Evaluation of novel BET inhibitors and epigenetic markers in CF
Research type
Research Study
Full title
Pre-clinical evaluation of novel bromodomain inhibitors and epigenetic markers in patients with cystic fibrosis
IRAS ID
261834
Contact name
Andres Floto
Contact email
Sponsor organisation
Royal Papworth Hospital NHS Foundation Trust
Duration of Study in the UK
4 years, 11 months, 30 days
Research summary
Cystic Fibrosis (CF) is the most common life-limiting genetic condition in the UK affecting approximately 10,000 individuals. The vast majority of lung decline is due to progressive inflammatory lung damage driven by persistent/recurrent bacterial infections.
A novel anti-inflammatory agent which blocks inflammation at the level of gene expression (protein production) has been developed by GSK. It is a Bromodomain and Extra-Terminal domain (BET) inhibitor (I-BET).
In preliminary studies at Royal Papworth Hospital, we assessed the effects of I-BET on macrophages and neutrophils (cells in the blood that fight infection) from individuals with CF. We found that there was a reduction of some of the harmful pro-inflammatory cytokine release whilst not significantly affecting bacterial killing.
Recently new compounds have been developed by GSK. We propose to study the effects of this new generation of BET inhibitors on blood neutrophils/monocytes and sputum macrophages from individuals with CF and healthy controls.
The aim is to evaluate the impact on bacterial clearance, cytokine release (inflammatory signals), function, cell death and viability. We will do this by taking blood and sputum at Day 0, Day 14 and 8 weeks after a lung infection or at one-time point during health. We will study the impact on the above parameters.
The microenvironment around the cell plays a role in gene expression. Chronic inflammation has been shown to disrupt the normal function of monocyte/macrophages, neutrophils, T-cells, and bronchial epithelial cells through DNA associated protein re-arrangement. This is termed ‘epigenetic scarring’.
We aim to describe these epigenetic changes in CF immune cells, during a lung exacerbation and after a period of recovery. We aim to characterise whether these epigenetic changes are chronic or dynamic.
We hope that this study will provide proof of a beneficial effect and then proceed to examine these medications in clinical trials.
REC name
East of England - Cambridge South Research Ethics Committee
REC reference
19/EE/0241
Date of REC Opinion
5 Nov 2019
REC opinion
Further Information Favourable Opinion