Inflammation and scarring, or fibrosis, are important responses to injury,
but when excessive they result in disease and death. I integrate structural biology approaches
with cell and tissue studies, to understand how these occur and how they are linked, right
down to the molecular level. I look at how genetic mutations and environmental stimuli affect protein
conformation and interactions, to cause disease and how new drugs may target and prevent this.
A protein called galectin-3 forms molecular lattices at the cell's surface in response
to acute injury or pro-fibrotic signaling by the cytokine TGFbeta. We have shown how this clusters
transmembrane proteins, including mediators of inflammation and mediators of fibrosis.
We call this assembly the gal-3 fibrosome. Recently we have interrogated its involvement
in the severe lung inflammation that causes most death in COVID19,
but for the last few years we've been studying how it enables and accelerates
the fatal lung disease idiopathic pulmonary fibrosis, or IPF for short. In IPF,
scar tissue gradually replaces lung tissue. Median survival with this is three years from diagnosis
and it accounts for one percent of all UK deaths. Disease progression is punctuated by sudden
inflammatory flares, known as acute exacerbations, that accelerate decline and have high mortality.
Current treatments help by slowing the rate of decline but they do not cure, reverse,
or even stabilize the disease and there are no treatments proven for acute exacerbations.
Targeting key features of the gal-3 fibrosome prevents
the positive feedback between inflammation and fibrosis that is a motor of disease,
whilst preserving important pathways like TGFbeta signalling in other contexts. So we
want to target gal-3 fibrosome constituents and assembly, to treat fibrotic diseases such as IPF.
Galectin-3 is a biomarker for multiple fibrotic diseases and targeting galectin-3 rescues a wide
range of experimental models of fibrosis in vivo. We have also successfully targeted other
gal-3 fibrosome constituents using small molecules or gene silencing in models of acute exacerbation,
blocking inflammation and the knock-on pro-fibrotic effects.
I work both as a consultant in a major respiratory and translational research centre and as an
investigator using the biophysical and structural capabilities here at LISCB. This means that I can
directly cross-check findings from my molecular studies using biosamples from patients including
cultured lung tissue and vice versa. As a doctor I want to see the new therapeutic strategies
that we have defined and proof-of-concept concept in, developed their fullest potential for patient
benefit. We've already attracted support from a company whose IND blocking galectin-3
is in phase IIb trials in IPF but detailed characterization of the gal-3 fibrosome as a whole
identifies a wider range of targets across multiple disease contexts with huge unmet clinical
need. We would be delighted to collaborate with industrial partners to make inroads into this.