A novel genetic mechanism underlying COPD has been identified by researchers as a key regulator in mitochondrial function and emphysema parthenogenesis. Early findings demonstrating the correction of a causal splicing defect using a first-in-class therapeutic approach show potential for greater precision in the treatment of COPD.
The abstract, “PABPC4: A Genetic Driver of Mitochondrial Dysfunction and Emphysema in COPD Targeted by a First-in-Class Therapeutic Agent,” was presented by researchers at the 2026 American Thoracic Society International Conference in Orlando, Florida, and appeared in the American Journal of Respiratory and Critical Care Medicine.
The researchers identified 40 noncoding variants at the locus of poly(A) binding protein cytoplasmic 4 (PABPC4) that were highly prevalent and associated with reduced lung function, increased COPD risks and lower PABPC4 mRNA levels in the lung epithelial compartment. PABPC4 is a novel COPD susceptibility gene that regulates mitochondrial function in lung epithelia through post-transcriptional control of the electron transport chain.
The study found that the top dysregulated pathway in homozygous individuals compared to wild-type for these variants was the mitochondrial electron transport chain. In addition, PABPC4 knockdown in lung epithelial cells via RNAi-disrupted the electron transport chain pathway and impaired mitochondrial function.
Mice that had PABPC4 knockdown spontaneously developed emphysema. According to the researchers, PABC4 deficiency increased mRNA but decreased protein levels of electron transport chain mediators, indicating post-transcriptional regulation consistent with its role as a poly-A binding protein.
But perhaps the most important finding of the study was that a first-in-class splice-switching anti-sense oligonucleotide (ss-ASO) corrected the splicing defect that led to the loss of PABPC4, which restored PABPC4 expression and electron transport chain mediator protein levels in lung epithelial cells in a homozygous individual in vitro.
“A first-in-class therapeutic agent that corrects this splicing defect may represent a novel treatment for mitochondrial dysfunction in COPD,” the researchers wrote.
The paper has received positive attention since its presentation. GlobalData, a leading data and analytics company, said the findings provide insight into how noncoding genetic variants contribute to disease, addressing a major gap in COPD research.
“The identification of PABPC4 provides a direct link between genetic susceptibility and mitochondrial dysfunction in COPD,” said Graysen Vigneux, healthcare analyst at GlobalData. “This is a meaningful advance, particularly as mitochondrial pathways are increasingly recognized as central to emphysema development.”
Most current COPD treatments rely on bronchodilators and anti-inflammatory therapies, which Vigneux said do not address the underlying mechanisms of the disease.
“Targeting the underlying genetic mechanism through splice correction represents a differentiated therapeutic strategy,” Vigneux said. “By addressing the disease at its source, this approach has the potential to move beyond symptomatic management toward disease modification.”
The research remains in the early stages, with results limited to in vitro data. Vigneux said more studies are needed to confirm optimal efficacy and define optimal patient selection strategies.
“While early, these data highlight a promising new direction for COPD treatment,” Vigneux said. “If successfully translated, PABPC4-targeted therapies could redefine treatment by introducing a mechanism-based, genetically informed approach.
