Inhaled drug delivery for the targeted treatment of asthma

Abstract

Asthma is a chronic lung disease affecting millions worldwide. While classically acknowledged to result from allergen-driven type 2 inflammatory responses leading to IgE and cytokine production and the influx of immune cells such as mast cells and eosinophils, the wide range in asthmatic pathobiological subtypes lead to highly variable responses to anti-inflammatory therapies. Thus, there is a need to develop patient-specific therapies capable of addressing the full spectrum of asthmatic lung disease. Moreover, delivery of targeted treatments for asthma directly to the lung may help to maximize therapeutic benefit, but challenges remain in design of effective formulations for the inhaled route. In this review, we discuss the current understanding of asthmatic disease progression as well as genetic and epigenetic disease modifiers associated with asthma severity and exacerbation of disease. We also overview the limitations of clinically available treatments for asthma and discuss pre-clinical models of asthma used to evaluate new therapies. Based on the shortcomings of existing treatments, we highlight recent advances and new approaches to treat asthma via inhalation for monoclonal antibody delivery, mucolytic therapy to target airway mucus hypersecretion and gene therapies to address underlying drivers of disease. Finally, we conclude with discussion on the prospects for an inhaled vaccine to prevent asthma.

Keywords: Asthma; Gene therapy; Immunotherapy; Inhaled delivery; Mucolytics; Vaccines.

Figure 1.. CDHR3 protein variant CDHR3-Y₅₂₉ is highly expressed on the surface of cells and leads to greater infection by rhinovirus.

(A) CDHR3 expression is increased on the surface of cells producing CDHR3-Y₅₂₉ compared to the wild type CDHR3-C₅₂₉. Infection of cells expressing (B) wild type CDHR3-C₅₂₉ or (C) CDHR3-Y₅₂₉ by the reporter virus RV-16-GFP. All scale bars = 100 μm. Reprinted with permission from the National Academy of Sciences (Ref. 71).

Figure 2.. Treatment of OVA-challenged mice with the DNA methyltransferase inhibitor 5Aza.

A) Number of eosinophils present in the BAL fluid. B) Airway reactivity in response to methacholine. C) Histological staining of airway tissue with periodic acid-Schiff showing inflammation and mucus secretion by goblet cells. Reprinted from “DNA methylation of TH1/TH2 cytokine genes affects sensitization and progress of experimental asthma”, Journal of Allergy and Clinical Immunology. 129 (2012) 1602–1610.e6. with permission from Elsevier (Ref. 94).

Figure 3.. Schematic of current mAb therapeutic targets of inflammation in asthma.

Key abbreviations include ILC2, innate lymphoid type II cell; Th2 cell, type II helper T cell; IgE Ab, IgE antibody; TSLP, thymic stromal lymphopoietin.

Figure 4.. Clinical evaluation of an inhaled monoclonal antibody targeting IL-13.

Mean percentage change from baseline in FeNO levels in participants with asthma on treatment with the inhaled monoclonal antibody (VR94) targeting IL-13. Reprinted under the terms and conditions of an CC-BY 4.0 open access license from the journal eBioMedicine (Ref. 166).

Figure 5.. Inhaled TCEP mucolytic treatment reverses mucus plugging in allergic asthma mouse model.

Alcian Blue/PAS staining of lungs shows mucin glycoproteins obstructing the airways in untreated vehicles (Veh), whereas this is disrupted by TCEP treatment (Tx). Scale bar, 500μm (low power) and 25μm (high power). Reprinted under the terms and conditions of an CC-BY 4.0 open access license from the journal Nature Communications (Ref. 174).

Figure 6.. Dual vaccination with IL-4 and IL-13 kinoids reduce IgE levels and mast cell numbers in lungs after HDM challenges.

(A) Representative Lung sections that were stained with avidin (this stains mast cells, red), anti-IgE (green) and DAPI (blue) 24 hours after HDM challenge. (B) Quantification of IgE in lung mast cells. Reprinted under the terms and conditions of an CC-BY 4.0 open access license from the journal Nature Communications (Ref. 211).