Dr McLachlan gained his PhD at the Department of Medicine and Therapeutics, University of Aberdeen in 1992.  His early postdoctoral research in the lab of Prof David Porteous  at the MRC Human Genetics Unit, Edinburgh involved the characterization of a Cystic Fibrosis(CF)  Knock-Out Mouse model and the development of Gene Therapy  for CF.  He was awarded a Wellcome Trust Research Fellowship in 1998 to study beta- defensins in the ovine lung. He continued in the theme of Innate immunity in the lung as an MRC Research Fellow at the Respiratory Medicine Unit, MRC Centre for Inflammation Research.  Dr McLachlan then returned to the field of CF Gene Therapy and  moved to the School of Veterinary Medicine in the position of Senior CF Trust Research Fellow (in 2002) within the UK Cystic Fibrosis Gene Therapy Consortium, a collaborative program involving groups at the University of Oxford and Imperial College London. Dr McLachlan is now a member of the Consortium Strategy Group.

The main focus of this research has been developing the sheep lung as a model for pre-clinical development of CF gene Therapy protocols to evaluate both safety and efficacy of candidate gene transfer agents. These studies fomed a significant part of the Investigators Brochure submitted to the MHRA in support of the recently completed large-scale multi-dose clinical trial in CF patients which reached its primary endpoint with a significant beneficial effect in lung function compared with placebo.

Dr McLachlan is currently a Group Leader at The Roslin Institute where he has developed an interest in other models of respiratory disease/biology and in particular the application of large animal models, building on the considerable expertise developed through the UK CF Gene Therapy consortium funded work. Dr McLachlan is also a Board member of the British Society for Gene and Cell Therapy.

Preclinical studies to evaluate safety and efficacy of vectors for respiratory gene/miRNA delivery in mice & sheep.

Sheep as a large animal model for respiratory disease.

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. The CFGTC has also successfully obtained a Wellcome Trust Portfolio awward that will exploit the synergies provided by our CF respiratory gene delivery platform technology, a critical mass of researchers with complementary extensive expertise, the use of common resources, and respiratory gene transfer expertise and apply them to range of other diseases that may benefit from the expression of a therapeutic transgene in the lung.

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 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.

3)    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.

This group is part of the UK Cystic Fibrosis Gene Therapy Consortium
www.cfgenetherapy.org.uk

Medical Genetics Section, Centre for Molecular Medicine, Western General Hospital
www.genetics.med.ed.ac.uk

The Cystic Fibrosis Trust
www.cftrust.org.uk

Divisional Postgraduate Convenor for Developmental Biology Division

Postgraduate Representative on the Career Development Committee

Roslin Institute Animal Welfare and Ethical Review Board

British Society for Gene and Cell Therapy Board member

Personal tutor for undergraduate BVM&S students

Run practical class on molecular diagnostics for first year undergraduate BVM&S students

Lecture on gene therapy and gene editing for MSc in Animal Biosciences course

Coordinator of Comparative Animal Models and One Health module for MSc in Animal Biosciences and MSc in Infectious Diseases and One Health