Examples of emerging techniques to deliver therapy in patients with COPD and idiopathic pulmonary fibrosis (IPF) and their limitations

TechniqueDescriptionUses and advances made with the techniqueCurrent limitations
PROTACProteolysis-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

CRISPRCan 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 oligonucleotidesSingle-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 systemsA 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.