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Our work focusses on promoting the regeneration of tissues and reducing fibrosis. Tissue injury often results in sub-optimal repair and impaired function. Persistent low grade inflammation leads to fibrosis and long-term morbidity. Unraveling the mechanisms of that underlie repair and fibrosis using the laboratory facilities at the Kennedy Institute of Rheumatology combined with the knowledge of the natural history of the processes and access to surgical specimens provides an unparalleled opportunity. Our studies based on diseased and normal human tissues have revealed novel therapeutic targets that are the subject of early stage clinical trials.

PI

current research

Fibrosis

Fibroproliferative disorders are estimated to contribute to 45% of deaths in the USA. Whilst this huge number includes atherosclerosis, the biggest killer in the developed world, less common conditions such as idiopathic pulmonary fibrosis, fibrosis of the liver and kidney and systemic sclerosis are also associated with high mortality. Localised fibrotic conditions, which receive much less attention, including endometriosis, abdominal adhesions, frozen shoulder and Dupuytren's disease, also cause considerable morbidity and together affect more than 10% of the population. The magnitude of the unmet clinical need has resulted in intense efforts to develop novel therapeutic strategies. Despite this, success remains elusive for a multitude of reasons:

  1. Detection: Fibrosis is the end stage of a process that develops over many years, often decades, and patients usually present late, once organ function has been significantly compromised. Early predictors and biomarkers are scarce.
  2. Reversibility: Elimination of the initiating insult such as hepatitis B viral infection results in regression of fibrosis and restoration of function in the liver. However, in the majority of organs and even other liver disorders such as non-alcoholic steatohepatitis, this process is irreversible.
  3. Matrix: Late stage fibrotic tissues are relatively acellular, leaving few cells to target and a densely cross-linked matrix that is barely susceptible to proteolysis. 
  4. Tissue availability: The study of primary cells from diseased human tissues has proven to be highly successful in the identification of therapeutic targets, as exemplified by TNF in inflammatory arthritis. In fibrotic diseases human samples are available in very limited quantities and, even when they can be accessed, have failed to provide insights that have translated to successful clinical trials. 
  5. Cell and animal models: Consequently, investigators have turned to the study of cells in culture to identify and study potential new targets in fibrosis. The main effector cells in fibrosis are myofibroblasts derived from a heterogeneous pool of precursors to produce and remodel collagen matrix into scar tissue. However, it is difficult to emulate in cell culture the mechanical and biochemical conditions found in vivo. Animal models of fibrosis have provided useful information but also have significant weaknesses and invariably involve the administration of toxins or other insults that are rarely encountered in clinical practice. Consequently, many targets identified in cell culture and tested in animal models have failed to translate to the clinic. 

We have been studying Dupuytren's disease, a local fibrotic condition of the hand that affects 4% of the general UK and US populations. The cell responsible for the matrix deposition and contraction in all fibrotic diseases is the myofibroblast and surgically excised specimens from patients with Dupuytren's disease provide an abundant supply of material to develop assays that can be applied to other fibrotic conditions where primary early disease stage human tissues are less readily available.

We found that TNF is the primary driver for development and maintenance of myofibroblasts in Dupuytren's disease. There is no approved therapeutic to prevent progression of early disease and we have commenced a phase II clinical trial funded by the Health Innovation Challenge Fund (Wellcome Trust and Department of Health) to assess the efficacy of local injection of the anti-TNF drug adalimumab. The persistent localised inflammation in Dupuytren's disease would necessitate repeated injections of anti-TNF. We have now identified a potential target to overcome this.

We are working with Somalogic and Celgene to identify novel therapeutic targets for fibrotic diseases using Somascan and Quanticel single cell RNAseq. In parallel, we are developing new assays to study the phenotype of primary myofibroblasts from clinical samples of early stage fibrosis. Our aim is to use these techniques to identify and validate novel therapeutic targets in a variety of fibrotic disorders

Team members

COLLABORATORS

  • Sallie Lamb, Kadoorie Professor of Trauma Rehabilitation and co-director of Oxford Clinical Trials Unit
  • Marco Fritzsche, Kennedy Institute of Rheumatology 
  • Kim Midwood, Kennedy Institute of Rheumatology
  • Chris Buckley, Professor of Rheumatology, University of Birmingham
  • Dominic Furniss, University Research Lecturer and Honorary Consultant Surgeon 
  • Wei Lin, Celgene Corporation, USA 
  • Stephen Williams, Somalogic, USA

Key publications

RIDD

The RIDD trial aims to test whether the progression of Dupuytren’s disease can be halted or slowed by treatment with anti-TNF injection. Currently, Dupuytren’s disease is left to progress until the finger deformity is severe enough to warrant a surgical procedure in hospital. If successful, anti-TNF treatment would prevent loss of hand function and the need for surgery, and would allow patients to be treated conveniently and quickly.

Find out more here.

Team members

TISSUE REGENERATION AND HEALING

We have been studying the molecular mechanisms underlying the healing of fractures. We have shown that the early innate immune and inflammatory response is crucial for orchestrating downstream repair. We are especially interested how endogenous stem cell recruitment and activation could be improved to accelerate tissue repair following injury.

Team members

COLLABORATORS

  • Nicole Horwood Lecturer Kennedy Institute of Rheumatology 
  • Marco Bianchi, Professor of Molecular Biology, University of San Raffaele, Milan 
  • Thomas Vogl, University of Muenster Professor 
  • Chas Bountra, Professor of Translational Medicine, Structural Genomics Consortium, University of Oxford.

SYSTEMATIC AND OTHER REVIEWS

Systematic reviews are crucial for evidence based medicine. The group is particularly interested in the management of open fractures of the lower limb

key publications

Team members

  • Matthew Gardiner

    Honorary Departmental Clinical Lecturer in Plastic and Reconstructive Surgery

Related research themes