Viral and Epigenetic Influences in CRSwNP

Condition(s) studied

Investigational drug(s) / intervention(s)

Endoscopic sinus surgery (ESS): Endoscopic sinus surgery for removal of nasal polyps and sinus tissue.

Study summary

Background/rationale

While multiple disorders feature a Type 2 (T2) inflammation, triggers for T2 remains unknown. In Chronic Rhinosinusitis with Nasal Polyposis CRSwNP), a classic Type 2 disorder, dysfunction of the epithelial barrier is suggested by loss of epithelial cell differentiation, impaired response to wounding, and impairment of innate defense mechanisms. After unsuccessful attempts to describe T2 disorders solely by host genetic or environmental factors, the role of epigenetics in the modification of innate immune response and epithelial integrity appears an important unexplored mechanism for a novel appreciation of T2 disease.

In addition, the investigators explore the possibility that these changes may be induced by viral pathogens. This concept has been supported by the recent observation that SARS-CoV-2 viral reduction measures resulted in a reduction of the frequency of respiratory viruses and a concomitant reduction in chronic airway disease, suggesting a role for viruses in T2 disease.

Hypothesis

The investigators believe T2 chronic rhinosinusitis (CRSwNP) involves epigenetic mechanisms where external factors, possibly viruses, contribute to disease via epigenetic manipulation and/or chronic viral infection.

Objectives

The investigators aim to identify epigenetic signatures associated with T2 CRS and explore the contribution of viruses. Method A robust methylation profiling with extensive coverage will be used for epigenome-wide association studies in T2 CRS patients assessing healthy subjects, CRS patients in remission, and diseased patients undergoing surgery. Moreover, advanced transcriptomic and metagenomic methods will identify gene expression profiles and viruses. This proposal also includes a cross-sectional study of patients undergoing surgery to assess transcriptomic patterns and epigenetics at the single-cell level.

Expected outcome

The investigators expect to identify epigenetic biomarkers and implicate several pathogenic viruses to open new targets for novel therapies.

Eligibility

Primary outcome measure(s)

• Identification of epigenetic biomarkers and pathogenic viruses — 12 months
  The investigators expect to identify viruses and epigenetic markers associated with CRS. Viruses will be identified using bulk sequencing of collected tissue. Viruses will be considered "present" only if they are seen on at least 5 reads in sequencing. These identified viruses will be considered as associated with disease or healthy states assessed only when they are seen in at least 25% of tissue samples for the given condition. Association with disease will be defined as a higher proportion of candidate virus in diseased as opposed to healthy conditions. Epigenetic markers will be identified by comparing methylation profiles across the whole genome between active CRSwNP disease with disease in remission. Machine learning techniques will be used to identify putative sequences of epigenetic biomarkers associated with active disease or presence of an identified viral pathogen.

Trial sites (1)

More Centre hospitalier de l'Université de Montréal (CHUM) trials in Canada