Cell-free lung model for mycobacterium abscessus 3D-biofilm formation

Mycobacterium abscessus is an environmental microorganism that has found a deadly niche in the cystic fibrosis (CF) lung. Both adults and children infected with M. abscessus face 18 months of intensive antibiotic intervention, including both intravenous and nebulised formulations which result in severe and traumatic side effects. Furthermore, treatment is often unsuccessful, and patients present with recurrent infections that contribute to the high mortality rate associated with M. abscessus. Additionally, incidence of infections is rising. The bacterial persistence within the lung environment is thought to be attributed to biofilm formation, aided by the thick mucus matrix typical of the CF lung. We have previously developed a 2D in vitro lung model that enables us to assess the efficacy of nebulised antibiotics against M. abscessus. Beyond this, we have identified compounds that potentiate the antibacterial efficacy of known antibiotics when delivered in combination with them. As a next step, we would like to further develop this model into a 3D hydrogel-based system to determine this efficacy in a more physiologically relevant biofilm as would be observed in the CF lung environment. This will provide us with a much clearer understanding of the way in which M. abscessus grows and responds to antibiotic stress within the host lung, and will enable us to further test the efficacy of the potentiator compounds in a cell-free culture system.

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