy parameters in human-relevant tissues. Clinicians will also benefit from development of ATMP-based regenerative medicine.

- Patients - benefit from skills for faster and more economically streamlined development of new medicines that will improve lifespan and healthspan.

- Public and Society - benefit from the economic growth of a thriving drug development industry. Benefits will be direct, via jobs creation and access to wider and more targeted healthcare products; and indirect, via increased economic benefit of patients returning to work and increased tax revenues, that in turn feed back into the healthcare systems.


[1]. Cook. Nat Rev Drug Discov 13, 419-431 (2014).
[2]. Pammolli. Nat Rev Drug Discov 10, 428-438 (2011).
[3]. DiMasi. Health Econ 47, 20-33 (2016).
[4]. Cotovio. Altern Lab Anim 33, 329-349 (2005).
[5]. Kandarova. Altern Lab Anim 33, 351-367 (2005).
[6]. https://goo.gl/i6xbmL