Title: Epigenetic editing in human lung cells for discovery of novel drivers and treatments for chronic lung diseases
Funder: The Academy of Medical Sciences

Abstract: Chronic obstructive pulmonary disease (COPD) is a life-limiting and currently incurable disease where patients experience progressive decline in lung function. Currently, the molecular mechanisms driving disease onset are poorly understood and there are no effective treatments. The overarching goal of my research is to determine how epigenetic dysregulation of genes in lung cells contributes to development of COPD and harness this information to develop new curative therapies. Using high-resolution epigenetic profiling of lung cells across COPD stages, I have already identified several sites within the genome severely disrupted in early COPD. The aim of this specific project is to test the functional relevance of these alterations by developing and applying epigenetic editing to primary human lung cells. Epigenetic editing employs an inactivated CRISPR/Cas9 protein fused to an engineered DNA methyltransferase or demethylase effector domain to precisely target and modify epigenetic marks. I will adapt this novel technology for application to primary human lung cells. I will introduce specific epigenetic changes at selected regions, modelling what I have observed in patient samples, and examine their impact on driving gene expression changes. I will then investigate whether these engineered transcriptional signatures resemble different stages of progression to COPD. Through this approach, I will determine which sites play a causal role in COPD and therefore provide the most promising targets for interventions and drug development. This project will provide a first understanding how epigenetic signalling drives lung disease development, thereby accelerating discovery and validation of epigenetic therapeutics and biomarkers for chronic lung diseases.

Lay abstract: Despite decades of intensive research, 250 million patients with chronic obstructive pulmonary disease (COPD) are still desperately waiting for curative treatments. For these to be developed, we need to understand how healthy individuals progress to COPD and identify suitable targets for drug development. We know that epigenetic mechanisms control how and when our genes are switched on or off. We also know that epigenetic marks can be dysregulated causing disease. Excitingly, epigenetic marks can also be manipulated with potential to cure disease. I have identified profound epigenetic changes occurring in patients with early COPD, suggesting the pathogenic role of epigenetic signalling in disease development. However, currently it is not possible to know which epigenetic alterations are the cause and which are merely the consequence of the disease process without the development of new methodological approaches for modification of epigenetic signals. In this proposal, I will establish a technology called “epigenetic editing” in cultured patient-derived lung cells, pioneering the use of this powerful technology for respiratory diseases. Epigenetic editing will allow the precise manipulation of epigenetic marks. I will use this technology to specifically introduce aberrant epigenetic changes and examine their relevance for COPD development. Application of this versatile technology will provide a platform for molecular understanding of how epigenetic regulation contributes to development of lung diseases. As such, it will accelerate discovery and validation of novel diagnostic and therapeutic interventions for chronic lung diseases. This project, hence, has a high clinical, economic, and social impact.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY