A protein that acts like biological glue is the target of a new oral drug candidate for a fatal lung disease that scars and stiffens the lungs until they can no longer work. Idiopathic pulmonary fibrosis (IPF) affects roughly 30,000 people in the UK and up to 300,000 across the Western world. Current treatments have limited effectiveness and serious side effects; most patients die within three to five years of diagnosis. The enzyme transglutaminase 2 (TG2) crosslinks proteins in lung tissue, creating thick, irreversible scar tissue that blocks normal repair. The researchers have already shown that small molecules blocking TG2 can stop this scarring in cells and animal models. If this candidate passes preclinical testing, it could become the first oral treatment that directly targets the scarring process itself, rather than just managing symptoms. That would offer IPF patients a genuinely disease-modifying therapy for the first time. The project aims to generate the data needed to attract the substantial investment required to move the drug into human clinical trials.
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Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, ultimately fatal lung disease with high morbidity. IPF is characterized by thick collagen scar tissue and expansion of collagen synthesising cells in the lung which results in severe restriction of lung capacity and function. IPF is classified as a rare disease affecting between 200,000 and 300,000 in the Western world. In the UK it is estimated there are around 30,000 cases with limited treatment options. Given ageing and Covid infection is a risk factor of IPF, a significant increase in IPF cases has been predicted. Current treatments are limited by their side effects, their inability to change the overall progression of the disease and high mortality within 3 to 5 years after diagnosis. IPF remains a very substantial unmet medical need. It has been shown that the pro-fibrotic enzyme Transglutaminase 2 (TG2) plays a key role in IPF progression. TG2 acts by crosslinking matrix proteins like a glue. It also activates key fibrotic growth factors leading to the activation of fibrosis causing cells. This crosslinked fibrous tissue is highly resistant to remodelling and normal tissue repair is compromised, which can lead to organ failure. Our innovative work has demonstrated the potential of TG2 small molecule inhibitors as an effective treatment of IPF in both cell and animal models. Through a £2.1million MRC DPFS research programme, we have developed a new series of TG2 inhibitors with good druggable properties and significant potential for development into an oral treatment for fibrotic disease. This would offer an effective treatment to sufferers of IPF. In this project, based on our existing comprehensive properties of our candidate inhibitors, we have selected one of our lead candidates with the aim of advancing our knowledge of this candidate via generating further preclinical data which will validate this compound as a candidate to attract further substantial investment funding allowing us to take it to the clinic.
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