Dr Gerry McLachlan

The Roslin Institute

Research Interests

The main long-term focus of my research has been on developing lung-directed gene therapy as a viable clinical entity. My group is part of the UK Cystic Fibrosis Gene Therapy Consortium (CFGTC), a grouping of leading gene therapists in the UK. Over two decades the CFGTC has pooled the resources of three major groups in the UK (University of Edinburgh, University of Oxford and Imperial College London), progressing from laboratory studies, to the first demonstration that gene therapy can produce improvements in the lungs of CF patients in the largest ever human gene therapy trial for this condition. Studies to date have focussed on non-viral gene transfer agents (GTAs). At Roslin, we have delivered a programme of preclinical evaluation of safety and efficacy in the sheep lung including MHRA-approved toxicology study of repeated administration to the airways (Alton EWFW et al. 2013). The subsequent Phase IIb double-blind placebo-controlled clinical trial reached its primary endpoint with a significant beneficial effect in FEV1 compared with placebo (Alton EWFW et al. 2015). CFGTC have also developed a lentiviral gene delivery platform based on an SIV virus (rSIV.F/HN) specifically pseudotyped with the F and HN proteins from Sendai virus (SeV) for lung gene transfer. rSIV.F/HN transduces murine and sheep lungs and human ex vivo models efficiently and leads to gene expression at least 100-fold higher than the gold-standard lipid formulation GL67A which reached its primary clinical endpoint in a Phase IIb trial. In addition, in the mouse, a single dose achieves stable gene expression for the life-time of the animal (~ 2 yr) due to integration of the vector into the genomic DNA. Importantly, unlike many other viral vectors, repeated administration of these lentiviral vectors is feasible. CFGTC has generated pharmacopeia-compliant vectors carrying a range of promoter/enhancer elements, enabling selection of a lead candidate for a first-in-man CF clinical trial.

We are now in a position to take advantage of this unique expertise in delivery, sampling and lung function measurement in a large mammalian lung that we have established. An added objective of the CFGTC is the translation of gene therapy for a Portfolio of diseases by exploiting the synergies provided by our respiratory gene delivery platform technology, a critical mass of researchers with complementary extensive expertise, the use of common resources, and respiratory gene transfer expertise.

Other interests include:

Studies in the sheep lung to explore the functional relevance of the respiratory microbiota. We are investigating potential spatial heterogeneity within different regions of the healthy lung, the longitudinal stability and the potential changes following infection and/or antibiotic treatment (Glendinning et al. 2016). This involves the application of appropriate in vivo sampling procedures that minimise the risk of cross contamination with oral microflora. Composition of the microbiota is determined by a combination of 16S rDNA PCR and Illumina MiSeq analysis. We also have an interest in evaluating protocols to manipulate the composition of the respiratory microbiota in vivo.

Large animal models of respiratory disease including

1)    Chronic lung infection with Pseudomonas aeruginosa is a major contributor to morbidity, mortality and premature death in cystic fibrosis. Relevant and translatable animal models are required to identify and test therapeutic concepts. Research in my lab, in collaboration with David Collie, aims to improve on existing models of infection in small animals through developing a lung segmental model of chronic Pseudomonas infection in sheep. Local lung instillation of P. aeruginosa suspended in agar beads led to the development of a suppurative, necrotising and pyogranulomatous pneumonia centred on the instilled beads. Infection persisted for as long as 66 days after initial instillation (Collie DDS et al. 2013).  The aim is to utilise this model to investigate both the pathobiology of such infections as well as novel approaches to their diagnosis and therapy. Areas of interest include analysis of the effects on microbiota in both directly infected and remote sites in the lung following antibiotic therapy (Collie DDS et al. 2015).

 

2)    A model of localised epithelial damage to investigate the time course & mechanism of epithelial repair in airways following injury in the adult lung. Understanding the processes involved in repairing the airway wall following injury is fundamental to understanding the way in which these processes are perturbed during disease pathology. Indeed complex diseases such as asthma and COPD have at their core evidence of airway wall remodelling processes that play a crucial functional role in these diseases. Our studies are aimed at understanding the dynamic cellular events that occur during lung bronchial airway epithelial repair in sheep (Yahaya et al, 2011, 2013).

 

3)    A sheep model for radiation-induced lung injury (RILI). The primary response to radiation varies between individuals and a proportion go on to develop RILI. RILI typically manifests as pneumonitis, occurring four to twelve weeks following irradiation, and fibrosis occurring six to twelve months after irradiation. Whilst the incidence of RILI varies, one study found clinical pneumonitis in 5 to 15 percent, and radiographic abnormalities in 66 percent, of patients treated for lung cancer. Although there are some correlates between the primary response to the radiation and susceptibility to RILI there is currently no way of predicting whether an individual will develop RILI before receiving radiotherapy. RILI is assumed by many to represent a failure in the repair response but the pathophysiology underlying this failure is undefined. Our studies present an opportunity, using a large animal model, to investigate the nature and extent of any radiation-induced perturbation in the lung’s ability to repair itself following injury.   We also have an interest in using this model to evaluate novel radio-protectant substances.

 

4)    Generation of novel gene edited animal models for Cystic Fibrosis (CF). CF is a severe, life-limiting autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). A number of different transgenic mouse models have been created and although these models fail to reproduce the lung disease which is the hallmark of CF in humans, they have been extensively used in preclinical evaluation of new treatments such as gene therapy, and small molecule drug therapies (for example, potentiators of CFTR function). Pig and ferret models of CF have been developed more recently through gene targeting and somatic cell nuclear transfer. While these are exciting developments, both models exhibit severe perinatal intestinal disease which requires surgical intervention. Since the existing CF models either fail to reproduce the respiratory phenotype, or their widespread usefulness for CF research is limited by severe intestinal and/or respiratory phenotypes, there remains a need for additional animal models. Gene editing technologies have opened the way for efficient and precise genetic targeting in a broad range of species.

Selected Publications

  • Laura Glendinning, Steven Wright, Peter Tennant, Andrew C Gill, David Collie, Gerry McLachlan. 2017. Microbiota in Exhaled Breath Condensate and the Lung. Applied and Environmental Microbiology Vol: 83. More»
  • Alan Boyd, Heather Davidson, Ann Doherty, Laura Hyndman, Gerry McLachlan, James Alastair Innes, Barbara Stevenson and 31 others. 2017. Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis. Thorax Vol: 72 Pages: 137-147. More»
  • Laura Glendinning, Steven Wright, Jolinda Pollock, Peter Tennant, David Collie, Gerry McLachlan. 2016. Variability of the Sheep Lung Microbiota. Applied and Environmental Microbiology Vol: 82 Pages: 3225-3238. More»
  • David Collie, Laura Glendinning, John Govan, Steven Wright, Elisabeth Thornton, Peter Tennant, Catherine Doherty, Gerry McLachlan. 2015. Lung Microbiota Changes Associated with Chronic Pseudomonas aeruginosa Lung Infection and the Impact of Intravenous Colistimethate Sodium. PLoS One Vol: 10 Pages: e0142097. More»
  • A Christopher Boyd, D David S Collie, Steve Cunningham, Heather E Davidson, Ann Doherty, Laura Hyndman, Alan W Maclean, Dominique Mccormick, Michael Mcgovern, Gerry Mclachlan, Gordon D Murray, David J Porteous, Keith Smith, Barbara J Stevenson and 66 others. 2015. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. The Lancet Respiratory Medicine Vol: 3 Pages: 684-691. More»
  • E. W. Alton, Alison Baker, Eilidh Baker, Christopher Boyd, S. H. Cheng, Rebecca Coles, David Collie, Heather Davidson, Jane C Davies, D. R. Gill, Catherine Gordon, U. Griesenbach, T. Higgins, S. C. Hyde, J. A. Innes, Dominique McCormick, Michael McGovern, Gerry McLachlan, David Porteous, I. A. Pringle, R. K. Scheule, Darren Shaw, Sionagh Smith, Stephanie Summer-Jones, Peter Tennant, Christina Vrettou. 2013. The safety profile of a cationic lipid-mediated cystic fibrosis gene transfer agent following repeated monthly aerosol administration to sheep. Biomaterials Vol: 34 Pages: 10267-10277. More»
  • David Collie, John Govan, Steven Wright, Elisabeth Thornton, Peter Tennant, Sionagh Smith, Catherine Doherty, Gerry McLachlan. 2013. A Lung Segmental Model of Chronic Pseudomonas Infection in Sheep. PLoS One Vol: 8. More»
  • G McLachlan, H Davidson, E Holder, L A Davies, I A Pringle, S G Sumner-Jones, A Baker, P Tennant, C Gordon, C Vrettou, R Blundell, L Hyndman, B Stevenson, A Wilson, A Doherty, D J Shaw, R L Coles, H Painter, S H Cheng, R K Scheule, J C Davies, J A Innes, S C Hyde, U Griesenbach, E W F W Alton, A C Boyd, D J Porteous, D R Gill, D D S Collie. 2011. Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung. Gene Therapy Vol: 18 Pages: 996-1005. More»
  • U. Griesenbach, G. McLachlan, T. Owaki, L. Somerton, T. Shu, A. Baker, P. Tennant, C. Gordon, C. Vrettou, E. Baker, D. D. S. Collie, M. Hasegawa, E. W. F. W. Alton. 2011. Validation of recombinant Sendai virus in a non-natural host model. Gene Therapy Vol: 18 Pages: 182-188. More»
  • Uta Griesenbach, Catarina C. Vicente, Megan J. Roberts, Cuixiang Meng, Samia Soussi, Stefania Xenariou, Peter Tennant, Alison Baker, Eilidh Baker, Catherine Gordon, Christina Vrettou, Dominique McCormick, Rebecca Coles, Anne-Marie Green, Anna E. Lawton, Stephanie G. Sumner-Jones, Seng H. Cheng, Ronald K. Scheule, Stephen C. Hyde, Deborah R. Gill, David D. Collie, Gerry McLachlan, Eric W. F. W. Alton. 2011. Secreted Gaussia luciferase as a sensitive reporter gene for in vivo and ex vivo studies of airway gene transfer. Biomaterials Vol: 32 Pages: 2614-2624. More»
  • Lee A. Davies, Gerry McLachlan, Stephanie G. Sumner-Jones, David Ferguson, Alison Baker, Peter Tennant, Catherine Gordon, Christina Vrettou, Eilidh Baker, Jie Zhu, Eric W. F. W. Alton, David D. S. Collie, David J. Porteous, Stephen C. Hyde, Deborah R. Gill. 2008. Enhanced lung gene expression after aerosol delivery of concentrated pDNA/PEI complexes. Molecular Therapy Vol: 16 Pages: 1283-1290. More»