A novel genetic mechanism underlying chronic obstructive pulmonary disease (COPD) is gaining attention, with new data identifying PABPC4 as a key regulator of mitochondrial function and emphysema pathogenesis. Early findings demonstrating the correction of a causal splicing defect using a first-in-class therapeutic approach signal potential for precision medicine in COPD, says GlobalData, a leading intelligence and productivity platform.
At the American Thoracic Society (ATS) 2026 meeting on May 18, during the B109 cellular, genetics and developmental drivers of COPD, emphysema and sarcopenia session, researchers from the University of Pittsburgh, Vanderbilt, North Carolina, as well as TGen presented data linking PABPC4 (Polyadenylate-Binding Protein Cytoplasmic-4) to mitochondrial dysfunction in lung epithelial cells. The findings provide insight into how non-coding genetic variants contribute to disease biology, addressing a major gap in COPD research despite genetics accounting for 30–40% of disease risk, according to the poster presented by TGen.
The study identified 40 non-coding variants at the PABPC4 locus associated with reduced lung function, increased COPD risk, and decreased PABPC4 expression. Individuals carrying these variants showed significant dysregulation of the mitochondrial electron transport chain, a critical pathway for cellular energy production.
Functional studies confirmed a causal role, with PABPC4 knockdown impairing mitochondrial respiration in lung epithelial cells and knockout mice spontaneously developing emphysema. Mechanistically, a causal single nucleotide polymorphism was found to disrupt pre-mRNA splicing, triggering nonsense-mediated decay and reducing PABPC4 protein levels
Graysen Vigneux, Healthcare Analyst at GlobalData, comments: “The identification of PABPC4 provides a direct link between genetic susceptibility and mitochondrial dysfunction in COPD. This is a meaningful advance, particularly as mitochondrial pathways are increasingly recognized as central to emphysema development.”
Importantly, a splice-switching antisense oligonucleotide corrected the splicing defect in vitro, restoring PABPC4 expression and downstream electron transport chain protein levels in lung epithelial cells from affected individuals.
Vigneux adds: “Targeting the underlying genetic mechanism through splice correction represents a differentiated therapeutic strategy. By addressing disease at its source, this approach has the potential to move beyond symptomatic management toward disease modification.”
The COPD treatment landscape remains dominated by bronchodilators and anti-inflammatory therapies, which do not address underlying disease mechanisms. Targeting mitochondrial dysfunction and genetically defined patient subsets could represent a shift toward precision medicine.
However, the findings remain early, with therapeutic validation currently limited to in vitro data. Further studies are required to confirm clinical efficacy and define optimal patient selection strategies. Adoption will also depend on routine genetic screening, which is not currently standard in COPD care and may present real-world implementation challenges.
Vigneux concludes: “While early, these data highlight a promising new direction for COPD treatment. If successfully translated, PABPC4-targeted therapies could redefine treatment by introducing a mechanism-based, genetically informed approach.”
