Systemic sclerosis (SSc) is a devastating auto-immune disease, in which a high proportion of patients (40%) develop clinically significant lung fibrosis (SSc-ILD). Early onset and premature mortality of SSc-ILD place a vast social burden on patients and their families. Annual treatment costs (over £10k) and early retirement (over 40%), contribute to the huge economic burden to patients, healthcare systems and society. Despite some improvement in the treatment of autoimmune diseases, poor outcomes from lung complication remain a challenge and advances in SSc-ILD management are lacking. There are still limited therapeutic options leaving patients with high disease-related morbidity, healthcare utilization, and mortality, strongly implicating an unmet need for further research.
However, SSc-ILD research is significantly hindered by reduced accessibility to lung fibroblasts and disease relevant models. To overcome these limitations, we established a novel pre-clinical model of peripheral-blood-derived induced pluripotent stem cell (iPSC) differentiated fibroblasts.
We recently described the disease specific inflammation and the lung specific microenvironment for SSc-ILD, which is pro-inflammatory and pro-fibrotic on fibroblasts. We propose here that pharmacologically targeting the SSc-ILD disease specific microenvironment will reduce inflammation and progressive fibrosis in SSc-ILD. Using our patient-derived disease model, we will:
Characterise the fibrogenic and inflammatory effect of the microenvironment in SSc-ILD.
Identify antifibrotic and immunomodulatory therapies for SSc-ILD through drug repurposing to target the effects of the microenvironment.
Disease-specific gene signatures from SSc-ILD fibroblasts stimulated with the microenvironment will be applied to statistically significant connection map (sscMap), to identify candidate drugs that can be repurposed to manage SSc-ILD. Drug repurposing accelerates the drug development pipeline so that new treatments come to the clinic faster than through conventional drug discovery.
Finally, our collaboration between Northern Ireland, the Republic of Ireland and our patient partners in research will bring direct benefits to all patients on the island.