Advanced MRI lung imaging using hyperpolarised xenon gas.

Professor Mark Lythgoe (UCL) and Dr Marta Tibiletti (Bioxydyn Limited)

This PhD offers an exciting opportunity to join a team of leading UCL imaging scientists, biologists, drug developers and respiratory clinicians, in collaboration with the spinout company Bioxydyn, to develop the next generation of MRI lung imaging. The project builds on recent investment at UCL in hyperpolarised 129Xe MRI for lung imaging and a track record of novel lung MRI research including work on oxygen-enhanced MRI [1-3].

Lung diseases are among the leading causes of death worldwide. Respiratory infections, lung cancer and chronic obstructive pulmonary disease together accounted for 9.5 million deaths worldwide during 2008, one-sixth of the global total. In the UK, respiratory disease affects 1 in 5 people, and even before COVID-19, was the UKs third biggest cause of death costing society £9.9 billion annually [4-6]. Despite major advances in brain and body imaging, lung imaging remains incredibly challenging, often holding back patient diagnosis and treatment planning, as well as drug development.

Project Aim: To investigate a new MRI technology, hyperpolarised 129Xe gas MRI, to visualise lung function

MRI can provide exquisite detail of the human body, yet lacks the sensitivity to provide detailed information about the lungs. Lung MRI using conventional scanning methods based on imaging of tissue water is challenging due to low signal levels and air-tissue interfaces causing MRI signal loss. Additionally, conventional MRI provides no information about the airways of the lung, as signal generation is restricted to the lung tissue. An effective solution to both of these limitations is to use inhaled hyperpolarised 129Xe gas [7]. Hyperpolarisation ‘boosts’ MRI signal production many times, thereby resolving the low signal challenge in the lung. Inhaled 129Xe gas is distributed through the large and small airways of the lung, providing a unique view of airways and fundamental function of the lung.

The studentship is based in a world leading Advanced Imaging Centre [8] and would suit an individual from a background in the biological, pharmacological, medical or physical sciences, with an interest in developing and using advanced imaging methods to understand disease processes.

Project outline:

• Year 1: Develop methods for assessment of lung blood-air barrier structure & function using HP- 129Xe MRI in small animal models of pulmonary fibrosis (e.g. bleomycin) and inflammation (e.g. elastase or LPS instillation)
• Year 2: Make new mechanistic discoveries by relating HP-129Xe MRI measurements to disease pathogenesis and progression, and by observing response to pharmacological intervention. For example, selective modulation of molecular targets of interest, such as TRPV4 (Transient receptor potential cation channel subfamily V member 4) might provide insight into new therapies.
• Year 3: Validation of measurements against CT with PET and/or SPECT, PFTs and histological analyses (e.g. histology, -omics, flow cytometry or CyTOF)
• Year 4: Optimise clinical data acquisition and analysis protocols for future translation of HP-129Xe MRI findings to human volunteers and patient studies. Explore use of preclinical HP-129Xe MRI for tissue barrier and transport assessment in other organ sites such as the intestines and brain.

This PhD studentship placement offered in collaboration with Bioxydyn Limited

Bioxydyn Limited is an SME based in Manchester, UK (Bioxydyn.com). The company was spun out from the University of Manchester by Prof Geoff Parker, with a remit to translate advanced quantitative imaging methods from academia to use ultimately for patient benefit. One of Bioxydyn’s main areas of activity is in the use of MRI to quantify lung function; and area where the company’s personnel has published widely in collaboration with academic clients (bioxydyn.com/biomarkers/respiratory). Bioxydyn’s expertise and focus is thus closely aligned with the topic of this studentship. The placement is expected to be split into three periods of approx. 1 month, occurring in years 2, 3, 4 of the studentship.

During the placement at Bioxydyn the student will benefit from the training that all Bioxydyn employees experience, providing an in-depth foundation on research in a contract research organisation. The student will experience the full range of operational activities and will gain a valuable understanding of this component of translation of research methodology for patient benefit.

References:

1. M. Tibiletti, J.A. Eaden, J. Naish, P.J.C. Hughes, J.C. Waterton, M.J. Heaton, N. Chaudhuri, S. Skeoch, I.N. Bruce, S. Bianchi, J.M. Wild, G.J.M. Parker. Imaging biomarkers of lung ventilation in interstitial lung disease from 129Xe and oxygen enhanced 1H MRI. Magnetic Resonance Imaging. DOI: 10.1016/j.mri.2022.10.005. (In press).

2. A. Salem, R.A. Little, A. Latif, A.K. Featherstone, M. Babur, I. Peset, S. Cheung, Y. Watson, V. Tessyman, H. Mistry, G. Ashton, C. Behan, J.C. Matthews, M.-C. Asselin, R.G. Bristow, A. Jackson, G.J.M. Parker, C. Faivre-Finn, K.J. Williams, J.P.B. O'Connor. Oxygen-enhanced MRI Is Feasible, Repeatable, and Detects Radiotherapy-induced Change in Hypoxia in Xenograft Models and in Patients with Non–small Cell Lung Cancer. Clinical Cancer Research, 25, 3818-3829, (2019). doi: 10.1158/1078-0432.CCR-18-3932

3. K. Martini, C.M. Gygax, C. Benden, A.R. Morgan, G.J.M. Parker, T. Frauenfelder. Volumetric dynamic oxygen-enhanced MRI (OE-MRI): comparison with CT Brody score and lung function in cystic fibrosis patients. Eur. Radiol. 28(10), 4037-4047, (2018). doi: 10.1007/s00330-018-5383-5

4. British Lung Foundation (2016) The Battle for Breath - the impact of lung disease in the UK p.38

5. NHS England (2013) Planning for Patients 2014/15 to 2018/19: Reduce premature mortality: respiratory disease

6. https://www.blf.org.uk/support-for-you/idiopathic-pulmonary-fibrosis-ipf

7.  Stewart et al., ‘Lung MRI with Hyperpolarised Gases: Current & Future Clinical Perspectives’. 10.1259/bjr.20210207

8. https://www.ucl.ac.uk/centre-for-advanced-biomedical-imaging/centre-advanced-biomedical-imaging