Targeting deubiquitinaseas as a novel therapeutic strategy for the treatment of muco-obstructive lung disease

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Major lung diseases, such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), are characterised by a build-up of mucus which cannot be removed by the normal lung clearance mechanisms responsible for airway health. The trapped mucus obstructs airflow whilst inflammation leads to recurring infections that, over time, damage lung tissue and result in a devastating decline in pulmonary function. COPD is the 3rd leading cause of death worldwide and is responsible for 1 in 8 hospital admissions in the UK. There are currently 90,000 people with CF worldwide, and for a child with CF born today the average life expectancy is ~47 years. In addition to the number of lives affected, the associated costs for treatment and management of these diseases are vast (UK £4.7Bn & USA $42.6Bn pa). Across these lung diseases there is a real need for new and improved medicines. The harnessing of the body's own defence processes to keep the airways healthier for longer is a compelling approach, which could have widespread benefits.A group of enzymes called "DUBs" have emerged as an attractive new focus (target) for the development of new medicines. An increasing body of literature indicates DUBs are involved in many aspects of chronic lung disease including the regulation of pathways that affect inflammation and critical lung clearance mechanisms. The aim of this academic-industrial collaboration is to improve outcomes for patients with such diseases via DUB targeting. To this end, the work will focus on identifying which specific DUBs should be targeted, subsequently enabling the development of (or the repurposing of existing) DUB inhibitors. To do this successfully we will combine the existing knowledge of DUB drug discovery and technology platforms of Almac Discovery, with the disease-area and lung model expertise provided by the secondee.This secondment will add significant value to Almac Discovery concerning the development of new drugs for major respiratory diseases characterised by mucus obstruction. Pre-COVID, lung disease was the 4th costliest disease across the UK. Although this project is focussed initially on COPD and CF, the proposed project is anticipated to have wider relevance which could provide much-needed tools to assist pulmonary recovery post-COVID. Although the longer-term impacts of COVID-19 infection remain unknown, the staggering number of cases and severity of the disease raise serious concerns in regard to the long-term management of a potentially new population of chronic respiratory disease patients. As such, innovative new approaches, such as DUB targeting, that have potential to reduce airway inflammation and improve lung clearance mechanisms will be of major importance in the coming years. This will have direct benefits to the Biomedical Science sector of the UK.