Figures
- FIGURE 1
Causes, pathogenesis and opportunities for therapeutic intervention in a) COPD and b) idiopathic pulmonary fibrosis (IPF). CRP: C-reactive protein; ECM: extracellular matrix; miRNA: microRNA; mTOR: mammalian target of rapamycin.
Tables
- TABLE 1
Examples of emerging techniques to deliver therapy in patients with COPD and idiopathic pulmonary fibrosis (IPF) and their limitations
Technique Description Uses and advances made with the technique Current limitations PROTAC Proteolysis-targeting chimaera that uses the cell's ubiquitin–proteasome system to target-specific proteins for degradation Could induce the degradation of proteins previously considered “undruggable” [50]
Highly selective for the target protein, with rapid, effective and prolonged degradation of the target [51]
Valuable for mechanisms requiring precise targeting for degradation
Can only target a protein for degradation, not for modification
CRISPR Can manipulate gene function through gene deletion, correction or replacement; enhancement of gene expression; base editing Huge potential for target-specific genetic medication for gene therapy in COPD and IPF to target dysregulated genes or pathways (e.g. epigenetic changes to genes implicated in mucus hypersecretion in COPD) [52]
Concerns exist around safety and off-target effects; these are under investigation [53]
Inhaled antisense oligonucleotides Single-stranded DNA or RNA (20–21 base pairs) complementary to the target mRNA Knocks down the expression of the target gene [54]
Can modulate molecules that cannot be targeted using antibodies [54]
Inhalation could minimise toxicities associated with systemic exposure of antisense oligonucleotides [54]
Currently in the investigational stage
Intracellular delivery to the site of action is a challenge [54]
Exosomes as delivery systems A potential delivery system for nucleic acid drugs Potential use in delivering drugs such as antagomirs or miRNA molecules, thanks to their low antigenicity and toxicity [55]
Could target particular cell types
In vitro and in vivo studies have shown promise in successfully delivering molecules [56]
Currently in the investigational stage
PROTAC: proteolysis-targeting chimaera; CRISPR: clustered regularly interspaced short palindromic repeats.
- TABLE 2
Examples of new or emerging techniques for studying COPD and idiopathic pulmonary fibrosis (IPF)
Technique Description Uses and advances made with the technique Current limitations Micro-CT imaging High-resolution CT imaging Higher-resolution versus standard CT imaging [61]
Can reveal structural changes associated with small airway disease [61]
Reveals massive loss in number and area of terminal bronchioles in patients with centrilobular emphysematous COPD [6]
When partnered with parametric response mapping as an imaging biomarker, micro-CT could identify terminal bronchiole pathology in COPD [62]
Performed on ex vivo samples, or explants, rather than on the patient [6, 61, 62] PET Molecular imaging; most commonly measuring 18F-FDG uptake Has been explored as a noninvasive biomarker for pulmonary inflammation [63]
Ability to quantify inflammation is under investigation [63]
Validation of imaging approaches required; changes in lung air, blood and water volumes depending on disease severity can cause variations in signals [63] Gas diffusion MRI Noble gases such as 3He and 129Xe used to visualise lung structure Could be used to monitor disease progression and response to therapy [59]
Can detect microstructural changes in the lung, even in asymptomatic smokers [59]
Quantitative microstructure data obtainable by measuring gas diffusion in alveoli; the technique can differentiate between patients with COPD and healthy individuals [64]
Alveolar sizes can be visualised to form a picture of alveolar loss in COPD [64]
Provides sensitive and reproducible data on gas exchange impairment in IPF, correlating with spirometry data [65]
Adaption of existing scanners is required [66] SPECT Radiotracers used to image the lung, where both airways and blood flow can be imaged Both the airways and blood flow can be imaged, allowing the detection of comorbidities such as pulmonary embolism [67, 68]
Can detect abnormalities in apparently healthy smokers [69]
Only semi-quantitative [69]
Not as high resolution as other imaging methods [68]
Takes a long time to acquire an image (e.g. 45 min) [68]
IOS Noninvasive measurement of respiratory mechanics in response to pressure oscillations A reliable tool for investigating proximal and peripheral airways resistance in patients with COPD [70]
Peripheral airway resistance and compliance using IOS closely linked to COPD severity and exacerbations [58]
Could be used as a screening tool for early-stage COPD [58]
Useful for patients who cannot perform spirometry manoeuvres [71]
The minimal clinically important difference in IOS parameters needs to be established
OCT A high-resolution optical imaging method Resolution down to micrometre scale [72]
Can be used to accurately measure distal airways [73]
Could detect early changes to the distal airways and appears to be more sensitive than CT [72, 73]
Ultrafine bronchoscopy (with sedation) required to reach the distal airways [73]
Multiple-breath nitrogen washout Noninvasive measurement of residual nitrogen in the airways to detect any abnormalities in gas distribution in the lung Does not require maximal effort and can be used in a paediatric setting [74]
Provides information on abnormalities in the small airways, including terminal bronchioles [75]
Can detect abnormalities in early disease [76]
Limited standardisation, which impacts the availability of widely applicable reference values [75]
Breathomics Exhaled breath analysis to detect changes in volatile organic compounds Could be used to diagnose COPD and differentiate COPD from asthma [77]
May be able to predict disease progression [77]
Could help distinguish COPD phenotypes [77]
Results can be confounded by parameters such as medication use, comorbidities, smoking and study site [77]
CT: computed tomography; PET: positron emission tomography; 18F-FDG: 18F-2-fluoro-2-deoxy-d-glucose; MRI: magnetic resonance imaging; SPECT: single-photon emission computed tomography; IOS: impulse oscillometry; OCT: optical coherence tomography.
