Our goals are to identify novel targets and develop therapeutics for cardiovascular, inflammatory and fibrotic disease.
Inflammation, fibrosis and regeneration are major unsolved problems in cardiovascular medicine, contributing to the pathogenesis of myocarditis, atherosclerosis, post-myocardial infarction injury and stroke. This is currently the major focus of our lab, which is based at the Wellcome Centre for Human Genetics.
In a program of target and therapeutic discovery we have identified novel regulators of the BMP signalling pathway (a major determinant of fibrosis), and the effect of the retinoid against Tazarotene in wound healing. We are now focussing on targeting inflammation.
Inflammation is driven by the chemokine network, which is a validated therapeutic target. Traditional anti-chemokine therapies that target single chemokines or receptors fail in treating inflammation, as diseased tissue typically expresses multiple chemokines with overlapping functions, making the chemokine network highly robust to attack. Evolution and natural selection for over 250 million years has resulted in the creation of a diverse arsenal of anti-inflammatory salivary peptides in tick saliva. These peptides combat inflammation at the site of tick bite and enable them to suck blood for days to weeks. One of these peptides, the complement inhibitor COVERSIN®, is now licensed for therapy. Another class of small peptides in tick saliva suppress chemokine-driven inflammation by acting as "ligand traps" – binding and neutralizing multiple chemokines, and are called evasins.
We have developed a biotechnology platform – Bug-to-Drug – that uses yeast surface display of tick peptides. This has allowed us to efficiently mine tick salivary transcriptomes for evasin-like peptide molecules that bind chemokines. We have identified over 30 novel evasins that are potent inhibitors of chemokine signaling. They have potential application in a variety of orphan inflammatory disorders such as myocarditis and idiopathic lung fibrosis where the chemokine network plays a major role, and also in more common disorders such as myocardial infarction and stroke. Our goals are to pharmacologically characterize & develop these novel evasins as therapeutics, identify further evasins using the 'Bug-to-Drug' platform, use protein engineering approaches to modify properties of evasins and understand their mechanism of action using structural approaches.
A second stream of research targets congenital heart disease, where we have had a long–term interest. We are currently a part of two large programs: DMDD (Deciphering the Mechanisms of Developmental Disorders) which uses model organism genetics together with phenotyping of embryonic lethal mutants and UK10K, which uses exon sequencing to identify gene variants in patients with congenital heart disease. These studies will allow us to understand the mechanisms of congenital heart disease, and potentially identify new therapeutic targets.
BHF: We are supported by BHF Chair, BHF Program ("Precision Therapeutics for Cardiovascular Inflammation", BHF Project Grant ("Targeting the chemokine network in myocarditis using ligand traps derived from tick saliva"), BHF Centre of Research Excellence and BHF Centre for Regenerative Medicine Awards that fund our Bug to Drug, myocarditis and myocardial infarction work
MRC Confidence in Concept: Funding to develop 2-warhead evasins as therapeutic agents in myocarditis
Wellcome Trust: We are supported by strategic awards (DMDD, UK10K) that fund our work in congenital heart disease