Airway Biomarker Panel and Targeted Intervention Strategy for Steroid-Refractory Severe Asthma

This invention provides a method for identifying patients with, or at risk of, severe asthma by measuring the expression of specific airway genes or related protein glycosylation and keratin markers in patient samples. This approach offers a novel path to identify severe, corticosteroid-refractory asthma patients and enables targeted therapeutic intervention through gene expression knockdown or activity inhibition of these markers.

Description

The invention centers on a set of biomarkers identified through machine-learning-based analysis of airway epithelial gene expression in patients with severe asthma compared to those with mild-to-moderate asthma or healthy controls. The method involves obtaining a patient sample and determining expression levels of MUC1, MUC4, KRT16, GALNT5, and/or GALNT6, where elevated expression relative to non-severe or non-asthmatic individuals indicates severe asthma or risk thereof. The method can also assess glycosylation status of MUC1 and/or MUC4 protein, or elevated keratin levels in airway epithelial cells, as alternative or additional severity indicators. Once a patient is identified, the invention provides for treatment by knocking down expression of these genes or inhibiting their protein activity, including through compositions with defined sequence identity to the disclosed MUC1, GALNT5, and GALNT6 protein sequences. Treatment may also include administration of established asthma therapies or agents that inhibit/reverse O-glycosylation, either in combination with or independent of the gene-targeted approach.

Applications

- Companion diagnostic assays to stratify asthma patients by severity risk based on airway gene expression
- Clinical decision-support tools to identify corticosteroid-refractory patients for alternative therapeutic pathways
- Development of siRNA/RNAi or CRISPR-based therapeutics targeting GALNT5, GALNT6, MUC1, MUC4, or KRT16
- Inhaled small-molecule inhibitor programs targeting the GALNT5/GALNT6 catalytic domain
- Biomarker-based patient selection tools for clinical trials in severe asthma therapeutics

Advantages

- Identifies a distinct, previously underutilized set of biomarkers (GALNT5, GALNT6, KRT16 alongside MUC1/MUC4) for severe asthma beyond conventional Type 2 inflammation markers
- Method validated for cross-cohort predictive performance, supporting reproducibility across independent patient populations
- Flexible sample types (airway brushings, sputum, exhaled breath condensate, or blood) offer options for less invasive testing
- Addresses an "undrugged" target space (GALNT5/GALNT6), for which no selective inhibitors currently exist
- Supports a targeted, mechanism-based treatment approach that can be combined with existing standard-of-care asthma therapies

Invention Readiness

The diagnostic/biomarker aspect of this invention has been evaluated using retrospective bulk RNA-sequencing and protein expression data from two independent, previously characterized human patient cohorts, with cross-cohort predictive testing demonstrating discriminative performance between severe and mild-to-moderate asthma. The associations between marker expression and clinical parameters have been established through correlational analysis of existing cohort data. Further studies are needed to experimentally validate the therapeutic knockdown/inhibition strategies and to develop and test candidate inhibitor compositions.

IP Status

Patent Pending